Textbook of Toxicology 9789389520279

Table of contents :
Cover
Half Title
Title
Preface
Contents
Chapter 1: Toxicology and Toxicological Chemistry
1.1 Introduction
1.2 Classification of Toxicology
1.3 Acute and Chronic Effects
1.4 Tolerance and Ecological Gradients
1.5 Chemical Interactions
1.6 Reversible and Irreversible Toxic Effect
1.7 Toxicological Chemistry
Exercise
Chapter 2: Principles of Toxicology
2.1 Introduction
2.2 Mechanistic Toxicology
2.3 Descriptive Toxicology
2.4 Regulatory Toxicology
2.5 Dose-Response Concept
2.6 Toxin Exposure
2.7 Physico-Chemical SpecIation in Relation to Exposure
2.8 Quantitative Aspects of Exposure
2.9 Interactive Effects of Toxicants
Exercise
Chapter 3: Fundamentals of Chemistry
3.1 Atomic Structure
3.2 Periodic Table and Periodic Properties of an Electron
3.3 Chemical Bonding
3.4 Acids, bases and salts
3.5 Thermodynamics
3.6 Phase Rule
3.7 The colloids
3.8 Electrochemistry
3.9 Chemical Kinetics
3.10 Fundamental Reactions And Their Mechanism
Exercise
Chapter 4: Toxic Inorganic and Radioactive Elements
4.1 Introduction
4.2 Factors Influencing the Metal Toxicity
4.3 Complexation and Chelation
4.4 Metal Toxicity with Multiple Effects
4.5 Toxic Radioactive Elements
Exercise
Chapter 5: Toxic Organic Compounds
5.1 Introduction
5.2 Hydrocarbons
5.3 Toxicity of Acyclic Saturated and Unsaturated Hydrocarbons
5.4 Toxicity of Mono- and Polycyclic Aromatic Hydrocarbons
5.5 Toxic Effects of Oxygen-Containing Organic Compounds
5.6 Nitrogen-Containing Organic Compounds
5.7 Phosphorus Containing Organic Compounds
5.8 Sulphur Containing Organic Compounds
5.9 OrganOmetallics and Organo Metalloids
Exercise
Chapter 6: Movement and Distribution of Toxins in Environment and Ecosystem
6.1 Introduction
6.2 Transport Across Membranes
6.3 Absorption of Toxic Compounds
6.4 Distribution of Toxicants Over the Organism
Exercise
Chapter 7: Fate of Toxins
7.1 Introduction
7.2 Biotransformation of Xenobiotics
7.3 Oxidation of non-carbon elements
7.4 Metabolic Reduction
7.5 Metabolic Hydrolysis
7.6 Phase-II Reactions of Toxicants (Enzyme Reactions)
7.7 Bioaccumulation and Biomagnification
7.8 Bioavailability and Bioconcentration
7.9 Persistence and Biodegradation
Chapter 8: Toxicity
8.1 Introduction
8.2 Local and Systemic Toxicity
8.3 Immediate and Delayed Toxicity
8.4 Reversible and Irreversible Toxicity
8.5 Toxicity of Mixtures
8.6 Variation in Toxic Responses
8.7 Acute Toxicity
8.8 Chronic Toxicity
8.9 Factors Affecting Toxicity of Reactive metabolites
Chapter 9: Toxic Effects of Natural and Synthetic Products
9.1 Introduction
9.2 Toxic Effects of Solvent and Vapours
9.3 Toxic Effects of Pesticides and Biocides
9.4 Toxic Effects of Drugs
9.5 Toxic Effects of Natural Products
9.6 Toxic Effects of Cosmetics
Chapter 10: Toxicology of Organs and Organ Systems
10.1 Introduction
10.2 Dermatotoxicity (Organ–Skin)
10.3 Haematotoxicity (Organ–Blood)
10.4 Hepatotoxicity (Organ–Liver)
10.5 Nephrotoxicity (organ—kidney)
10.6 Neurotoxicity (Organ—nervous system)
10.7 Respiratory Toxicology (Organ – Lungs)
10.8 Reproductive Toxicity (Reproductive System)
10.9 Cardiovascular Toxicology (Organ–Heart)
10.10 Toxic effects on Endocrine System (organ—Endocrineglands)
10.11 Toxic response of the Immune System
Chapter 11: Biomarkers
11.1 Introduction
11.2 Environmental and Biological Monitoring
11.3 Biomarkers of exposure
11.4 Biomarkers of Effect
11.5 Biomarkers of Genetic damage
11.6 Biomarkers of Susceptibility
11.7 Biomarkers in Plants
11.8 Significance of Biomarkers
Exercise
Chapter 12: Evaluation of Toxicity and Risk Assessment
12.1 Introduction
12.2 Chemical and Physical Properties (Structure/Activity relationships)
12.3 In Vivo and Short-term Tests
12.4 Subchronic Tests
12.5 Toxicity Ratings
12.6 Risk Assessment
12.7 Risk management
Chapter 13: Air Pollution
13.1 Introduction
13.2 Sources of Air Pollution
13.3 Types of Air Pollutant
13.4 Some Major Air Pollutants and their Effects
13.5 Properties of Pollutants
13.6 Control of Air Pollution
13.7 Fate and Transportation of Air Pollutants
13.8 Global and Regional Air Pollution Problems
13.9 Indoor Air Pollution
Exercise
Chapter 14: Water Pollution
14.1 Introduction
14.2 Types of water
14.3 Types of Water Pollutant and Their Sources
14.4 Organic Pollutants
14.5 Inorganic pollutants
14.6 Sediments
14.7 Radioactive Materials
14.8 Thermal Pollution
14.9 Groundwater Pollution
14.10 Marine Pollution
14.11 Engineered System for Water Pollution Control
Exercise
Chapter 15: Toxicity Related to Soil
15.1 Introduction
15.2 Sources of Soil Toxicity
15.3 Types of Soil TOXICANT
15.4 Inorganic Toxicants in Soils
15.5 Solid Waste In Soils
15.6 Radionuclides In Soils
15.7 Soil Salinity
15.8 Effect Of Acid Rain On Soils
Chapter 16: Ecotoxicology
16.1 Introduction
16.2 Ecosystem
16.3 Ecosystem Structure and Community Dynamics
16.4 Evolutionary Ecology
16.5 Biological Productivity
16.6 Energy Flow
16.7 Distribution of Toxicants in the Ecosystem
16.8 Terrestrial Ecotoxicology
16.9 Aquatic Ecotoxicology
16.10 Effects of Toxicants on Terrestrial Ecosystem
16.11 Genotoxicity
Chapter 17: Mechanisms for Minimizing Toxic Effects
17.1 Introduction
17.2 Detoxification (Bioinactivation)
17.3 Elimination
17.4 Excretion of Toxicants
17.5 Hepatic Excretion
17.6 Exhalation (Pulmonary Excretion)
17.7 Other Excretory Routes
Chapter 18: Applications of Toxicology
18.1 Introduction
18.2 Food Toxicity
18.3 Medical and Clinical Toxicology
18.4 Occupational Toxicology
Reference
Index
Backcover

Citation preview

Textbook of TM

Toxicology The book also provides the fundamental knowledge of the principles related to toxicology, chemical toxicology, environmental toxicology and related sciences so as to meet the challenging requirements of students as well as teachers in environmental sciences, pharmacological, medical, veterinary, biomedical science and toxicological sciences. All essential aspects of toxicology have been covered in this book. It comprises 18 chapters in a logical sequence. Toxicology is distinguished by up-to-date insight into the harmful interactions between chemicals (xenobiotics) and biological synthesis. It gives better understanding on acute toxicology risk assessment, toxicity testing and many other areas directly or indirectly related to toxicology. Balram Pani is a faculty in the Department of Chemistry at Bhaskaracharya College of Applied Sciences, Delhi University, New Delhi. He obtained his Ph.D. from Jawaharlal Nehru University. Dr. Pani has 20 years of research and teaching experience in the field of Chemistry and Environmental Science. He has also authored various books on Environmental Science and Engineering Chemistry, which have been adopted by several universities, and engineering and science colleges.

Textbook of Toxicology

Toxicology is an interdiscipline that requires the knowledge of many areas such as analytical chemistry both organic and inorganic, biochemistry, pathology and physiology. The book is designed to provide a wide ranging overview of the various toxicants and their effects on living organisms, particularly on human beings.

Textbook of

Toxicology

978-93-89520-27-9

` 425/-

Distributed by: 9 789389 520279

TM

TEXTBOOK OF

TOXICOLOGY

TEXTBOOK OF

TOXICOLOGY

Balram Pani Faculty Department of Chemistry Bhaskaracharya College of Applied Sciences Delhi University New Delhi

©Copyright 2019 I.K. International Pvt. Ltd., New Delhi-110002. This book may not be duplicated in any way without the express written consent of the publisher, except in the form of brief excerpts or quotations for the purposes of review. The information contained herein is for the personal use of the reader and may not be incorporated in any commercial programs, other books, databases, or any kind of software without written consent of the publisher. Making copies of this book or any portion for any purpose other than your own is a violation of copyright laws. Limits of Liability/disclaimer of Warranty: The author and publisher have used their best efforts in preparing this book. The author make no representation or warranties with respect to the accuracy or completeness of the contents of this book, and specifically disclaim any implied warranties of merchantability or fitness of any particular purpose. There are no warranties which extend beyond the descriptions contained in this paragraph. No warranty may be created or extended by sales representatives or written sales materials. The accuracy and completeness of the information provided herein and the opinions stated herein are not guaranteed or warranted to produce any particulars results, and the advice and strategies contained herein may not be suitable for every individual. Neither Dreamtech Press nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. Trademarks: All brand names and product names used in this book are trademarks, registered trademarks, or trade names of their respective holders. Dreamtech Press is not associated with any product or vendor mentioned in this book. ISBN: 978-93-89520-27-9 EISBN: 978-93-89583-85-4 Edition: 2019

Dedicated to My wife Rajalaxmi and Dear daughter Akankshya

Preface The basic objective of the Textbook of Toxicology is “health is wealth”. The life of the human beings must be protected against the external harmful factors such as poisonous substances, polluted environments and foreign chemicals (xenobiotics). The book is designed to provide a wide ranging, accessible overview on the different toxicants and their effects on living organisms particularly on human beings. The book also provides the fundamental knowledge of the principles related to toxicology, chemical toxicology, environmental toxicology and related sciences, so as to meet the challenging requirements of students as well as teachers in environmental sciences, pharmacological, medical, veterinary, biomedical science and toxicological sciences. All essential aspects of toxicology have been covered in this book. The book comprises 18 chapters in a logical sequence. The textbook of Toxicology is distinguished by up-to-date insights into the harmful interactions between chemicals (xenobiotics) and biological synthesis. It gives better understanding on acute toxicology risk assessment, toxicity testing and many other areas directly or indirectly related to toxicology. Toxicology is an interdiscipline that requires the knowledge of many areas such as analytical chemistry both organic and inorganic, biochemistry, pathology and physiology. This book starts with the toxicological information at an introductory level and gradually comprehensive information on the physical and chemical study of all known poisonous substances is developed. I take this opportunity to express a deep sense of gratitude to my wellwishers, parents and parents-in-law for their sustained support and constructive suggestions to build up the goodwill to write this book. Finally, I am extremely thankful to my wife Rajalaxmi and daughter Akankshya without whose encouragement, help, patience and sacrifice this book would not have seen the light of the day. I request my fellow teachers as well as students to send me their valuable comments and suggestions for further improvement of this book. Balram Pani

Contents 1. Toxicology and Toxicological Chemistry 1.1 Introduction 1.2 Classification of Toxicology 1.3 Acute and Chronic Effects 1.4 Tolerance and Ecological Gradients 1.5 Chemical Interactions 1.6 Reversible and Irreversible Toxic Effect 1.7 Toxicological Chemistry Exercise

1.1 1.1 1.1 1.3 1.3 1.4 1.6 1.7 1.10

2. Principles of Toxicology 2.1 Introduction 2.2 Mechanistic Toxicology 2.3 Descriptive Toxicology 2.4 Regulatory Toxicology 2.5 Dose-Response Concept 2.6 Toxin Exposure 2.7 Physico-Chemical SpecIation in Relation to Exposure 2.8 Quantitative Aspects of Exposure 2.9 Interactive Effects of Toxicants Exercise

2.1 2.1 2.2 2.7 2.7 2.10 2.16 2.20 2.21 2.21 2.23

3. Fundamentals of Chemistry 3.1 Atomic Structure 3.2 Periodic Table and Periodic Properties of an Electron 3.3 Chemical Bonding 3.4 Acids, bases and salts 3.5 Thermodynamics 3.6 Phase Rule 3.7 The colloids

3.1 3.1 3.4 3.7 3.12 3.15 3.25 3.30

LEEE

CONTENTS

3.8 Electrochemistry 3.9 Chemical Kinetics 3.10 Fundamental Reactions And Their Mechanism Exercise

3.32 3.37 3.44 3.56

4. Toxic Inorganic and Radioactive Elements 4.1 Introduction 4.2 Factors Influencing the Metal Toxicity 4.3 Complexation and Chelation 4.4 Metal Toxicity with Multiple Effects 4.5 Toxic Radioactive Elements Exercise

4.1 4.1 4.2 4.3 4.4 4.14 4.21

5. Toxic Organic Compounds 5.1 Introduction 5.2 Hydrocarbons 5.3 Toxicity of Acyclic Saturated and Unsaturated Hydrocarbons 5.4 Toxicity of Mono- and Polycyclic Aromatic Hydrocarbons 5.5 Toxic Effects of Oxygen-Containing Organic Compounds 5.6 Nitrogen-Containing Organic Compounds 5.7 Phosphorus Containing Organic Compounds 5.8 Sulphur Containing Organic Compounds 5.9 OrganOmetallics and Organo Metalloids Exercise

5.1 5.1 5.1 5.3 5.5 5.6 5.9 5.13 5.15 5.16 5.17

6. Movement and Distribution of Toxins in Environment and Ecosystem 6.1 Introduction 6.2 Transport Across Membranes 6.3 Absorption of Toxic Compounds 6.4 Distribution of Toxicants Over the Organism Exercise

6.1 6.1 6.1 6.5 6.9 6.11

7. Fate of Toxins 7.1 Introduction 7.2 Biotransformation of Xenobiotics 7.3 Oxidation of non-carbon elements 7.4 Metabolic Reduction 7.5 Metabolic Hydrolysis 7.6 Phase-II Reactions of Toxicants (Enzyme Reactions) 7.7 Bioaccumulation and Biomagnification

7.1 7.1 7.1 7.8 7.10 7.13 7.15 7.25

CONTENTS

7.8 Bioavailability and Bioconcentration 7.9 Persistence and Biodegradation

EN 7.28 7.29

8. Toxicity 8.1 Introduction 8.2 Local and Systemic Toxicity 8.3 Immediate and Delayed Toxicity 8.4 Reversible and Irreversible Toxicity 8.5 Toxicity of Mixtures 8.6 Variation in Toxic Responses 8.7 Acute Toxicity 8.8 Chronic Toxicity 8.9 Factors Affecting Toxicity of Reactive metabolites

8.1 8.1 8.2 8.2 8.3 8.3 8.4 8.5 8.6 8.12

9. Toxic Effects of Natural and Synthetic Products 9.1 Introduction 9.2 Toxic Effects of Solvent and Vapours 9.3 Toxic Effects of Pesticides and Biocides 9.4 Toxic Effects of Drugs 9.5 Toxic Effects of Natural Products 9.6 Toxic Effects of Cosmetics

9.1 9.1 9.2 9.10 9.18 9.21 9.25

10. Toxicology of Organs and Organ Systems 10.1 Introduction 10.2 Dermatotoxicity (Organ–Skin) 10.3 Haematotoxicity (Organ–Blood) 10.4 Hepatotoxicity (Organ–Liver) 10.5 Nephrotoxicity (organ—kidney) 10.6 Neurotoxicity (Organ—nervous system) 10.7 Respiratory Toxicology (Organ – Lungs) 10.8 Reproductive Toxicity (Reproductive System) 10.9 Cardiovascular Toxicology (Organ–Heart) 10.10 Toxic effects on Endocrine System (organ—Endocrineglands) 10.11 Toxic response of the Immune System

10.1 10.1 10.1 10.6 10.7 10.10 10.13 10.15 10.17 10.18 10.19

11. Biomarkers 11.1 Introduction 11.2 Environmental and Biological Monitoring 11.3 Bi Om Arkers of exposure

10.20 11.1 11.1 11.2 11.2

N

CONTENTS

11.4 11.5 11.6 11.7 11.8

Biomarkers of Effect Biom arkers of Genetic damage Biomarkers of Susceptibility Biomarkers in Plants Significance of Biomarkers Exercise

11.3 11.4 11.5 11.5 11.6 11.6

12. Evaluation of Toxicity and Risk Assessment 12.1 Introduction 12.2 Chemical and Physical Properties (Structure/Activity relationships) 12.3 In Vivo and Short-term Tests 12.4 Subchronic Tests 12.5 Toxicity Ratings 12.6 Risk Assessment 12.7 Risk management

12.1 12.1 12.2 12.2 12.6 12.6 12.7 12.10

13. Air Pollution 13.1 Introduction 13.2 Sources of Air Pollution 13.3 Types of Air Pollutant 13.4 Some Major Air Pollutants and their Effects 13.5 Properties of Pollutants 13.6 Control of Air Pollution 13.7 Fate and Transportation of Air Pollutants 13.8 Global and Regional Air Pollution Problems 13.9 Indoor Air Pollution Exercise

13.1 13.1 13.2 13.3 13.6 13.7 13.17 13.17 13.25 13.37 13.38

14. Water Pollution 14.1 Introduction 14.2 Types of water 14.3 Types of Water Pollutant and Their Sources 14.4 Organic Pollutants 14.5 Inorganic pollutants 14.6 Sediments 14.7 Radioactive Materials 14.8 Thermal Pollution 14.9 Groundwater Pollution 14.10 Marine Pollution

14.1 14.1 14.2 14.3 14.4 14.13 14.15 14.15 14.18 14.21 14.22

CONTENTS

14.11 Engineered System for Water Pollution Control Exercise

NE

14.24 14.39

15. Toxicity Related to Soil 15.1 Introduction 15.2 Sources of Soil Toxicity 15.3 Types of Soil TOXICANT 15.4 Inorganic Toxicants in Soils 15.5 Solid Waste In Soils 15.6 Radionuclides In Soils 15.7 Soil Salinity 15.8 Effect Of Acid Rain On Soils

15.1 15.1 15.1 15.3 15.5 15.7 15.8 15.9 15.10

16. Ecotoxicology 16.1 Introduction 16.2 Ecosystem 16.3 Ecosystem Structure and Community Dynamics 16.4 Evolutionary Ecology 16.5 Biological Productivity 16.6 Energy Flow 16.7 Distribution of Toxicants in the Ecosystem 16.8 Terrestrial Ecotoxicology 16.9 Aquatic Ecotoxicology 16.10 Effects of Toxicants on Terrestrial Ecosystem 16.11 Genotoxicity

16.1 16.1 16.2 16.2 16.16 16.19 16.20 16.22 16.23 16.25 16.25 16.26

17. Mechanisms for Minimizing Toxic Effects 17.1 Introduction 17.2 Detoxification (Bioinactivation) 17.3 Elimination 17.4 Excretion of Toxicants 17.5 Hepatic Excretion 17.6 Exhalation (Pulmonary Excretion) 17.7 Other Excretory Routes

17.1 17.1 17.1 17.2 17.3 17.4 17.5 17.5

18. Applications of Toxicology 18.1 Introduction 18.2 Food Toxicity 18.3 Medical and Clinical Toxicology 18.4 Occupational Toxicology

18.1 18.1 18.1 18.3 18.4

CHAPTER



Toxicology and Toxicological Chemistry 1.1

INTRODUCTION

Toxicology is the science of poisons. Whether a particular substance is poisonous or not depends upon the type of organism exposed, the amount of the substance and the route of the exposure. Toxicological chemistry is the chemistry of toxic substances with an emphasis upon their interactions with biological tissue and living organisms. Toxicological chemistry deals with the chemical nature and reactions of toxic substances and involves their origin, uses and chemical aspects of exposure, fate and disposal (Manhan, S.E, 1986). Both toxicology and toxicological chemistry are the relationship between the quantity of chemical to which an organism is exposed, and the nature and degree of consequent toxic effects. The influence of the structures of chemical molecules upon biological activity is of great importance which is generally known as structure-activity relationship. (SAR) (Walton and Theodore, 1988). The basic principle of toxicology is that no chemical is poisonous if the dose is low enough, while all chemicals are poisonous if the dose is high enough. For example, substances like sugar and salts at high doses can be toxic to animals. Toxicology may be classified in many ways but in this chapter more emphasis will be given to environmental toxicology which deals with the exposure to toxic substances through polluted air, water and soil.

1.2

CLASSIFICATION OF TOXICOLOGY

Toxicology may be classified into several subdisciplines. Toxicology is an integrated approach of analytical chemistry, medical, biology, biochemistry, pathology and physiology to study the effects and behaviour of toxins even from the smaller units like molecules and cells.

1.2

TOXICOLOGY

Depending on the interactions of toxins with various disciplines, organisms and organs, toxicology can be distinguished into the following important subdisciplines (Fig. 1.0) Clinical Toxicology Reproductive and Developmental Toxicology

Occupational Toxicology

Environmental Toxicology

Toxicology

Nutritional Toxicology

ImmunoToxicology

Economic Toxicology

Cellular Toxicology

Fig. 1.0

The various subdisciplines of toxicology.

• Environmental toxicology is an integrated science which deals with the exposure to toxicants through the pathways like polluted air, water, industrial effluents and contaminated food. It also integrates with health science, ecology and environmental parameters—both biotic and abiotic materials. • Clinical toxicology deals with the diagnosis and treatment of poisoning by evaluating different methods of detection and intoxification. It also integrates with medicine, pharmacy, biochemistry and clinical biochemistry. • Nutritional toxicology which focuses on the toxicological aspects of foodstuffs and nutritional habits particularly of human beings. • Economic toxicology focuses on the harmful effects of substances administered intentionally to living organisms or biological tissues for a beneficial effect, for example, to minimize the side-effects of a drug. • Occupational toxicology deals with the exposure and effects of toxins at the working place. • Immuno-toxicology deals with the effects of toxicants on the immune system. • Reproductive and developmental toxicology focuses on the effects of chemicals or toxins on the reproductive system and the developing embryo.

TOXICOLOGY AND TOXICOLOGICAL CHEMISTRY

1.3

• Cellular toxicology deals with the process by which toxicants alter cells in potentially detrimental directions.

1.3

ACUTE AND CHRONIC EFFECTS

Based on the exposure of organisms to toxicants, the adverse effects can be classified as acute and chronic effects. An acute effect is the short time exposure, usually to a large amount of a toxicant. The time of exposure may vary from few seconds to a few hours. Generally, this type of exposure affects the exposure sites, particularly skin, eyes or mucous membrane. If this exposure continues for a few hours, the toxicants can enter the body through inhalation or ingestion and affect the inner organs (liver) of the body. Sometimes it is referred to as acute systemic exposure. Chronic effects occur due to exposure over a long period, usually to low levels of a toxicant. The time period may range from few days to several years. For example, an organism exposed to a high dose of toxicants for few seconds (single dose) may be killed (an acute effect), while same total amount of toxicants received slowly (in several years) in small amounts (many doses) may cause a serious disease which may affect the offspring if the disease is mutagenesis. In case of acute effect, the exposure site plays an important role. For example, the permeability of skin is inversely proportional to the thickness of stratum corneum. The thickness of stratum corneum varies by location on the body. In human beings, the order of the thickness is as follows: Soles and palms > abdomen, back, legs, arms > genital (perineal). Thus, some organisms can serve as bioindicator of pollutants.

1.4

TOLERANCE AND ECOLOGICAL GRADIENTS

Every toxicant in the environment varies through a wider range of intensity than any individual organism can tolerate. Characteristically, for each individual organism, there is a lower limit of exposure to a toxicant, below which no effect occurs. This lower limit of exposure to a toxicant is often termed threshold effect. Thus, the threshold is the minimum exposure to toxicant quantity that produces no effect in the organism. Above the threshold effect, toxic effects begin to occur. Similarly, for each organism there is an upper limit of exposure to toxicant quantity within which the organism can withstand the toxic effects, is referred to as tolerance. Thus, upper limit to tolerance is intensity levels of toxicant exposure at which only half of the total organisms (LD50) can survive. The threshold and the tolerance limits are shown in Fig. 1.1.

TOXICOLOGY

Response

To ler an ce Lim it

1.4

LD5

0

Threshold Log dose

Fig. 1.1

Threshold and tolerance effect.

The organisms vary in their limits of tolerance to the same toxicant. Tolerance in organisms may result from physiological, behavioural and genetic adaptation. Probably the first response of any organism to a toxicant in the environment is physiological. Physiological tolerance refers to the body of an individual adjusted to tolerate a higher level of pollutant. Exposure to pollutant, there is a change in physiological processes which is followed by the change in biological activities. For instance, at high altitude the body increases the number of red blood cells to tolerate the low level of oxygen. Behavioural tolerance refers to the behaviour of an individual adjusted to tolerate the higher level of pollutants. For example, through exposure to pollutants, the organism moves away from points of danger and into a more favourable condition. Genetic tolerance refers to the individuals who are more resistant or able to withstand an exposure to toxicants and have more offspring than do other individuals under the same condition. These resistant individuals prevail in next generation. The dose-response relationship of toxicants produce the ecological gradient. The high toxic tolerant vegetations can grow near to a toxic source. These vegetations are relatively have short lifetime. The low tolerant species will grow at far away from the toxic source. Thus, this change in vegetation with distance is known as ecological gradient.

1.5

CHEMICAL INTERACTIONS

Generally, the toxicants are found associated with other chemical and biological factors in environment that interact and modify their toxicity. The chemical interactions among the toxicants can be broadly classified into four which are illustrated below: 1. Antagonistic effect: Some toxicants produce antagonistic reactions in which an active substance decreases the effect of another active toxicant. In this case, the total effect is less than the sum of the effects of each separately (1 + 1 < 2). For example, vitamins E and A can reduce the response to some carcinogens.

TOXICOLOGY AND TOXICOLOGICAL CHEMISTRY

1.5

2. Additive effects: The combination of two or more chemicals with some physiological function results in additive effects. The total effect is equal to the sum of the effects of each separately (1 + 1 = 2). For example, rats exposed to both lead and arsenic show twice the toxicity of only one of these elements. 3. Synergistic effect: In this case the interaction between two toxicants with the same physiological function becomes more toxic than can be predicted. The total effect is greater than the sum of the effects of each separately (1 + 1 > 2). For example, occupational asbestos exposure increases lung cancer rate 20-folds. 4. Potentiative effect: It occurs when an inactive substance enhances the action of an active toxicant (1 + 0 > 1). For example, a rise in the pH from 7 to 8 can increase the toxicity of ammonia by 200% on fish.

1.5.1

Xenobiotic and Endogenous Substances

Xenobiotic substances are the foreign bodies to a living system which enter into the body from the external source, while the endogenous substances occur naturally inside a biological system. For a normal metabolic process, the endogenous substances must fall within a particular concentration range. The concentration levels of endogenous substances above or below the normal range may affect the metabolic processes severely which can be shown graphically as in Fig. 1.2.

Effects

Normal metabolic processes Detrimental effect

Normal effect Deficiency point

Excess point Detrimental effect

Lethal effect

Lethal effect

Concentration of endogenous

Fig. 1.2

The relationship of biological effect and endogenous concentration.

The essential metal ions (Ca2+, K+ and Na+), various hormones, enzymes, and blood glucose are included in endogenous substances. For example, the normal range of Ca2+ in the human blood stream varies from 9 to 9.5 mg/dL. The range of Ca2+ when below the lower limit causes hypocalcemia (muscle cramping) and that above the upper limit causes hypercalcemia (kidney malfunction).

1.6

TOXICOLOGY

1.5.2 Immune System Effect The immune system of a body refers to the natural defence system to protect it from xenobiotic chemicals, infectious agents (viruses or bacteria), and neoplastic cells. The exposure of immune system of a body to the toxicants causes immunosuppression which is impairment of the body’s natural defence mechanisms. Sometimes, the xenobiotics cause severe damage to the immune system so that the immune system loses its ability to control cell proliferation, resulting in leukemia or lymphomia (lymphoma). When the immune system overreacts to the presence of xenobiotics, the toxic response is known as allergy or hypersensitivity. Some of the allergy produced xenobiotic materials are formaldehyde, pesticides, resins, plasticizers, nickel, beryllium and chromium.

1.6

REVERSIBLE AND IRREVERSIBLE TOXIC EFFECT

A toxic dose-response curve (LD50) shows a negative response in which the ultimate effect is lethal or causes death to the organism. When the effect of a toxicant in organism is permanent, i.e., even if there is a complete elimination of toxic elements from the organism, still then the effect of toxicant exposure persists it is known as irreversible effect. Lethal doses (LD) are usually included in irreversible effect. However, ED50 and TD50 show some positive response, i.e., the ultimate effect is not death of the organism. In many cases, the effective doses are detrimental as well as beneficial. When the effect from toxicant exposure is a temporary one and the effects are not observed after the elimination of toxic substances from the organism, the effect is said to be reversible. Organism on exposure to toxicants with reversible effects do not die, thus such effect may be called sublethal. The sublethal doses of most toxic substances are eventually eliminated from an organism’s system. There are various toxicants or chemicals in which toxic effects may range from the totally reversible to the totally irreversible.

1.6.1

Sensitivity

Sensitivity: The sensitivity of an organism to a particular dose of toxicant may be broadly divided into three groups: hypersensitivity, hyposensitivity and normal response. 1. Hypersensitivity: In this, an organism is very sensitive to a particular toxicant, so that even in LD5 of that toxicant, the organism dies. These organisms can be used as a bioindicator for the particular pollutant. 2. Hyposensitivity: This refers to organisms which can resist the toxic effect of a toxicant. Hyposensitivity organisms can survive a dose corresponding LD95. 3. Normal: The midrange between the hypersensitivity and hyposensitivity

TOXICOLOGY AND TOXICOLOGICAL CHEMISTRY

1.7

is known as normal sensitive organisms. All these sensitivities are shown in the Fig. 1.3.

Response

Hyposensitivity Normal Hyposensitivity

Log dose

Fig. 1.3 Sensitivity of organism to toxicant exposure.

1.7

TOXICOLOGICAL CHEMISTRY

Toxicological chemistry deals with the chemical nature and changes of toxic substances, including their origins, uses, fate, chemical aspects and disposal. It also deals with chemical changes that are brought about by living organisms. In this chapter, the chemical reactions of toxic substances will be discussed. The chemical reactions carried out in the living organisms may be classified as extracellular and intracellular. Extracellular Reactions

Xerobiotic chemicals are those that are foreign to natural biota. Anthropogenic compounds are those that are synthetic. Hydrolytic reactions are generally extracellular in character. These reactions are very important because such reactions are required to reduce the complexity of organic compounds to a point at which they can dialyze through the cell wall. In such reactions particularly lipophilic (lipid soluble) xenobiotic chemicals in the body undergo hydrolytic reaction to make them more water-soluble as the polar functional groups attached to them. Since the product has polar functional group, it is very reactive. Generally, the energy requirement for hydrolytic reactions is considered low, therefore, such reactions are carried out at far lower temperatures than would be needed in their absence. But the body temperature is more than that of the required temperature of these reactions. Therefore, the catalysts that markedly lower the activation energy of the reactions are required and are known as enzymes in the living organisms. The enzymes initiate the reactions and also control the rate of reactions in such a manner that serves the interest of a particular organism. Some enzymes are secreted by the cell and are known as extracellular enzymes. The enzymes that catalyze hydrolytic reactions are known as hydrolases. Most of the intracellular reactions are catalyzed by the cytochrome P-450 enzyme system associated with

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the endoplasmic reticulum of the cell. The reactions are illustrated as: Lipophytic water insoluble xenobiotic substances

Cytochrome P-450 Enzyme system

Water-soluble product attached with functional group are more reactive

Intracellular Reactions

Oxidative reactions are generally intracellular reactions. The polar functional groups attached to a xenobiotic compound in extracellular reaction provide the reaction sites for the intracellular reactions in which the enzymes (desmolases or respiratory enzymes which can catalyze the non-hydrolyzable substances) the conjugation reactions. In this reaction, the conjugating agents attach to the polar functional groups of xenobiotic compounds. These products are more watersoluble and so are readily eliminated from the body of the organisms. These conjugation products are usually less toxic than the original xenobiotic compound. Extracellular Product (more toxic)

+

Conjugating agents (in the cells)

Enzyme

Conjugation Product (more water-soluble and less toxic)

1.7.1 Biochemical Pathways of Toxicants on the Body The biochemical pathways of toxicants in the body may be carried out in two major phases, such as kinetic phase and dynamic phase. The kinetic phase involves the extracellular reactions in the body. The absorption, metabolism and distribution of the products of extracellular reactions are all included in kinetic phase, which have been discussed in the earlier section. In the kinetic phase hydrolysis is an important biochemical reaction in the body. Generally, brominated compounds are susceptible to hydrolysis than chlorinated compounds since bromine is a better leaving group than chlorine. Dynamic phase involves the interaction of the kinetic phase products with the cells, tissues or other organs in the body to cause some toxic response. Oxidative reactions are included in the dynamic phase. Oxidation is a process where, electrons are released through enzyme catalyzed reactions. Primary reaction in the dynamic phase involves some xenobiotics and other toxic compounds (benzene, toluene, phenol, chlorobenzene, etc.) which may serve as primary substrates. Some enzymes like methane monooxygenase, toluene dioxygenase, toluene monooxygenase, etc., can catalyze the additional reactions. These enzymes are involved in biochemical pathways responsible for the initial steps in the oxidation of benzene, toluene, methane, phenol, etc. One important example is the oxidation of benzene, trichloroethane to their epoxide derivatives by the enzymes.

TOXICOLOGY AND TOXICOLOGICAL CHEMISTRY

1.9

Toluene dioxygenase Enzyme oxidation Benzene

Benzene epoxide O

Cl C H

C

Cl Toluene dioxydenase Oxidation Cl

Cl

Cl C

H

C Cl

In this oxidation reaction the terminal electron acceptor is required to complete the process. The epoxide products combine with the nucleic acid unit in DNA to give an adduct product which may cause some toxic response, i.e., alteration of DNA may occur. The reactions involving the toxicant and the DNA are generally irreversible. Therefore, the toxic effect in these reactions are more severe. In the reversible reactions, the toxicants can be eliminated from the body. For example, COHb + O2 Hb + CO In the reduction reactions, xenobiotic compounds may serve as electron acceptors and cofactors (ferredoxin, vitamin B12, etc.) serve as electron donor in the biological system. The electron donors may serve as primary substrate. Generally, oxygen, nitrate, sulphate and carbon dioxide serve as terminal electron acceptors. For example, CO2 + 8H+ + 2e– ® CH4 + 2H2O The products will combine with the cell wall and tissues and produce the toxic effects.

1.7.2 Factors Influencing the Biochemical Reactions on the Body Usually, enzymes, cofactors, temperature and pH value in the body are the major factors which influence the biochemical reactions. In the proceeding section, enzymes have been discussed. Some enzymes require non-protein structures for their activity and are known as cofactors. The cofactors may be a metal ion or it may be a complex organic molecule. The metal ions include iron, manganese, zinc, copper, nickel, cobalt, potassium and sodium, while the complex organic molecules or coenzymes include ferredoxin, nicotinamide adenine dinucleotide, flavoproteins, F420 and others. The presence of cofactors can activate many enzymes to carry out biochemical reactions in the body. Temperature

Van’t Hoff’s rule states that with every 10° rise in temperature, the rate of biochemical reaction increases by two times. It is designated as Q10. But the rate

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of biochemical reaction increases with temperature to a certain limit. After that limit, the rate tends to decrease with temperature rise due to denaturation of the enzyme. It is shown in Fig. 1.4. [Biochemical reactions occur at a temperature range of about 0 to 60°C. Organisms that thrive at 0 to 10, 10 to 40, and above 40°C are grouped as psychrophilic, mesophilic, and thermophilic, respectively.]

Reactive activity

70 60 50 40 30 20 10 0 10

20 30 40 50 60 Temperature °C

70

80

Fig. 1.4 Effect of temperature on reactive activity (Sawyer and Rohlich 1939)

pH Value

An enzyme can act effectively at a particular pH range. This range is quite narrow. Majority of enzymes act effectively in neutral conditions. Some enzymes are more effective at a high pH value and some others at low pH level.

EXERCISE 1. Define toxicology and give the relationship of toxicology with toxicological chemistry. 2. Describe briefly the subdisciplines of toxicology. 3. What are the biochemical pathways of toxicants on the body? 4. What are the factors influencing the biochemical reactions on the body? 5. Differentiate xenobiotic and endogenous substances. 6. Explain the tolerance and ecological gradients of toxicology. 7. What is chronic effect of toxicants? 8. Explain the chemical interactions of the toxicants. 9. What are reversible and irreversible effects of toxicants? 10. Explain the sensitivity of toxic elements.

CHAPTER

Principles of Toxicology 2.1

INTRODUCTION

The principles of toxicology describe that how the chemical substances or toxicants enter into the ecosystem and how these chemical substances exert their toxic effects in biological systems. The flux of chemical elements enters into biological system along with the transfer of the chemical compounds they form. Their mobility is largely influenced by their compatibility position in solid and gas, the solubility character in water and their tolerance by biota. Within the biotic compartments, chemical compounds flow along the trophic structure of ecosystems. There are large differences between ecosystems with regard to the speed of transfer, the percentage of internally circulating compounds and the tenure time of some compounds within the ecosystem. (Helmut Lielth, 1998) All chemical substances are potential poisons depending on their amount and duration of exposure. The high dose and excessive exposure of any substance can cause injury or death. Thus, exposure is a function of the amount of chemical involved and the time and frequency of its interaction with biota. The ultimate adverse effect of the toxicants is death but it can be observed as an abnormal, undesirable or harmful change following exposure. For very highly toxic substances, the tolerable exposure may be close to zero. Most substances that are not highly reactive discharged into the environment, may be absorbed and distributed among the affected organisms carrying systemic injury at a target organ or tissue distinct from the absorption site. The toxic effect may be considered harmful or adverse only when it causes functional, structural or anatomical damage, irreversible change on homeostasis or increased susceptibility to other chemical or biological stress including infectious disease (Duffus, JH, 19, 2006). The variety of adverse effects and diversity of toxicants in the environment make it very difficult to analyse the toxicological behaviour in a specialized manner. In this chapter, we will discuss and give more emphasis on mechanistic toxicology, descriptive toxicology and regulatory toxicology.

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TOXICOLOGY

2.2 MECHANISTIC TOXICOLOGY Mechanistic toxicology describes the different pathways (the celluar, biochemical, and molecular mechanisms) by which the chemical substances exert their toxic effects in the biological systems. The basic aim of mechanistic toxicology is to identify that how do xenobiotics (foreign compounds to the body) enter an organism and how these are distributed or metabolised inside the body. The other aim of this study is to understand the mechanism by which xenobiotics do interact with target molecules and exert their toxic effects at the molecular level. With an understanding of the mechanism, valuable preventive measures may be discovered which will be very beneficial and highly effective in the treatment of certain infectious diseases, a variety of inflammatory diseases and some types of cancer. All chemical substances are potential poisons depending on the amount, time and exposure frequency of these substances to the living organisms which ultimately cause adverse effects on biological systems. The mechanisms of a chemical substance in the ecosystem depend on many different factors. Between emission (discharge) and imission (exposure), a number of processes (transmission) occur. The mechanistic toxicology can be studied separately at different levels of both toxicants and the affected organisms as explained below: • The different levels of organism Species ® Xenobiotic ® Molecular mechanism ¯ (death) Ultimate effect ¬ End point ¬ Biochemical reaction • The different levels of toxicants, Molecular mechanism: Toxicokinetics; Toxicodynamics; Factors influencing mechanisms, and biological response. In this chapter, more emphasis will be given to molecular mechanism and mechanism of toxicity will be discussed in later part of this book.

2.2.1 Toxicokinetics Toxicokinetics refers to the study of the kinetics (movements) of xenobiotics around the body, i.e., the changes of the concentrations of a xenobiotic compound in the organism over a time period. Toxicokinetics determines the rate of absorption, distribution, biotransformation and excretion of xenobiotics in the whole organism. The rates at which the changes of concentration of xenobiotics occurred are mostly determined by the uptake of the xenobiotics into the organism, its body distribution, its metabolic conversion and excretion of the xenobiotics. Thus, toxicokinetics is also known as metabolic toxicology. The toxicokinetics relates to the whole organism—tissues, organs and fluids in the body that do not differ from each other in terms of kinetics.

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2.3

The organism may be divided into compartments which usually represent the particular tissues, organs or fluids. Each of these compartments contains a discrete quantity of xenobiotic which is subjected to particular rates of transfer and biotransformation. Majority of xenobiotics, particularly drugs used in medicine, combine with the receptors very loosely and their concentration changes take place very slowly. These reactions are reversible. Some xenobiotics form covalent bonds very strongly with the receptors. In these cases, the rate of change of the concentration of xenobiotics is very fast. These are irreversible reactions. Thus, the toxic effect of xenobiotics depends on rate of the reaction, i.e. the reversibility or irreversibility of the reaction. The simplest and most realistic model that describes the behaviour of a xenobiotic in the body is known as pharmacokinetic models. The compartmental pharmacokinetic models consist of a central compartment which is surrounded by one more peripheral compartment. The compartment at pharmacokinetic models are of two types such as: • One-compartment model. • Two-compartment model. One-Compartment Model

One-compartment model is the simplest and most realistic model that describes the uptake and elimination process. In one compartment model, once a xenobiotic enters the circulation of the body is quickly distributed over the entire organism and subsequently readily exchanged between the circulation and the tissues and organs. In one compartment model, it is assumed that uptake rate is proportional to the concentration in the environment and the elimination route is proportional to the concentration in the tissues or organs as in Fig. 2.1. The xenobiotics whose toxicokinetics can be described with a one compartment model rapidly equilibrate between blood and various tissues relative to the rate of elimination. Environment k1 (Ci)

Co k2 CE

Fig. 2.1

k3

CM k4 CME

One-compartment model.

Ci = Amount of the xenobiotics in the environment which is administered into the body of an organism. Co = Amount of xenobiotics present in an organism body after the administered time (t). CM = Amount of xenobiotics metabolized after administration. CE = Amount of xenobiotics directly excreted after administration.

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TOXICOLOGY

CME = Amount of metabolite excreted. k1 = Rate constant of absorption of xenobiotics. k2 = Excretion rate constant. k3 = Metabolic rate constant. k4 = Rate constant for the excretion of the metabolite. The elimination rate of the xenobiotics from one compartment expressed in first order kinetics as

dCo is dt

dCo = – (k2 + k3 )Co = – kCo dt where k is the elimination rate constant. k = k2 + k3 For integrating it from

t = 0 to

t = t it gives

Co = Ci e–kt k is the first order elimination rate constant. k=

amount of xenobiotics eliminated in unit time amount of xenobiotics present in the body

Taking the logarithm value lnCo = ln Ci – kt kt 2.303 By plotting the graph in both linear and logarithmic scale (Fig. 2.2).

log Co = log Ci – k.t log e = log Ci –

–kt

Co

Slope =

ie =C

Time (t)

(A)

log Co

Concentration (c)

Ci = A (Total amount)

(in hr)

Fig. 2.2

Ci = A/2 (half amount)

k –2.303

T1/2

Time (in hr)

(B)

First order kinetic.

Figure A ® The tissue concentration of xenobiotics falls exponentially with time. Figure B ® The log of the tissue concentration of xenobiotics falls linearly with time.

PRINCIPLES OF TOXICOLOGY

2.5

Two-Compartment Model

The substance, after having entered the circulation, if it is readily exchanged between the circulation and the rest of the body, then the organism can be described as two-compartment model. In these models, the xenobiotics require a longer time for their concentration in tissues to reach equilibrium with the concentration in plasma. The two-compartment model consists of a central and peripheral compartment, each with its own apparent volume of distribution. Sometimes central and peripheral may be designated as plasma and tissues compartment respectively as in Fig. 2.3. Environment k1 A

kAB kBA

B

kE

Fig. 2.3 Two-compartment model.

where

A = central compartment B = peripheral compartment kAB = the rate constant for the transport from A to B kBA = the rate constant for the transport from B to A k E = the rate constant for elimination from the central compartment (A). k 1 = the first order rate constant for entering into the central compartment (A). From Figure 2.3, it is evident that after the substance enters into the central compartment, rapid distribution of substance over the first compartment takes place. Simultaneously, the substance starts to disperse more slowly into the peripheral compartment which comprises tissues and fluids and a portion of substance also get eliminated from the central compartment. As a result, there is a rapid net loss of the substances (xenobiotics) from the central compartment (plasma). It can be well explained by the following mathematical equation as CA = Xe– a t + Ye–b t CA = concentration of substance in central compartment (A). X and Y = proportionality constant. = = distribution phase rate constant. > = elimination phase rate constant. t = time period. During the distribution phase (=), concentrations of the substances (xenobiotics) in the plasma decrease more rapidly because of irreversible elimination from the central compartment and uptake by the peripheral compartment.

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TOXICOLOGY

The distribution phase may last for only a few minutes or for hours or days. After a certain period of time, steady state is reached in the distribution if substances over various tissues and fluids depending on the magnitude of rate constants such as kAB and kBA. The equivalent of k (k = k2 + k3) in a onecompartment model is ‘>’ in a two-compartment model. This process can be shown in the graph (Fig. 2.4). For the graph, the equation log Co = -

kt + log Ci can be used. 2.303

–kt

C o=

ie

C

log Co

Environment (c)

Ci = A (Total amount)

Ci = A/2

Slope = –

b 2.303

T1/2 Time (hr)

(A) Linear scale Fig. 2.4

Time (hr)

(B) Logarithmic scale Graphs of two-compartment model.

The graph (Fig. 2.4) indicates the rapid decline of the concentrations during = phase and relatively slow decline during the > phase.

2.2.2

Toxicodynamics

Toxicodynamics is the study of toxic action and dynamic reactions of a xenobiotic with the biological system particularly the biological target. For example, some xenobiotics form covalent bonds with the receptors and in this way they bring about a dynamic change (functional or structural alterations) that is difficult to reverse. The toxic effect of the xenobiotics may result from the irreversible interaction between the substance and the targets (receptors). Adverse effects of a xenobiotic in a biological system are not produced unless the biotransformation products of these substances reach appropriate site in the body at a particular concentration or more for a specific period of time. The interactions between the chemical substances and a target specific molecule depend on high affinity binding sites that make the interactions very selective. This may describe that toxicity can be restricted to certain tissues or organs, because these high-affinity binding sites to selective chemicals are present in high concentration. The same chemical may be at low levels on non-target tissues, so they are not toxic to those tissues. For example, enzymes, proteins, transmembranes are the high affinity targets that specifically bind to a xenobiotic. Toxicodynamics also explains that a xenobiotic may not necessarily be reactive by itself and damage the endogenous macromolecules but due to its high affinity and

PRINCIPLES OF TOXICOLOGY

2.7

persistent binding may prevent the macromolecule or part of it from interaction with other molecules. Thus, the chemical substance inhibits a vital physiological process or interferes with a regulatory step which may be very adverse and ultimately lead to death. The basic difference between toxicokinetics and toxicodynamics is as: Toxicokinetic refers to the process of absorption, distribution, elimination and metabolism of a toxicant. Toxicodynamics refers to the actions and reactions of the toxicants within the organism and describes the process at organ, tissue, cellular and molecular levels. Thus, both toxicokinetic and toxicodynamic factors can greatly determine the toxicity of an xenobiotic.

2.3

DESCRIPTIVE TOXICOLOGY

Descriptive toxicology is concerned directly with toxicity testing which describes the relationship between the quantity of chemicals to which an organism is exposed and the nature and degree of consequent toxic effects. Thus, a biological effect is the ultimate result of an interaction between a substance and a target molecule in the body. In the toxicity testing, dose-response relationships provide the basis of assessment of hazards and risks presented by environmental toxic elements. This information used for safety evaluation and regulatory requirements. These testings also provide information to identify the structural and functional properties of a chemical responsible for its toxic effects. This explains why one substance is carcinogenic and another is not, or why one inhibits an enzyme or protein while the other one does not. The proper and right toxicity tests in experimental animals give sufficient information to evaluate risks posed to humans and the environment by exposure to specific chemicals. Descriptive toxicology involves two main principles. The first principle states that the effects produced by a chemical in laboratory animals are also applicable to humans. The second principle is that exposure of experimental animals to toxic agents in high doses is an essential method of discovering possible hazards in humans. Toxicity tests are observed to characterize the toxic effects a chemical can produce.

2.4

REGULATORY TOXICOLOGY

Regulatory toxicology deals with the relationship between the discipline of toxicology and regulatory institutions. The toxicology regulatory institutions have the responsibility for deciding on the basis of data provided by descriptive and mechanistic toxicology, whether a particular substance or chemical poses a sufficiently low risk or low toxicity for humans and other organisms. Thus, the regulatory authorities have to protect the health of humans which relies heavily on toxicologic principle and toxicity evaluation data to formulate a decision.

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TOXICOLOGY

The regulatory authority has to take a decision on acceptable daily intake (ADI) of a chemical so that the quantity of that chemical exposure is adjudged ‘safe’ in terms of health. The authority has to show or prove from the existing data obtained from descriptive and mechanistic toxicology that a substance is hazardous before exposures can be restricted. They have also the power to formulate some law or regulatory roles and to implement them rigidly. Toxicology principle says “No chemical is safe”. All the chemicals are potentially toxic depending on their exposure concentration, time, frequency and nature of the chemicals. Therefore, regulators formulate the threshold doses to reduce human expose concentration that any associated risk may be minimized to highest level. Procedural Laws Related to Environmental Fraction from Toxicants

The procedural laws are the instrumental tools for implementation of any law. Thus, there are various rules and regulations formulated under substantive environmental legislations through which the central and state governments formulated the following procedural laws in India to implement the environmental laws. These procedural laws are discussed chronologically: (i) Rules framed under the Water (Prevention and Control of Pollution) Act, 1974 and Water Less Act, 1977: The Water (Prevention and Control of Pollution) Act, 1974 under section 64(a) and (e) empowers that each state government shall make its own state rules for prevention and control of water pollution. The central government after consultation with the control board made the Water (Prevention and Control of the Pollution) Rules, 1975. Similarly, under section 17 of the Water (Prevention and Control of Pollution) less Act, 1977, the Government of India framed the Water (Prevention and Control of Pollution) less Rules 1978. The central government after consultation with the control board made the water pollution (Procedure for Transaction of Business) Rules, 1975. (ii) Rules framed under the Air (Prevention and Control of Pollution) Act, 1981: Under section 54 of the Air (Prevention and Control of Pollution) Act, 1981 confers that every state government shall make their rules of the respective state. Similarly, under section 53 of Air Act, 1981, the central government framed the Air (Prevention and Control of Pollution) Rules 1982. (iii) Rules framed under the Environment (Protection) Act, 1986: The Environment (Protection) Act, 1986 (29 of 1986) under sections 6 and 25 empowers that the Government of India formulated the Environment (Protection) Rules, 1986. In exercise of powers conferred by sections 6, 8, and 25 of the Environment (Protection) Act, 1986 (29 of 1986), the Government of India formulated the following Rules.

PRINCIPLES OF TOXICOLOGY

2.9

(a) The hazardous wastes (Management and Handling) Rules, 1989 (b) The manufacture, storage, and import of hazardous chemicals Rules, 1989 (c) The chemical accidents (Emergency Planning, Preparedness and Response) Rules, 1996 (d) The biomedical wastes (Management and Handling) Rules, 1998. (iv) Rules framed under National Environment Appellate Authority Act, 1997 and Public Liability Insurance Act, 1991: Under section 22 of the National Environment Appellate Authority Act, 1997 (22 of 1997) the central government made the National Environment Appellate Authority (Appeal) Rules 1997. Similarly, under section 22 read with section 13 of the National Environment Appellate Authority Act, 1997 (22 of 1997) the central government of India made the National Environment Appellate Authority (Financial and Administrative powers) Rules, 1998. In exercise of the powers conferred by section 23 of the Public Liability Insurance Act 1991, the central government made the Public Liability Insurance Rules, 1991. (v) Rules framed under Wildlife (Protection) Act, 1972: In exercise of the powers conferred by clause (a) of subsection (1) of section 63, read with clause (b) of subsection (4) of section 44 of Wildlife (Protection) Act, 1972 (53 of 1972), the central government made the Wildlife (Protection) licensing (Additional matters for consideration) Rules, 1983. Under clause (a) of subsection (1) of section 63 of the Wildlife (protection) Act, 1972, (53 of 1972), the central government made the wildlife (stock Declaration) Rules 1973 and the wildlife (stock Declaration) central rules, 1973. Similarly, the wildlife (Transaction and Taxidermy) Rules, 1973, was made by the central government under clause (b) of sub-section (1) of section 63 of the Wildlife (protection) Act 1972 (53 of 1972). There are various quasi laws or administrative regulations and guidelines for implementation of environmental laws under the Parents Act. These are as follows: (a) Emission standard as per section 17(1)(g) of the Air (prevention and control of pollution) Act, 1981. Clause (g) of section 17(1) reads as: “(g) to lay down, in consultation with the central board and having regard to the standards for the quality of air laid by the central board, standards for emission of air pollutants into the atmosphere from industrial plants and automobiles or for the discharge of any air pollutant into the atmosphere from any other source whatsoever not being a ship or aircraft: Provided that different standards for emission may be laid down under this clause for different industrial plants having regard to the quantity and composition of emission of air pollutants into the atmosphere from such industrial plant”.

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(b) Guidelines for diversion of forest lands for non-forest purpose under the forest (conservation) Act, 1980. (c) Guidelines for Environmental Impact Assessment. (d) Guidelines for Environmental Appraisal of Industrial Project. (e) Guidelines for Integrating Environmental Concerns with Exploitation of Mineral Resources. (f) Environmental Guidelines for formulation of River Valley Project. (g) Environmental Guidelines for Development of Beaches. (h) Environmental Guidelines for Thermal Power Plants. (i) Guidelines for Environmental Impact Assessment of shipping and Harbour Projects. (j) Prevention of Hazards from Industrial units: Government of India’s Instructions. (k) Environmental clearance of industrial licence conditions of letter of Intent/Industrial licence. (l) Safety and Health Accident Reduction Action Plan (SAHARA). (m) Guidelines for Dereservation of Reserved forests or Diversion of Forest land to any non-forest use. (n) Guidelines for massive tree plantation for abatement of air pollution caused by Industries. (o) Decision of cabinet on Amendment of the Rules of Business of effecting the Guidelines of the Department of Environment. (p) Incentives to Industries for Prevention and control of pollution and for conservation of Resources. (q) Environmental Guidelines for siting of Industry. (r) 74th Amendment Act, 1992 of the constitution of India lays down in Article 243 Z D(3) that every District Planning Committee will involve in preparing the development plan with regard to “environmental conservation”. The same provision was also inserted in Article 243 ZE (3) in cases of every Metropolitan Planning Committee.

2.5

DOSE-RESPONSE CONCEPT

Toxicants vary widely in their effects upon organisms, i.e., every toxicant has a spectrum of possible effects on a particular organism. Generally, a substance with an excess amount can be dangerous, while anything in extremely small amounts (dilute condition) can be relatively harmless. Thus, the levels of toxicants must usually fall below the lower limits or minimum level in order to cause normal metabolic processes and other biological activities. Above the minimum levels of toxicant concentration, the toxic effect is observed. Similarly, there is an upper limit or maximum level of toxicants at which the lethal effect of toxicants are

PRINCIPLES OF TOXICOLOGY

2.11

observed. For example, there are many essential elements (copper, manganese, iron, chromium, selenium, etc.) required by the living organisms in small amounts for smooth functioning of their biological activities, but the same elements in higher concentrations are toxic. Thus, the effect of a certain chemical or toxicant on an individual depends on the dose or concentration of the toxic factor which is one of the vital concepts of toxicology. This concept is known as dose-response concept. Dose is the concentration of a toxicant exposed per unit body mass, while the response is the effect upon an organism resulting from exposure to a toxicant. A general dose-response curve is plotted by taking the various concentrations of a chemical or toxic factor present in a biological system against the effects on the organism, as illustrated in Fig. 2.5.

Lower M limit

Maximum benefit to life N

Less beneficial to life

More harmful to life Toxic

L

sh a to l rmfu l ife

O Essential Dangerous to life (lethal effect)

Les

Response

Exceeding upper limit of concentration

P Death

K Deficiency Dose

Fig. 2.5

General dose-response curve.

Dose-Response Relationship

In order to define a dose-response relationship, it is necessary to specify a particular response usually negative response, i.e., death of the organism which is plotted against the increasing intensity of exposure to a toxicant. At relatively low doses, no organism exhibits the response (0% of the population) and at the upper limit of doses, all the organisms exhibit the response (100% of the population). In between, there is a range of doses over which some of the organisms (0–100%) respond in the specific manner, as the individuals differ in their response to environmental toxins. It is difficult to estimate the exact dose that will cause a response in a particular response. Therefore, the average effect of a toxin on a population is plotted to get a generalized dose-response curve in which different doses of a toxin are administered uniformly to a homogeneous population and its

2.12

TOXICOLOGY

response as a percentage of deaths. This response is a function of the log of the dose. It is illustrated in Fig. 2.6. The dose at which 50% of the population dies is called the median lethal dose 50 (LD-50). Similarly, LD-5, LD-10 to LD90, LD95 can be obtained.

Response (% of death)

100 75 LD50

50

LD-50

25

0

Log dose

Fig. 2.6

Dose-response curve (LD-50).

Like lethal dose-50, the effective dose-50 (ED50) is the dose that causes an effect in 50% of the population. Similarly, the toxic dose-50 (TD50) is the dose that causes toxic effect to 50% of the population. In case of ED50 and TD50, the response is that none will die by the exposure of the toxicants. Generally, TD50 is used to indicate responses such as reduced enzyme activity, decreased reproductive success, loss of hearing, nausea, or sherred speech and ED50 is used to treat a particular disease. For example, the ED50 of paracetamol would be the dose that relieves high temperature of body in 50% of the people. The ED50 and TD50 dose-response curve is shown in Fig. 2.7. Response (% of population)

100 75

50

25

0

Fig. 2.7

ED50

TD50

Log dose

Dose-response curve for ED50 and TD50.

The dose-response relationship plays a very important role of a particular toxic agent requirement for specific use. For example, for use of insecticides or

PRINCIPLES OF TOXICOLOGY

2.13

pesticides, generally LD95 is used so that 95% of the insect population die. But when a toxicant is used for human health, it is LD0, i.e., no one die. Similarly, TD0 is used for human health. There are two types of dose-response relationship. 1. The individual dose-response relationship which is also known as graded response. Graded response means the measured effect is continuous or gradual over a range of doses. 2. A quantal dose-response relationship which characterises the distribution of intensity of the effect (response) to different doses in a population of individual organisms.

2.5.1

Graded, Dose-Response Relationship

The graded, dose-response relationship describes the response of an individual organism to varying doses of chemical. The graded responses can be observed in an organ or a issue preparation as well as in the whole organism. The sites of action in the organism generally known as receptor. Certain xenobiotics or chemicals could only bind to a particular site (receptor) of the organism and exert its toxic effects on those sites. The effects are due to the result of forming a specific complex between the receptor and the active chemical. The active chemical sometime is also called agonist. There are also many xenobiotics or chemicals which produce more than one toxic effect or biological effect because they have multiple target sites (receptors) in different tissues. Therefore, it is a complicated issue to observe the graded response in the whole organism. To avoid the complication to study the toxicity of a substance, isolated organ is considered. The graded, dose-response relationship for an isolated organ may be characterized as in Fig. 2.8.

Biological effect (% inhibition)

100 80 60 40 20 0 1

2

3

4

5

6

Dose (mg/kg)

Fig. 2.8

Graded, dose-response relationship.

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TOXICOLOGY

The measurable effect is directly proportional to the number of receptor sites occupied by the active chemicals. The maximum effect is observed when occupation of all receptor sites by an agonist occurs.

2.5.2 Quantal, Dose-Response Relationship (Frequency and Cumulative Response) The determination of toxicity of a substance through dose-response relationship in a population of individual organisms is called quantal, dose-response relationship. In toxicology, the quantal dose-response relationship is used extensively. In this dose-response relationship, all animals are randomly distributed over a number of groups. All animals in one group are administered with the same dose of a toxicant or xenobiotic and then in each group the dosage is gradually increased. For example, Number of groups of animals =

1, 2,

3,

Dosage of xenobiotic (mg/kg) = 0.5, 1, 1.05,

4,

5

......

2, 2.05

......

Now the number of animals which die or adversely are affected by toxicants within a particular period of time, 24 hrs, 48 hrs, 72 hrs, etc. are counted. If all animals of certain number of groups with certain dosages of substance were equally sensitive and remain alive, then that dose is called a threshold dose. Thus, Threshold dose is that below which all animals remain alive and above which all would die. Frequency, Quantal Dose-Response Relationship

Mortality frequency (%)

The more sensitive individuals which are generally less in number, die at a lower dose than the more resistant ones. Similarly, there are less number of animals which have very high resistant so die at higher dosages. But the larger number of animals respond to doses in intermediate between these two extremes. This can be observed from the frequency diagram (Fig. 2.9a). From the Figure 2.9a, it is evident that the maximum frequency of response occurred in the middle position of the dose range.

300 250 200 150 100 50 0 10

Fig. 2.9a

20

30

40 50 60 Dose (mg/kg)

70

80

Frequency-quantal, dose-response relationship.

PRINCIPLES OF TOXICOLOGY

2.15

The bell-shaped diagram is also known as normal frequency distribution. The animals responding at the left end of the curve are referred to as hypersensitive which have the high percentage of susceptibility to adverse effect, i.e., death. The animals at the right end of the curve are called resistant. Cumulative, Quantal Dose-Response Relationship

300 250 200 150 100

Thr esh dos old e

Cumulative mortality (%)

A cumulative, quantal dose-response relationship is obtained when the number of individuals responding at each consecutive doses are added together (for example, 1 + 1.5; 1 + 1.5 + 2; ... etc). In this process, when a sufficiently large quantity of doses are used with a large number of animals (organisms) per dose, the biological or toxic effects will be observed as in Fig. 2.9b.

50 0 1

Fig. 2.9b

2

3 4 5 Dose (mg/kg)

6

7

Cumulative-dose-response relationship curve.

The Figure 2.6b indicates that when the dose is below the threshold, the response is zero (0) per cent and it increases as the dose amount increases upto 100 per cent.

2.5.3

Homeostasis and Hormesis

Homeostasis refers to the dose-response relationship for essential nutrients in an individual organism. The essential elements which are required by organisms for their normal physiologic functions and survival, for example, vitamins, proteins, macro- and micronutrients, etc. These essential elements provide normal and internal stability of the organs in an organism that automatically compensate for environmental changes. It is also evident that at very low doses (concentration) of essential nutrients there is a high level of adverse effect which may cause death. As the doses increase, the adverse effect decreases to minimum point. This region of dose-response relationship for essential nutrients is commonly referred to as a deficiency. The region where the deficiency is no longer existing, no adverse response will be observed. At this point, the normal physiological circumstances, the integral building blocks of organs and tissues, are in equilibrium (homeostasis) with the surrounding internal environment. Then the organism is in the state of

2.16

TOXICOLOGY

homeostasis. From this point when the dose of essential nutrient increases (called overdose), an adverse effect is again observed which can be seen as the reverse graph of bell-shaped, i.e. graded, dose-response relationship in Fig. 2.10.

Biological effect

se ver Ad ffect e

e ers dv a for ncy) se do ficie d l ho (de res ct Th effe

se adver ld for dose) o h s e Thr ct (over effe

Region of equilibrium (homeostasis)

Deficiency

Fig. 2.10

se ver Ad ffect e

Dose

Toxicity

Graded dose-response relationship for essential nutrients (homeostasis).

Hormesis is the stimulatory effect of small doses of a potentially toxic substance that is inhibitory in larger doses. It means, toxicants, sometimes stimulate reproduction at low concentrations, rather than reduce it which is beneficial. But these substances produce adverse effects at higher doses. In plotting dose versus response over a wide range may also result in similar effect as homeostasis.

2.6

TOXIN EXPOSURE

Toxin exposure may be defined as the condition in which the toxicants or chemicals come into contact with an organism. Exposure of an organism to the toxicants in the environment of workplace is referred to as ambient exposure. The ambient exposure to a chemical that is absorbed, may be calculated as the amount of a chemical taken into the body of an organism. The exposure of substance may have certain consequences for the individual health. The toxic effects in a biological system due to exposure depend on the exposure concentration (C) and exposure time (t). The relation between toxicity and exposure concentration and exposure time may be expressed as: = =C´t = = toxicity which remains constant as long as concentration and time of exposure remains constant. This effect will also depend on the sensitivity of the exposed individual. By considering the logarithmic concentration effects, the above equation becomes

PRINCIPLES OF TOXICOLOGY

2.17

log = = log C + log t or

log C = log = – log t

Log (c) in (mg/l)

By plotting the graph exposure time vs. exposure concentration, we will get as in Fig. 2.11.

5

10 15 Log (t)

20 25 (in hr)

Fig. 2.11 The relationship between exposure time and exposure concentration.

After a short exposure to a high concentration immediate effects may occur, known as acute exposure. The long-term effects of relatively low exposure concentrations are known as chronic exposure. A very low effect may be observed for short-term exposure to low concentration of toxicants.

2.6.1 Routes and Sites of Exposure The major routes of accidental or intentional exposure to toxicants by humans and other animals through food, air and liquid which come into contact with skin (percutaneous route, topical or dermal), the lungs (inhalation, respiration or pulmonary route), gastrointestinal tract (ingestion) and the mouth (oral route). Generally, for exposure to any given concentration of a substance for a given time, inhalation is likely to cause more harm than ingestion which in turn will be more harmful than topical exposure. The toxic agents produce greatest effect and the most rapid response when the exposure occurs directly into an organ (lungs) or bloodstream (the intravenous route). The minor routes of exposure are rectal, vaginal, and parental (other than intestinal canal like intravenous or intramuscular). The way that a toxic substance is introduced into the complex system of an organism is strongly dependent upon the physical and chemical properties of the substance (Loomis, 1978). From the toxicological point of view, it is always important to understand by which route a substance has entered the body because the route of administration can influence the toxicity of the xenobiotics. For example, if the absorption rate of the toxicant is slower than the rate of excretion or elimination of toxicants, the

2.18

TOXICOLOGY

toxic effects will be much lower. An approximate descending order of effectiveness for different routes would be as follows: Inhalation > intraperitoneal > subcutaneous > intramuscular > intradermal > oral > dermal. The uptake of toxicants via the lungs, intravenous, or skin, the substance enters directly into blood circulation so toxic effect is more. After oral ingestion, the substance first transported to the liver with its many biotransformation pathways. These can lead to products that are more or less toxic. Skin (Percutaneous or Dermal Exposure)

Some lipophilic substances (easily soluble in fats) can enter the skin epidermal cells, sebaceous gland cells as the intact skin is relatively inaccessible to watersoluble substances. For example, the chemicals that are absorbed through the skin are trichloroethylene, perchloroethylene, aniline, hydrogen cyanide, nitrobenzene, organophosphate compounds, phenol, nicotine and strychnine compounds. OH N N Phenol

CH3

Nicotine

Most cases of exposure through skin are occupational. Pulmonary (Inhalation) Exposure

The major site of entry for numerous toxicants is the pulmonary system. Gases and vapours are easily inhaled depending on the shape and size of the inhaled particles. The major function of lungs is to exchange gases between the circulation and the air in the lungs. Gas exchange occurs in a vast number of alveoli in the lungs where a tissue, the thickness of only one cell, separates blood from air. The smaller particles of toxicants enter into the respiratory tract. But the particles of 0.5 to 7 mm can persist on the alveoli and respiratory bronchioles after deposition. The effective toxicant particle size varies from 0.1 to 2 mm which directly enter into the respiratory tract to bypass organs that have the screening effect. For example, liver is the greatest screening organ of the body which detoxifies the toxicants to a large extent. The particles which enter into the body through respiratory tract can enter the bloodstream directly. Then these particles have greater toxic effects. A significant portion of inhaled dust consists of microorganisms. Thus, there is a possibility of bacterial infection. But the macrophage cells in the lung that normally remove the bacteria and organic matter in the insoluble form from the body. This is known as phagocytosis.

PRINCIPLES OF TOXICOLOGY

2.19

Gastrointestinal (Ingestion) Exposure

Many potentially toxic substances enter in our body through ingestion process. The important organs of this system are mouth, esophagus and stomach. Through food or water, a chemical may accumulate in the body if absorption exceeds excretion. These chemicals may combine with other substances in the body to make it more toxic. Many substances that combine fairly high degree of lipid solubility with chemical stability produce more toxic effects.

2.6.2 Duration and Frequency of Exposure Based on the duration and frequency of exposure, the exposure process is divided into four categories such as • Acute exposure • Subacute exposure • Chronic exposure • Subchronic exposure • Acute exposure: The acute exposure is defined as the exposure of an organism to a toxicant for less than 24 hours. In this exposure, the routes of exposure are intravenous, subcutaneous injection, extraperitoneal, oral intubation and dermal. Generally, acute exposure refers to single administration of toxicant with a high concentration for less than 24 hours. • Subacute exposure: The subacute exposure is defined as the repeated exposure of a toxicant for longer period of about 1 month or less. • Chronic exposure: The chronic exposure is defined as the repeated exposure of a toxicant for longer period (more than three months). • Subchronic exposure: The subchronic exposure is defined as the repeated exposure of a toxicant for a comparatively less period of time than chronic exposure, i.e., 1 to 3 months. The acute exposure to an organism produces immediate toxic effects but the chronic exposure produces long-term effects even on low concentration of the toxicants. The production of toxic effects of a toxicant depends on the frequency of exposure rather than the duration of exposure. For example, it is possible that the affected tissue or cell may get sufficient time to recover fully after exposure, i.e., the frequency of exposure is very less. In this case, there will be no much toxic effects. If exposure is repeated then the cell or tissue may not get time to recover. Therefore, it has more toxic effect even in small concentration as these toxicants get accumulated. Here the rate of absorption exceeds the rate of elimination.

2.20

TOXICOLOGY

2.6.3 Form of Exposure The occurrence and magnitude of toxic effects in biological system depend on the form of the toxicant (chemical) in which an organism is exposed to that toxicant. The form of toxicant depends on the physico-chemical properties of that toxicant. If the toxicant is very stable, then it produces less toxic effects. If the chemical substance is unstable, it undergoes biochemical reaction, i.e., biotransformation products which reach at appropriate sites in the body to produce larger toxic effects.

2.7 PHYSICO-CHEMICAL SPECIATION IN RELATION TO EXPOSURE Different physico-chemical forms of many elements may exist in the environment. The total concentrations of the elements alone cannot explain the transport, behaviour, effects and fate of such elements in the environmental system including air, water, soil and biological system. So the term “speciation” has become widely accepted to describe the distribution of an element between different physico-chemical forms or a “species”. Thus, the immediate and longterm effects of a chemical substance to a biological system are influenced by its speciation. The detection and determination of the different forms of a chemical substance are quite essential to establish their influence on various ecosystems and also to monitor and control the pathways by which they reach the biosphere. Every element is capable of forming at least a few molecular species. An element may occur just as a single molecular species or more molecular species on the environment depending on environmental conditions. If more species of an element are present, then the different species are competitive in nature, i.e., the concentration of one of them may be higher than the concentration of the others. The total concentration of the element can be used to assess its environmental impact only if it is present in the environment as a single species. However, it is quite difficult to identify individual species and quantify them in the environment. In speculation analysis, covalently bound elements are considered species in its classical meaning. The elements like cadmium, copper, zinc, nickel. Chromium, antimony, arsenic, selenium, tin and lead are species of classical meaning. Mercury is having special properties. The organic species of mercury are more toxic than the inorganic ones. Mercury is the only one which forms insoluble (Hg S), soluble (Hg + + ) and volatile compounds (Hg 0 ). Thus, it is considered the most toxic element. The dynamic species can change their form from one form (ionic) to other forms. For example, ionic mercury can change its form very quickly to volatile species under environmental conditions with the influence of bacteria (Ebinghaus et al. 1994).

PRINCIPLES OF TOXICOLOGY

2.8

2.21

QUANTITATIVE ASPECTS OF EXPOSURE

The quantitative exposure refers to the amount of toxicants or xenobiotics which are accessible for an organism to be exposed through different routes of exposure. To explain the quantitative exposure different terminologies are used. Stating from the source of the exposure of the toxicants to the organisms are as follows: • Emission: Emission is a process in which chemical substances (toxicants) are released or discharged into the environment which includes air, water, soil and biosphere. Emission is usually expressed as weight per unit time. • Transmission: After emission of the toxicants, transmission process takes place which refers to the dispersion of toxicants into the environment. In the transmission process, the toxicants from the source of origin to the exposed organism, undergo various physico-chemical, biochemical breakdowns or transformation. One part of the substances are available for exposure and other part may deposit in the soil or water sediments due to their stability which is called deposition. • Deposition: Deposition is the amount of toxic elements or substances are deposited on the soil or water sediment after going minimum physicochemical or biochemical transformation. Deposition is expressed as weight per unit surface area per unit time.

2.8.1

Quantitative Exposure-Response Relationship

In general, quantitative exposure-response relationship is related to the extent and duration of exposure which in turn determines the severity of the toxic effect of a toxicant. The larger the extent and the longer the duration of exposure, the greater is the percentage of toxic effects (response) which is known as quantitative exposure-response relationship. The severity of the toxic effects on an organism depends on the characteristics of individual. For example, the toxic effects will be more for highly sensitive species than the less sensitive species to that toxicants.

2.9 INTERACTIVE EFFECTS OF TOXICANTS In the natural environment, organisms are frequently exposed to a large number of different chemicals or xenobiotics. Thus, it is necessary to assess the spectrum of responses, to consider how different chemicals may react with each other. The toxic effects of xenobiotic-metabolites can cause either an increase or decrease in toxicity. The toxic effects of various chemicals because of chemical interactions such as absorption, protein binding, and biotransformation may be observed as: • Additive effect • Synergistic effect. • Antagonistic effect. • Potentiation.

2.22

TOXICOLOGY

2.9.1

Additive Effect

Additive effects of two toxic chemicals may be additive of their individual responses on the organism. The combined effect of two toxic chemicals is equal to the sum of the effects of each toxic chemical (e.g. 1 + 1 = 2). The additive effects are generally observed when only two chemicals are simultaneously administered into an organism. For example, administration of two organophosphate insecticides together, the effect, cholinesterase inhibition is usually additive.

2.9.2 Synergistic Effect In synergistic effect, the combined effects of two chemicals are much greater than the sum of the effects of each toxic chemical (e.g. 1 + 1 > 2). For example, piperonyl butoxide, sesamex and related compounds increase the toxicity of insecticides to insects by inhibition of the insect monooxygenase system. Similarly, carbon tetrachloride and ethanol are hepatotoxic compounds, but together they produce more impact, i.e., more liver injury than the mathematical sum of their individual effects on liver at a given dose. The effectiveness of a synergist is usually measured by synergistic ratio (S.R.) as: S.R. =

Median lethal dose or concentration for chemical alone Median lethal dose or concentration for chemical + synergist.

2.9.3 Antagonistic Effect In antagonistic effect, the toxicity of two or more toxins administered together is less than that would be expected from a consideration of their toxicities when administered individually (e.g. 1 + 1 < 2). There are four types of antagonism such as: functional, chemical, dispositional and receptor. Functional antagonism Functional antagonism is observed when two chemicals counterbalance each other by producing opposite effects on the same organism so that the toxic effect is minimized. Chemical antagonism It is a simple chemical reaction between two compounds that produces a less toxic product, thus decreases their toxicity. For example, the strongly basic low-molecular weight protein protamine sulphate is used to form a stable complex with heparin which diminishes its anticoagulant activity. Similarly, dimercaprol forms chelating compounds with metal ions such as arsenic, mercury and lead to decrease their toxic effects. Dispositional antagonism It occurs when disposition (absorption, dilution, distribution, elimination or biotransformation) of a chemical is altered so that its concentration or dose and duration of the chemical to a target organ are reduced. Thus, toxic effect is minimized. For example, the pH value of urine is altered to reduce the acidic or basic value. Thus, toxic effect is minimised.

PRINCIPLES OF TOXICOLOGY

2.23

Receptor antagonism In receptor antagonism, two chemicals bind to same receptor produce less effect when given together than the addition of their individual effects. For example, antiestrogen drug tamoxifen to lower breast cancer risk in women. Tamoxifen competitively blocks estradiol from binding to its receptor.

2.9.4 Potentiation Potentiation refers to the toxic substances that do not have a toxic effect on a certain organ or system but when added to another chemical makes that chemical much more toxic. (0 + 1 > 1). For example, isopropanol is not hepatotoxic but when it is administered in addition to carbon tetrachloride, the hepatotoxicity of carbon tetrachloride is much greater than when it is given separately.

EXERCISE 1. What is mechanistic toxicology? Explain it. 2. Define the toxicokinetics. What are the different models used to describe the behaviour of a toxicokinetic in the body? 3. Discuss about the two-compartment model for the toxicokinetic in the body. 4. Write short notes on (a) Descriptive toxicology (b) Regulatory toxicology 5. What is toxicodynamics? Explain it. 6. What is dose-response concept? Write the significance of dose-response relationship. 7. Define the terms (a) Agonist (b) Receptor (c) Threshold dose 8. Differentiate between (a) Homeostasis and Hormesis.

(b) Acute and chronic exposure. (c) Additive and synergistic. 9. What are the different routes and sites of exposure of toxicants onto the body? 10. What are the interactive effects of toxicants in an organism?

CHAPTER

!

Fundamentals of Chemistry 3.1

ATOMIC STRUCTURE

An atom is the smallest particle of an element that can take part in chemical reaction. It cannot be further divided. Atom consists of much smaller fundamental particles—nucleus, proton and electron. Nucleus contains all the protons and neutrons. Protons (11P) are positively charged but the neutrons do not carry any charge and having the mass almost equal to (10n) that of a proton. Electrons are extremely small but negatively charged particles (01e.). The atom as a whole is a neutral one, i.e. the atom has equal number of protons and electrons. The electrons revolve around the nucleus. Atomic number of an element is defined as the number of unit positive charge on the nucleus. Atomic number = number of protons or = number of electrons Mosleys’ law states that both physical and chemical properties of an element depend on atomic number only. The elements in the periodic table are arranged in the increasing order of atomic number rather than their mass.

3.1.1 Quantum Theory of Radiation Planck’s quantum theory of radiation states that a black body emits or absorbs the energy such as light and heat not continuously but in whole number of small packet of energy called a quantum. The energy of each quantum is expressed as: E = hu E=

hC l

(\ u =

C ) l

...(1)

3.2

TOXICOLOGY

h = Plank’s constant (h = 6.62 ´ 10–27 erg-sec) C = velocity of light l = wavelength (in cm) u = frequency of radiation. The greater the frequency, the greater is the energy of the radiation. When the light of a certain minimum frequency strikes the surface of a metal, electrons are ejected from the metal. This is known as photoelectric effect. The minimum frequency to eject the electrons known as threshold frequency. The increase in intensity of light of a given frequency increases the number of photons only but not their energy. If the frequency of a light higher than the threshold frequency strikes on metal surface, the additional energy will increase the velocity (kinetic energy) of the ejected electron. Light has dual nature i.e. wave as well as particle in nature. It can be expressed as: E = hK (wave nature as it has frequency). E = mc2 (Particle nature as it has mass—Einstein theory) de Broglie gave the relationship between the wavelength, mass and velocity of moving particle as: where,

l=

h mn

(mn = momentum)

According to Planck’s quantum theory According to Einstein theory Then or

...(2) hc l E = mc2

E=

mc2 =

hc l

or mc =

h l

l=

h mc

(c is the velocity of light when its particle velocity is K)

l=

h h = mn p

\ P = momentum of particle

(de Broglie is only significant in case of very small particle.)

3.1.2 Quantum Numbers The quantum numbers are the identification numbers for an individual electron in an atom. These are four types—principal quantum numbers, azimuthal quantum numbers, magnetic quantum numbers and spin quantum numbers. All these quantum numbers completely describe the position and energy of an electron in an atom.

FUNDAMENTALS OF CHEMISTRY

3.3

Principal quantum numbers (n) represent the main energy level or principal shell to which an electron belongs. The principal quantum number represents as: Main energy level (n) = 1, 2, 3, 4, ... Principal shell = K, L, M, N, ... The maximum numbers of electrons in a principal shell is 2n2. Azimuthal quantum numbers (l) is the angular quantum number and it refers to the shape of an orbital. Its permitted values for a given value of principal quantum number (n) are l = 0, 1, 2, 3, ... (n – 2) (n – 1). orbitals = s, p, d, f, ... (s = sharp, p = principal, d = diffuse, f = fundamental) Magnetic quantum numbers (m) describe the orientation of different orbitals, i.e. it gives an idea of total sub-sub shell present in the orbital. Its permitted values are m = ±l. for example, l = 1, which represents P, m value will be –1, 0, +1. Thus P orbital has three subshells. Spin quantum numbers (s) describe the spining of an electron in its orbit. Its permitted values are s = ±1/2. Maximum number of electrons in subshell is 2(2l + 1), if, for example, l = 2 represents d orbital. The maximum number in d orbital is 2(2 ´ 2 + 1) = 10.

3.1.3 Electronic Configurations The electronic configurations refer to distribution of electrons in various shells, subshells, and orbitals of an atom. The rules for writing electronic configuration of a given atom are: An atom in its lowest energy state is called ground state which is the most stable state and the distribution of electrons takes place in the ground state. • Electrons enter the orbital with lower energy first and then the orbitals of higher energy will be filled i.e. the electrons enter the various orbitals in the increasing order of energy. This is known an Aufbau principle. • (n + l ) rule states that the orbital having the lowest value of (n + l) has the lowest energy, thus, should be filled first. In case of more than one orbital have the same (n + l) value, the orbital with lower value of ‘n’ will be filled first. For example, 3d ® (n + l) = (3 + 2) = 51 4p ® (n + l) = (4 + 1) = 5 5s ® (n + l) = (5 + 0) = 5 In this case 3d will be filled first, then 4p followed by 5s.

3.4

TOXICOLOGY

• Hund’s rule of maximum multiplicity states that electron pairing in any orbital is impossible until all the available orbitals of a given set have at least one electron each. • Pauli exclusion principle states that an orbital cannot contain more than two electrons. It is impossible for any two electrons in the same atom to have all the four quantum numbers identical. At least they will differ in spin quantum number as either +1/2 or –1/2. • Electrons prefer to enter those orbitals where they can get either completely filled or exactly half-filled.

3.2

PERIODIC TABLE AND PERIODIC PROPERTIES OF AN ELECTRON

Mosley formulates the modern periodic law as “the properties (both physical and chemical) of an element are periodic function of their atomic numbers”. Based on this rule, Bhor’s periodic table is most acceptable and widely used. The long form of periodic table is studied in groups and periods.

Groups The vertical columns in the periodic table are called groups. The total number of groups in the periodic table is 16. (i) IA, IIA, IIIA, IVA, VA, VIA, and VIIA groups. The elements of these seven (7) groups are called normal elements. The outermost shell of these elements is partly filled (ns1 to ns2 p5 ) while the inner shells are completely filled. (ii) The elements of IB, IIB, IIIB, IVB, VB, VIB, and VIIB groups are known as transition elements in which two outermost shells [nth and (n – 1)th] are partly filled while the remaining inner shells are completely filled. All these elements are metals. (iii) VIII group has three columns. (iv) In Zero group all shells are completely filled. Elements of this group are called noble gases. (v) Two groups of 14 elements in group IIIB viz. (Ce to Lu) and (Th to Lw) have their three outermost shells incomplete. These are called lanthanides and actinides, respectively.

Periods Periods are the horizontal rows in the periodic table. There are total 7 periods in the table. The first period contains two elements while second and third periods have eight elements each. The fourth and fifth periods have eighteen elements each. Sixth period has thirty-two elements and seventh period has nineteen elements. The seventh period elements are all radioactive elements.

FUNDAMENTALS OF CHEMISTRY

3.5

3.2.1 Classification of Elements in the Periodic Table Based on their Electronic Configurations The elements in the periodic table are divided into four types depending on the nature of the atomic orbital into which the last electron enters. This is called differentiating electron. s-block elements: In these elements the last electron enters the s-orbital of the outermost shell (ns) which is being progressively filled. p-block elements: The elements in which p-orbitals are being progressively filled called p-block elements. d-block elements: In these elements, the differentiating electron enters the (n – 1)th d-orbital of (n – 1)th main shell are called d-block elements. These elements are also called transition elements. f-block elements (Inner transition elements): In these elements, the differentiating electron enters the (n – 2)th orbitals of the (n – 2)th main shell.

3.2.2

Periodic Properties

In the periodic table, there is a gradual increase or decrease in a particular property of an element with the increase of atomic number of the elements in the same period or group. Some important properties are discussed below: Atomic and Ionic Radii

The atomic or ionic radius is usually considered the distance from the centre of the nucleus to the outermost shell electrons of an atomic or ionic particle. The atomic and ionic radii are the function of their atomic number. (i) The atomic and ionic radii both decrease with the increase of atomic number in the same period because the electrons are added into the same main energy level. (ii) The atomic and ionic radii both increase with the increase of atomic number in the same group (moving down in the graph) as the electrons are added to higher main energy level so that they are further away from the nucleus. But simultaneously nuclear charge also increases to increase the electrostatic force of attraction between nucleus and electrons. But the net result is that the former one predominates. Iso-electronic species are those which have the same number of electrons. In these cases size decreases with increase in atomic number. For example, C4–, N3–, O2– ® 10 electrons each—iso-electronic size O2– > N3– > C4–. The size of cation is smaller than of its parent atom while the size of anion is greater than that of its parent atom.

3.6

TOXICOLOGY

Ionization Potential

Ionization potential is the amount of energy required to remove the outermost electron from an isolated gaseous atom of an element in its lowest energy state to produce a cation. Ionisation M(g) (gaseous atom) + Energy

+

M (g) + e

–

(It is an endothermic reaction)

The energy required to remove first and second electron known as first and second ionization potential, respectively. The increasing order of ionization potential is I1 < I2 < I3 < I4 < I5 < ...... • The ionization potential increases with the increase in atomic number in the same period because in the same direction size of the atom decreases and nuclear charge increases. The completely and exactly half-filled orbitals have greater ionization potential energy. The decreasing order of ionization potential in the orbitals and period is: (i) s > p > d > f (ii) Ne > f > O > N > C > B > Be > Li • Ionization potential decreases with the increase in atomic number in the group (moving down in a group) as the size of atom increases. Screening effect increases on moving down the group. Decreasing order of ionization potential in a group is Be > Mg > Ca > Sr > Ba. Screening effect is defined as the decrease in the attractive force exerted by the nucleus on the outermost shell electron due to the presence of the electrons in between the nucleus and outermost shell electrons (Fig. 3.1). Attraction +

–

A

Outermost shell elements

Repulsion Inner shell elements

Nucleus

Fig. 3.1

Screening effect in atom.

• Higher the principal quantum number (n) lower is the ionization potential energy. The principal quantum number increases in moving down the group.

FUNDAMENTALS OF CHEMISTRY

3.7

Electron Affinity

Electron affinity of an element is defined as the amount of energy released in adding an electron to the outermost shell of an isolated gaseous atom at its ground state to make it an anion. This is an exothermic reaction. Mg + e– ® M– (g) + energy (first electron affinity) In case of second electron affinity, energy is required to add an electron into the first electron affinity ion. Energy

M–(g) + e–(g) + ¾ ¾¾® M2– (g) (second electron affinity) The second electron affinity is an endothermic reaction. • The electron affinity increases with the increase of atomic number in the same period (moving left to right) as the size of the atom decreases in the same period. • The electron affinity decreases in moving down the group. Electronegativity

The electronegativity of a bonded atom is defined as its relative tendency to attract the shared electron pair towards itself. Electronegativity increases in the same period moving left to right and it decreases in moving down in the same group. • The acidic character of the normal oxides of the elements goes on increasing in the period and it decreases in moving down the group because the higher the electronegativity, the greater is the acidic value and lower is the basic value. • Higher the electronegative value, lower is the metallic value. Thus, the metallic character decreases and non-metallic character of an element increases in moving from left to right in the same period. Whereas the metallic character increases on moving down the group.

3.3

CHEMICAL BONDING

At ordinary temperatures atoms are rarely capable of free existence. Atoms combine together to form molecules which are more stable and have a lower energy than the individual atom. The attraction between atoms within a molecule is called chemical bond. The formation of a chemical bond is possible because of the following reasons:

Attainment of a Stable Configuration The atoms of noble gases do not normally react because of their maximum stability and minimum energy. The atoms of noble gases have a stable configuration of 8 electrons in the outermost shell called an Octet. Only electrons

3.8

TOXICOLOGY

in the outermost shell of an atom are involved in forming bonds, and by forming bonds each atom acquires a stable electronic configuration either by the process of losing, gaining or sharing of electrons.

Lowering of Energy of Combining Atoms In the formation of each kind of bond there is invariably a lowering of potential energy of the system. When the atoms approach toward one another, (i) if the net result is attraction, the total energy of the system decreases and a chemical bond is formed (ii) if the result is repulsion, the total energy of the system increases and no chemical bonding is possible.

Net Attractive Force Between Atoms Atoms consist of positively charged nucleus and negative electrons. When atoms approach toward each other to form a bond between them, the attractive (due to nucleus and the electrons of opposite atoms) and repulsive force (due to nucleus or electrons of opposite atoms) come into existence between them. If the net result is attractive then bond formation is possible and if net result is repulsive no bond formation is possible, e.g. molecules of all noble gases are monoatomic.

3.3.1 Types of Bond A chemical bond is formed by the approachment of two or more atoms through redistribution of electrons in their outer shells in three ways: by losing electrons, by gaining electrons or by sharing electrons, depending on the nature of atoms of the elements. The resulting chemical bonds are of the three ideal types, namely (i) Ionic or electrovalent bond (Electropositive element + electronegative elements) (ii) Covalent bond (Electronegative elements + electronegative elements) (iii) Metallic bond (Electropositive element + electropositive element) There are some other chemical bonds which are formed like (a) coordinate or dative bond, (b) hydrogen bond and (c) van der Waals bond. Ionic or Electrovalent Bond

An ionic bond is formed as a result of complete transfer of one or more electrons from one electropositive atom to an electronegative atom. The resulting positive and negative ions are held together by electrostatic force of attraction with low potential energy of the system. The number of electrons transferred to acquire the stable configuration in the outer shell is known as electrovalency.

FUNDAMENTALS OF CHEMISTRY

Example: (a) Na (2, 8, 1) .

Na+ + e– (2, 8) +

Cl + e– (2, 8, 7)

;

3.9

Cl– (2, 8, 8)

–

:

Na + : Cl : ® Na (Cl ) ® NaCl

Mg+2 + 2e– (2, 8)

Mg (2, 8, 2) .

(b)

®

Mg

: :

Mg + : Cl :

+2

–

(Cl )

®

MgCl2

–

(Cl )

:

. Cl : Characteristics of Ionic Compounds

The significant features of the ionic compounds are as follows: (a) The compounds are the result of electrostatic force of attraction. (b) These compounds are polar, so soluble in polar solvents (H2O, NH3, etc.) and insoluble in non-polar solvents (C6H6, CCl4, etc.). (c) These compounds are ionizable in solution or in fused state. (d) The polar linkages are non-directional. (e) These are good conductors of electricity. (f) They possess high melting points and boiling points. Conditions for the Formation of Ionic Compounds

The three important factors are mainly responsible for the formation of ionic bonds between electropositive and electronegative elements. (i) The electropositive elements should have low ionization energy. Ionization potential or ionization energy is the amount of energy required to remove the most loosely bound electron from and isolated gaseous atoms of an element in its ground state. Formation of Cation: C(g) + Ionisation energy ® C + (g) + e– The lower the ionization potential energy the easier is the formation of cation. These are electropositive elements such as alkali metals or alkaline earth metals. (ii) The electron affinity of the electronegative atoms should be high. The electron affinity is the amount of energy released when an electron is added to an isolated neutral gaseous atom in its ground state to produce an anion.

3.10

TOXICOLOGY

Formation of anion: A ® A– Cl(g) + e– ® Cl– (g) + electron affinity energy The greater is the electron affinity value, the easier will be the formation of anion. These are electronegative elements such as halogens or VIIA group elements. (iii) The lattice energy of the ionic compound formed should be high. C+ (g) + A–(g) ® CA + lattice energy The higher the value of lattice energy of the resulting ionic compound, the easier is its formation. Covalent Bond

Chlorine atoms

:

: Cl × × Cl : :

®

:

:

: Cl × + × Cl :

:

:

:

:

When the electronegative atoms approach each other they share their electrons so as to attain a noble gas configuration. Neither of the atom has tendency to lose electrons.

Chlorine molecule

The Lewis theory was the first explanation of a covalent bond known as Octet theory. This theory states that in chemical combination atoms tend to attain the stable electronic configuration of the nearest noble gas by sharing one or more electron pairs between two atoms (except some exception). Since bond is formed by sharing of electrons, a covalent bond is non-polar and non-ionized. :

:

×

Cl :

:

×

(i) × Cl × + 4(× Cl :) ® Cl : C : Cl Single bond

:

(ii) : O : + : O : ® O (iii) : N M + M N : ® : N

:

O Double bond :

:

:

:

Cl

N : Triple bond

Thus, covalent bond may be single, double or triple bond. The factors influencing the covalent bond formation are: (i) High ionization energy of the atoms, so that they will not be able to form ionic bond. (ii) Equal electron affinities, so that no atom will have a tendency to lose electrons but they can share the electron pairs.

FUNDAMENTALS OF CHEMISTRY

3.11

(iii) Equal electronegativity. Characteristics of covalent compounds: (i) They are soluble in non-polar solvent. (ii) The covalent bond is directional so that stereoisomerism is possible. (iii) Covalent compounds are generally soft, easily fusible and volatile. (iv) They will have low melting and boiling point. (v) They are not good conductors of electricity. Coordinate or Dative Bond

A covalent bond is formed by the mutual sharing of two electrons both of which are contributed by only one of the combining atoms. This bond is called coordinate covalent bond. They differ from normal covalent bonds only in the way they are formed, and once formed, they are identical to normal covalent bonds as shown below: —

—

—

—

: :

H

F

H

F

—

H—N®H

:

—

:

+

H : N : + [H] ® H

H

:

:

F

–

—

:F:+:B:F ®

F

F—B®F

—

:

:

F (iii)

+

H

H (ii)

F

H:N:+B:F ® H—N®B—F

:

(i)

H

F

:

H

F

Due to unequal sharing, one atom becomes partially positive and the other becomes negative, thus coordinate linkage is a semipolar. Conditions for the formation of a coordinate bond: (i) In coordinate covalent compounds the donor atom should have a lone pair of electrons (ii) Acceptor atoms should have a vacant orbital to accommodate the donor electron pairs. Characteristics of coordinate compounds: Coordinate compounds exhibit intermediate characteristics of covalent and ionic compounds but somehow they are more similar to covalent compounds.

3.12

TOXICOLOGY

(a) They are sparingly soluble in polar solvents and soluble in non-polar solvents. (b) They do not ionize water and are poor conductors of electricity. (c) Coordinate linkage is directional as well as rigid. It can also exhibit space isomerism (orientation). (d) Possess intermediate melting points and boiling points of covalent and ionic compounds. (e) The acceptor and donor atoms have independent identities. Hydrogen Bond

In some compounds a hydrogen atom is attracted by strong forces of two atoms. The hydrogen bond is regarded as a weak electrostatic force of attraction. Thus, the hydrogen bond is the attractive force that binds a hydrogen atom, which is already attached with a strongly electronegative atom of a molecule, with an another electronegative atom of some other molecule, e.g. (i) –d +d –d +d A—H B—H Then the existence of hydrogen bond between A—H and B—H molecules like A — H ......... B — H Here H-atom acts as a bridge between the electronegative atoms A and B. (ii)

3.4

...... H — F ......... H — F ......... H — F .......

ACIDS, BASES AND SALTS

According to Lowry and Bronsted (1923) concept of acid base, an acid is defined as a substance which has a tendency to lose proton (H+) and the base is a substance which has a tendency to gain a proton. Thus, an acid is a proton donor and a base is a proton acceptor. For example, (i)

(ii)

A HCl Acid NH3 + H+ HCO3– + H+ Base + Proton

H+ + B H+ + Cl– Acid Proton + Conjugate base NH4+ H2CO3 Conjugate acid

A strong acid reacts with a strong base to produce a weak acid and weak base. But the strong acid and weak base form one conjugate acid-base pair and weak acid and strong base form another conjugate acid-base pair.

FUNDAMENTALS OF CHEMISTRY

3.13

Conjugate Acid-Base Pair Strong Acid + Strong Base + Weak Acid + Weak Base – + HCl H2O H3O Cl Conjugate Acid-Base Pair

The strong acids and strong bases are considered to be 100% ionized or dissociated in a solvent. An acid is a solute that either by direct dissociation or by reaction with the solvent gives the anionic character to the solvent whereas base is a solute which gives cationic character to the solvent on reaction. For example, (i) NH3 + H2O ® NH4+ + OH– (ii) HSO4– + H2O ® H3O+ + SO4– (iii) H2O + H2O ® H3O+ + OH– Acid Base Acid Base From the equations (i) and (ii) it is evident that water behaves as an acid as well as base. From equation (iii) it is found that all those compounds which produce H3O+ ions in H2O are acids and those produce OH– ions in H2O are bases. In Lewis system, an acid is an electron pair acceptor and base is an electron pair donor.

3.4.1 Ionization of Acids and Bases The strong acids and bases are completely dissociated thus dissociation constant value is very high. e.g. HA H+ + A– Ka =

[H + ][A – ] [ HA]

In this [HA] is very less or almost negligible, since there will be no undissociated acid in solution. However, the weak acids and bases are partially dissociated, thus equilibrium relationship between the dissociated and undissociated acids or bases existed as: HAc H+ + Ac– (weak acid) KA = In case of base

BOH KB =

[H + ][A – ] [ HAc]

B+ + OH– [B+ ][OH – ] [ BOH]

in terms of concentration

3.14

TOXICOLOGY

In case of polybasic acids there are more than one ionisation stages, thus more than one dissociation constants are obtained, for example, H2CO3

H+ + HCO3–

KA1 =

[A + ][ HCO 3- ] [ H 2 CO3 ]

HCO3–

H+ + CO2– 3

KA2 =

[ H + ] [CO 23 - ] [ HCO 3– ]

3.4.2 Common Ion Effects The common ion effect states that the presence of a common ion with one of those produced by dissociation will suppress the dissociation reaction i.e. the reaction will move toward reactant side. H+ + Ac–

HAc

KA =

[A + ][Ac - ] [ HAc]

If the solution already contains either {H+} or {Ac–} ions then dissociation will be less.

3.4.3 Solubility Product The solubility product of a sparingly soluble salt is the product of ions in the solution. For example, Ag+ + Cl–

AgCl

LS = CAg+ ´ CCl– where Ls = Solubility product. Solubility product of a sparingly soluble salt is constant. Ca3(PO4)2 = 3Ca++ + 2PO4-LS = C3Ca++ ´ C2PO-4 Solubility of a sparingly soluble salt is defined as g moles of the solute present in one liter of solution. It is expressed in g moles per liter. S represents the solubility. Then

CAg+ = S LS = S

CCl– = S 2

Ca3(PO4)2 Ca

++

C3Ca++C2PO4--

(Assuming it is completely soluble) ++

3Ca = 3S

+ 2PO4-PO4-- = 2S 3

= LS = (3S) ´ (2S)2 = 27S3 ´ 4S2 = 108S5

FUNDAMENTALS OF CHEMISTRY

3.4.4

3.15

Salts

The salts are formed in four different ways and the solutions of these salts are not neutral but depends on how it is formed. For example,1s Salts (ways of formation)

Solutions on hydrolysis

Strong acid + weak base

Acidic in nature

Strong base + weak acid

Basic in nature

Weak acid + weak base

Depends on pH value

Strong acid + strong base

No hydrolysis reaction as they are

completely dissociated. pH is defined as the negative logarithm of H+ ion concentration. pH = –log CH+ In pure water (neutral) = CH+ = COH– = 10–7 pH of neutral water is 7. pH > 7, the value is basic. pH < 7, the value is acidic. pH = 7, the value is neutral.

3.5

THERMODYNAMICS

Thermodynamics concerns with the flow of heat and it deals with the relations between heat and mechanical energy (work). It governs not only the transformation of heat into work and vice versa but also includes all kinds of interconversion of one kind of energy into another. Thermodynamics is based on three empirical laws and nothing contrary to these laws will ever be known. Most of the important laws of physical chemistry, including van’t Hoff law of dilute solutions, Raoult’s law of vapour pressure lowering, distribution law, law of chemical equilibrium, the phase rule and the laws of thermochemistry can be deduced from the laws of thermodynamics. The laws of thermodynamics cannot be applied to the individual atoms or molecules. Before we begin with the laws of thermodynamics it is necessary to define some of the terms most commonly used in thermodynamic discussions.

3.5.1

Terminology of Thermodynamics

Work, Heat and Energy

Work, heat and energy are the basic concepts of thermodynamics, and of these concepts the most fundamental is work. Whenever a system changes from one state to another, it is accompanied by energy change. The change in energy may appear in the form of mechanical work, heat, etc. Thus, thermodynamics is

3.16

TOXICOLOGY

concerned with energy changes that accompany a process. A process may be a simple change of state (such as expansion or cooling), a change in physical state (such as melting or freezing), or a complex chemical change in which new substances are produced. Work: A mechanical work is done whenever the application of a force causes a displacement of a system and the magnitude of the work is measured by the product of the force and the displacement. Then, W = F ´ DS, where F is the force and DS is the displacement. The usual convention in thermodynamics is that the work done by a system is positive, whereas the work done on the system is negative. Heat: Heat is an another form of energy which is different from other forms such as electrical, chemical, etc., because all other forms of energy can be completely transformed into work but heat cannot be wholly converted into work. Any attempt to convert the whole quantity of heat would affect a permanent change in the system or the neighbouring systems. Heat always flows from a region of higher temperature to a region of lower temperature. Hence, heat is energy in transit. Energy: The energy of a system is its capacity to do work. When the system does work, its energy is reduced because it can do less work than before, so it is negative. But when work done on the system, its capacity to do work is increased and thus the energy of a system is increased (positive). The process that releases energy as heat is called exothermic and the process that absorbs energy as heat is called endothermic. Energy should, therefore, be defined as a property which can be transformed into or produced from work. Thermodynamic System

For the purpose of physical chemistry, the universe is divided in two parts, the system and its surrounding. The thermodynamic system may be homogeneous (contains one phase or one kind of matter) or heterogeneous (contains more than one phase, or more kinds of matter). (i) Diathermal walls: These walls are the boundary walls of a system which allow the transition of heat or matter through them, into or out of the system. (ii) Adiabatic walls: These walls do not permit any heat or matter to enter into the system or to come out of the system. (iii) Isolated system: The system wholly enclosed by adiabatic walls is called an isolated system. (iv) Closed system: In this system energy exchange with the surrounding is possible but transfer of matter is not permitted. (v) Open system: In this system exchanging of both matter and energy with the surroundings is possible. (vi) Surroundings: The surroundings are where we make our observations.

FUNDAMENTALS OF CHEMISTRY

3.17

Surrounding is the rest of the universe around the system. The system and surroundings are separated by a boundary, and to specify these two parts we need to specify the boundary between them, through which matter and energy may be exchanged between the two. Ordinarily, surroundings means water, air, or both. State of a System

The thermodynamic state of a system is a set of variables such as pressure concentration, temperature, composition, etc., which describe the characteristics possessed by the system. The system in a given state must have definite values assigned to its properties. Thus, when one or more variables undergo change then the system is said to have undergone a change of state. In a homogeneous system, the composition is automatically fixed. The pressure (P), volume (V) and temperature (T) of a system are interrelated with one another in the form of equations of state. If the gas is ideal, it obeys the equation PV = RT. Evidently, if only two of these three variables are known, the third one can easily be calculated. The two variables, generally specified, are temperature and pressure. These are called independent variables. The third variable volume is said to be dependent variable. (i) Isothermal process: When a process is carried out at a constant temperature, it is called an isothermal process. (ii) Adiabatic process: It is a process in which no heat can enter or leave the system, i.e. it is thermally insulated. In exothermic chemical system, the temperature of the system may increase and in endothermic chemical system, the temperature of the system may decrease. (iii) Isobaric process: This process is carried out at constant pressure. In isobaric process, volume change always takes place. (iv) Isochoric process: It is one in which the volume of the system is kept constant. (v) Reversible process: In an ideally reversible process, that change must occur in successive stages of infinitesimal quantities. The small change should be carried out in such a way that throughout the transition, the system must maintain virtual thermodynamic equilibrium, at each of the small stages. A process is said to be reversible when the energy change in each step of the process can be reversed in direction by merely a small change in a variable (like temperature, pressure, etc.) acting on a system, i.e., the system may change in the opposite direction back to the initial condition along the same path and the magnitudes of the changes of the thermodynamic quantities in the different stages will be the same as in the forward direction but opposite in sign. (vi) Irreversible process: Any process which does not take place in the above manner, i.e. a process which does not take place infinitesimally slow, is said to be an irreversible process. Irreversible processes are also

3.18

TOXICOLOGY

called spontaneous processes. Natural processes are, therefore, all irreversible.

3.5.2

Thermodynamic Equilibrium

A system which satisfies all the three (i) thermal equilibrium (ii) mechanical equilibrium and (iii) chemical equilibrium, is said to be in thermodynamic equilibrium. (i) Thermal equilibrium: A system is said to be in thermal equilibrium if there is no flow of heat from one portion of the system to another, i.e. the temperature at all parts of the system remains same and identical with that of the surroundings. (ii) Mechanical equilibrium: When there is no unbalanced force existing between different parts of the system or between the system and the surroundings, the system is in mechanical equilibrium. (iii) Chemical equilibrium: A system is said to be in chemical equilibrium if the composition of the various phases in the system remains the same throughout.

3.5.3

State Function

This is a thermodynamic property which depends only on the state of the system and is independent of the path followed to bring about the change. These properties are like internal energy (DE), enthalpy change (DH), free energy change (DG), entropy change (DS), etc. (i) Extensive property: An extensive property of a system is that which depends upon the amount of substance or substances present in the system. For example, mass, volume and energy. (ii) Intensive property: An intensive property of a system is that which is independent of the amount of the substance present in the system. For example, temperature, pressure, viscosity, surface tension, refractive index, specific heat, etc. (iii) Internal energy: Energy system within itself possesses a definite quantity of energy called the internal energy or intrinsic energy which is a function of the temperature, pressure, volume and the chemical nature of the substance. In a system of constant composition, the magnitude of internal energy (E) will depend upon the thermodynamic variables (P,V,T), any two of which may be regarded as independent variables.1 Thus, E = f(P,T); or E = f1 (P,V); or E = f2(T,V) The internal energy E is a single valued function of the thermodynamic state of the system i.e. whenever the system will be in the thermodynamic state, its internal energy will have the same magnitude. When a system changes from one thermodynamic state, say A, to another thermodynamic state, say B, its internal energy E will also be changed. Then,

FUNDAMENTALS OF CHEMISTRY

3.19

DE = EA – EB where EA = internal energy in state A and EB = internal energy in state B. Thus, internal energy is a state function as it depends only on the initial and final states and not on the path followed between the state, i.e. DE is independent of the process. For example, if a system suffers a series of changes so as to come back to the original state, the system is said to have completed a cycle.

z

Hence,

3.5.4

E=0

Perfect Differentials

Let z = y(x, y), then dz will be a perfect differential when it is found that (i) z is a single valued function depending entirely on the instantaneous values of x and y (or) (ii) dz between any two specified points or states is independent of the path of transition (or) (iii)

z

dz for complete cyclic process is equal to zero, or

¶2z ¶2z = , i.e. the second differentials of z with respect to x and y ¶x ¶y ¶y ¶x carried out in either order become equal to one another. For example, ¶E, ¶S, etc. are perfect differentials.

(iv)

3.5.5 First Law of Thermodynamics The first law of thermodynamics originates from the relation between heat and work. It has been found that the heat and work are equivalent ways of changing a system’s internal energy, i.e. if or whenever, heat is obtained from work the amount of heat produced is proportional to the work spent, or conversely, if heat is transformed into work there is a proportionality between the work obtained and the heat disappeared. From a number of experimental observation, Helmholtz, Clausius and Kelvin enunciated a generalised law of nature known as the conservation of energy which may be called the first law of thermodynamics. Let ‘w’ be the work done on a system, ‘q’ be the energy transferred as heat to a system, and DE be the resulting change in internal energy, then from the first law of thermodynamics, i.e. laws of conservation of energy DE = q – w ...(1) Work done by the system is taken as positive, while work done on the system is taken as negative. Similarly, the increase in the internal energy of a system is regarded as positive and decrease in the internal energy of a systen is regarded as negative. For an infinitesimally small change, i.e. in the differential form

3.20

TOXICOLOGY

¶E = ¶q – ¶w ...(2) From this equation some observations can be made for different systems or processes as (i) In a cyclic process: It is already stated that in a cyclic process where the initial and final states are identical, the change of internal energy in this process DE = 0 i.e. EA = EB where EA is the internal energy in state A and EB is the internal energy in state B. Then, DE = q – w = 0 (or)

or we get,

z z z z z dq =

¶E +

¶q =

¶w

z

dE = 0

¶w substituting

z

dE value ...(3)

From this equation it is evident that the work done is equal to the heat absorbed in a cyclic process. (ii) In isolated system: In this system there is no heat exchange with surroundings, i.e. ¶q = 0 Now

¶E = ¶q – ¶w

so,

¶E = ¶w

...(4)

That is, the internal energy of the system is measured by that amount of work done by or on the system. (iii) In non-isolated system: Internal energy for the system ¶E = ¶q – ¶w ...(5) For the sourroundings only ¶E1 = ¶w – ¶q ...(6) Because, it loses energy ¶q to gain ¶w units of work. Then the net change in the internal energies of the system and surroundings, will be zero i.e., ¶E = ¶E1 ¶E + ¶E1 = 0

3.5.6

...(7)

Enthalpy

Suppose that the change of a system from state A to B is brought about at constant pressure (P). Let the volume increase from VA to VB, then the work done (w) by the system will be W = P(VB – VA)

FUNDAMENTALS OF CHEMISTRY

DE = q – W Then, or

3.21

(Substituting the value of W)

DE = q – P(VB – VA) EB – EA = q – P(VB – VA)

...(1) (EB + PVB) – (EA + PVA) = q Then, sum of the two energy terms (E + PV) associated with the system is called enthalpy or heat content of the system, which is denoted as H. It represents the total energy of the system.

or

Thus,

H = E + PV

...(2)

From equation (1) HB – HA = q = DH In the differential form ¶H = ¶E + P¶V + V¶P Since the system undergoes a change at constant pressure ¶HP = ¶EP + P¶VP

Then

...(3)

Since E depends only on the state of the system and P and V themselves specify the state, then enthalpy depends only on the state, i.e. independent of the path. From the first law of thermodynamics ¶Q = ¶E + ¶W ; ¶WP = P¶VP At constant volume, there will be no mechanical work Then

¶QP = ¶EP + ¶WP = ¶EP + P¶VP

...(4)

Comparing the equations (2) and (3), we get ¶HP = ¶QP

...(5)

That is, at a constant pressure the increase in enthalpy of a system during a given transformation is equal to the heat absorbed. At constant volume ¶V = 0, then ¶H = ¶E = P¶V so ¶H = ¶E

...(6)

That means enthalpy change is equal to the change in internal energy at constant volume.

3.5.7 Thermochemistry Most of the chemical reactions are invariably accompanied by energy changes. The study of the heat produced or required by chemical reactions is called thermochemistry. A chemical reaction is said to be exothermic if it is accompanied by evolution of heat and endothermic if it is accompanied by absorption of heat.

3.22

TOXICOLOGY

The amount of heat evolved or absorbed in a chemical reaction is called the heat of reaction, and the quantities depend on the way the change is carried out, i.e. on the path. In fact, the reactions are studied usually under two specified conditions either at constant pressure or at constant volume. Heat changes at constant pressure or at constant volume of a reaction are represented as QP and QV, respectively. We know that, QP = DHP = Hresultant – Hreactant Assuming work is performed in the process QP = DHP = DEP + PDV At constant volume QV = DEV Then

QP – QV = DEP – DEV + PDV

Compared to the large heat in other than ideal one, DEP and DEV differ very little extent, thus, DEP = DEV Therefore, or

QP – QV = PDV QP = QV + PDV PDV = DnRT then QP = QV + DnRT

...(1) ...(2)

where Dn is the increase in the number of moles in the chemical reaction. Or it can be represented as DHP = DEV + DnRT

...(3)

3.5.8 Second Law of Thermodynamics The first law establishes definite relationship between the heat absorbed and work performed by a system in a given process. But the first law does not indicate the following points. (i) It does not indicate whether the change would occur at all, i.e. whether a specific change or a process including chemical reaction can occur spontaneously. (ii) If the change occurs then upto what extent. (iii) Also, it does not tell the direction in which the process of transformation would take place. The second law of thermodynamics helps us in determining the direction and the extent of change. It will also give us the conditions under which the changes would occur. Therefore, the second law of thermodynamics can be discussed on the following three heads.

FUNDAMENTALS OF CHEMISTRY

3.23

Direction of Change

Changes taking place in a system without the external aid are termed spontaneous processes. (i) All spontaneous processes are irreversible and all spontaneous processes tend to be in equilibrium. (ii) Heat will not flow from a lower temperature body to a higher temperature body. Thus, the second law can be formulated on account of direction of change as it is impossible for a self-acting machine, unaided by any external agency, to convey heat from a body at a low temperature to one at a high temperature. Conditions for Change

Generally, there are two conditions under which the heat changes into the direction of work. (i) Without the aid of an external agency (engine) the conversion of heat into work is impossible. The engine must work in a reversible cyclic process. (ii) The engine must operate between two temperatures (higher and lower). Hence, under isothermal conditions no engine can convert heat into work. That is why we cannot run our vehicles with the heat of surrounding air. Thus, the second law accounts for conditions for change. It is impossible by an external aid (engine), to derive mechanical effect (work) from any portion of matter by cooling it below the temperature of the coldest of the surroundings. Extent of Change

Complete conversion of heat into work is impossible without leaving a permanent change elsewhere. Therefore, the second law states that “Only a fraction of a given quantity of heat may be converted into work, when it is allowed to flow from a body at higher temperature to a lower temperature one i.e. the engine would pick-up Q calories from the source (higher temperature), transform only a portion of it into work (W) and return the rest of the heat Q1 to the sink (lower temperature)”. Then, W = Q – Q1 Then the efficiency of the engine is h=

Work produced 1s Heat supplied

h=

W Q – Q1 = Q Q

3.24

TOXICOLOGY

h=1–

3.5.9

Q1 Q

Entropy

The second law uses the entropy to identify the spontaneous changes among permissible changes. Entropy of a system is a measure of randomness or disorder of the system and is denoted by the symbol ‘S’. The thermodynamic definition of entropy derives as the change in entropy ‘ds’ that occurs as a result of a physical or chemical change. Thus, it is defined as the heat change ‘dq’ and the temperature ‘T’ are thermodynamic quantities and this thermodynamic function whose change is measured by (dq/T) is independent of path. DS = Sfinal – Sinitial The entropy change ‘ds’ is measured by the ratio of the heat change and the temperature at which the heat change occurs i.e. ds =

dq HAL T

At different temperatures, then ds =

@G  @G + 6 6

z z dS =

+

@G ! + ... 6!

dq HAL T

Then we can state that, (a) Entropy ‘S’ is a thermodynamic function whose magnitude depends only on the temperatures of the system and can be expressed in terms of P, V, T. (b) The entropy change ‘ds’ is a perfect differential. Its value depends only on the initial and final states of the system, independent of the path of the change. The entropy change is measured by the reversible heat change of the system divided by the temperature in absolute state i.e. dq T (c) Absorption of heat increases the entropy of a system. The rejections of heat by the system leads to a decrease in its entropy. ,uring adiabatic changes (dq = 0) the entropy change is zero. Thus, the adiabatic changes to 3.2a are called isoentropic changes. Entropy change in a reversible cycle: Let us take a system which undergoes a reversible change in isothermal and adiabatic process, Fig. 3.2.

ds =

FUNDAMENTALS OF CHEMISTRY

A

T1

Pa

th

a T2

P

3.25

I b

Pa

th

II c B V

Fig. 3.2 Entroy change in a reversible cycle.

Giving positive sign to the heat absorbed (q2) and negative sign to the heat lost (q1) by the system, the equation from Carnot cycle

G G = can be written as 6 6

q q =–  T T

or

G 6

+

G =0 6

or

dq T

+

dq  =0 T

For other Carnot cycle also dq  dq  +  =0 T T

It follows that in Fig. 2 the path ABA comprising a series of Carnot cycles then dq

åT

z z

=0

dq =0 T

or or

ds = 0

Hence, in any reversible cyclic process, the net increase in entropy of the system is zero.

3.6

PHASE RULE

The phase rule is a relation between the number of components (C), the number of phases (P), and the variable parameter (F) of a heterogeneous system in equilibrium for a system of any composition. It is expressed as

3.26

TOXICOLOGY

F=C–P+2 ...(1) It is necessary to define appropriately, the terms which are frequently used, namely, Phases, Components and ,egrees of Freedom. Phase: A phase is defined as a physically distinct but homogeneous part of a system separated from other parts by boundary surfaces and is mechanically separable from other parts of a system. A gas or a gaseous mixture is a single phase, a crystal is a single phase, and two completely miscible liquids form a single phase. A system consisting of one phase only is said to be homogeneous. Similarly, the vapours in contact with the solution are two distinct phases, a mixture of two immiscible liquids, e.g. water and benzene will form two distinct phases. Every solid constitutes a separate phase unless a solid solution is formed. So, when calcium carbonate dissociates into calcium oxide and carbon dioxide, there are two solid phases (CaCO3 and CaO) and one gas phase (CO2). CaCO3

CaO + CO2

Thus, it is a three-phase heterogeneous system. Two distinct liquid phases with the vapour phase will also form three-phase system. Thus, a heterogeneous system consists of more than one phase. The phase rule is concerned with the effects that changes in pressure, temperature and concentrations will have on the equilibria of heterogeneous systems. When various phases are in equilibrium with one another in a heterogeneous system, there can be no transfer of energy or mass from one phase to another. Thus, at equilibrium the various phases must have the appropriate pressure and temperature and their respective compositions must be constant all along. Components: The minimum number of independent chemical constituents necessary to define the composition of all the phases of the system. The composition of every phase can be expressed by means of a chemical equation (when chemical reaction takes place). When no chemical reaction takes place, the number of components is equal to the number of constituents. Thus, pure water can exist in three phases, i.e. solid (ice), liquid (water) and vapour (steam), but it is a one component system because we need only the species H2O to specify its composition. Similarly, a mixture of ethanol and water is a two-phase and two-component system, since we need the species H2O and C2H5OH to specify its composition. Sulphur can exist in four phases but is a one component system because we need only the species ‘S’ to specify its composition. When a chemical reaction can occur, we need to decide the minimum number of species after completion of the reaction to specify the composition of all phases. For example, CaCO3(s) CaO(s) + CO2(g) Phase 1 Phase 2 Phase 3

FUNDAMENTALS OF CHEMISTRY

3.27

We need the species CO2 and CaO to specify the composition of the gas (CO2) and the composition of phase 2 (CaO), respectively. However, additional species is not required to specify the composition of phase 1 (CaCO3) because it can be expressed in terms of the other two constituents by using the chemical reaction. CaO + CO2 ® CaCO3 Hence, it is a two-component system. Similarly, in case of NH4Cl (s) NH3 (g) + HCl (g) Phase 1 Phase 2 Here, NH3 and HCl can be prepared by the following reaction NH4CI ® NH3 + HCl So, it is a one-component system. However, if NH3 or HCl is in excess, the system becomes a two-component system. Degrees of freedom: The degree of freedom of a system is defined as the number of independent variables (temperature, pressure and concentration) that can be changed independently without disturbing the number of phases in equilibrium. This can also be defined in an another way as the number of variables that must be specified in order to define the system completely. In a single component, single phase systems, the two variables (temperature and pressure) must be specified to get the same number of phases, so F = 2. Such a system is called bivariant. In a single component, two-phase systems, if temperature is specified, pressure becomes known automatically and vice versa. Only one variable, either temperature or pressure will have to mention. So, here F = 1 and it is called Monovariant. Similarly, in a single component, three-phase system F = 0 and it is called non-variant or invariant.

3.6.1 One Component System The water system, H2O: One component systems must comprise a pure substance only. For a one component system, the simplest example is pure water. Under ordinary circumstances, the water system consists of three phases, viz. ice, water and water vapour. Ice (s)

water (l) ®** water vapour (g)

1. If the system consists of only one phase, say water vapour, then, according to the phase rule, F = C – P + 2 = 1 – 1 + 2 = 2 (bivariant) Here, both pressure (P) and temperature (T) can be varied independently without changing the number of phases, i.e. a single phase is represented by an area on a phase diagram.

3.28

TOXICOLOGY

2. If a one component system has two phases in equilibrium say water and water vapour, or ice and water, or ice and water vapour, then the degree of freedom is, F = C – P + 2 = 1 – 2 + 2 = 1 (monovariant) It implies that pressure is not freely variable if the temperature is fixed and vice versa. Thus, the system consisting of a liquid in contact with its vapour. The equilibrium of two phases is represented by a line in the phase diagram. (a) when a liquid in contact with its vapour, water (l) water (g) (b) when a solid in contact with its liquid then, ice (s) water (l). (c) a solid in contact with its vapours. ice (s) water vapour (g). 3. When all the three phases are in equilibrium of one component system then the degree of freedom is F = C – P + 2 = 1 – 3 + 2 = 0 (invariant). Here, no external condition has to be specified to define the system. The equilibrium of three phases is, therefore, represented by a point called triple point, on the phase diagram. Since F cannot be negative, in one component system, more than three phases cannot coexist in true equilibrium. The phase diagram of the water system is represented in Fig. 3.3. Critical pressure C

Fusion curve

Ice

A

X

218 atm Water

N

Vapour curve Y

M

Pressure

1 atm 4.58 mm

Triple Point O

D

Water vapour

B Sublimation curve

Z

0.0075°C

100°C

Critical temp. 374°C

Temperature, °C

Fig. 3.3 Phase diagram of water system (Invariant).

FUNDAMENTALS OF CHEMISTRY

3.29

Every equilibrium involves in two phases as (1) liquid

vapour (2) solid

liquid

(3) solid

vapour

1. As it is mentioned that a single phase is represented by an area on a phase diagram, the areas AOC, BOC and AOB are the areas of existence of liquid, solid, and vapour phase, respectively. Within this area, the system is bivariant, i.e. F = 2. 2. Similarly, a boundary line in a phase diagram represents the equilibrium of two phases. Thus, any point on boundary line is a monovariant (F = 1). These boundary lines in the phase diagram are OA, OB and OC. The curve OA represents the equilibrium between water (l) and water vapour (g) at different temperatures (vapour pressure curve). It is evident that for any given temperature, equilibrium vapour pressure is fixed, i.e. there is only one variable. Thus, the degree of freedom of the system is one, i.e. univariant or monovariant as F = C – P + 2 = 1 – 2 + 2 = 1 (monovariant) For any point X and N above OA the system would be water. Similarly, any point Z and M below OA the system would be vapour. Hence, OA in the phase diagram is the boundary line between two phases (water and vapour). However, the line OA terminates at the critical point ‘A’ (t = 374°C and P = 218 atm) beyond which the liquid phase is no longer distinguishable from vapour phase. Similarly, the curve OB represents the equilibrium between ice and vapour (sublimation curve). Here, for each temperature there can be one and only one pressure and vice versa. The curve OC represents the equilibrium between ice and water. The line has a negative slope, i.e. melting point is lowered with increase in pressure. The triple point O, where the three lines meet, all the three phases, i.e. ice, water and vapour, should co-exist in equilibrium. The vapour pressure at this point is 4.58 mm and temperature is 0.0075°C. The system is non-variant at the triple point. F = 1 – 3 + 2 = 0 (non-variant). If either the temperature or the pressure is changed, the three-phase would not co-exist, one of the phases would disappear. A liquid below its freezing point is said to remain in supercooled state, which is not normally stable and usually described as metastable state. The vapour pressure of the supercooled water also changes with temperature. The curve OD represents the supercooled state of water which lies above the curve OB. Thus, the vapour pressure of the metastable phase is greater than that of the stable phase.

3.30 3.7

TOXICOLOGY

THE COLLOIDS

Thomas Graham in 1861 found that a colloid is a dispersion of small particles (< 500 mm diameter) of one material in another (solvent). In a colloid system, dispersion rate of one material in another is very slow. When this dispersion rate is more than enough then it is called crystalloid and the materials exist in crystalline state. These solutions of crystalloids can readily percolate through parchment or cellophane papers. But in case of colloidal solution, it cannot pass through the parchment or cellophane paper. When substances like sand, powdered glass, barium sulphate, charcoal, etc. are added to water, some remain floating or sink as a distinct phase and are called heterogeneous course suspensions. The solution which percolates through the parchment or cellophane paper easily is called a true solution. The solute particles in the true solutions are molecularly dispersed and are invisible. The diameter of the solutes in true solution is approximately 10–8 cm. The systems with properties intermediate between those of heterogeneous course suspensions and homogeneous true solution are called colloidal systems. In general, colloidal particles are aggregate of numerous atoms or molecules, but are too small (diameter between 10–7 – 10–4 cm approximately) to be seen with an ordinary optical microscope but can be detected by light scattering (Tyndall effect), sedimentation, and osmosis. A colloidal solution is a two-phase heterogeneous system in which finely divided particles of any substance (approximately 10–7 – 10–4 cm diameter) are dispersed in another continuous or dispersion medium. Generally, colloidal particles are charged either positively or negatively. The colloidal system is often called a sol. The ratio of colloid surface area to their volume is so large that their properties are dominated by events at their surfaces. Table 3.1 Different colloidal systems. S. No. Dispersed phase Dispersion medium Colloidal System Examples 1.

Solid

Solid

Solid sol.

2.

Solid

3.

Solid

Liquid, water/ benzene Gas

Sol, hydrosol/ benzosol Solid aerosol

4.

Liquid

Solid

Gel

5. 6.

Liquid Liquid

Liquid Gas

Emulsion Liquid aerosol

Rock salt, coloured precious stones. Starch, proteins, gold ink, paints, etc. Smoke, volcanic dust, fumes, etc. Jellies, gels, cheese, curd, butter, etc. Milk, cod-liver oil Mist, fogs, clouds

Contd.

FUNDAMENTALS OF CHEMISTRY 7.

Gas

Liquid

Foam or froth

8.

Gas

Solid

Solid foam

3.7.1

3.31

Whipped cream, foam detergent sud, etc. Adsorbed gases or occluded gases cake, rubber, etc.

Classification of Colloidal System

The name given to the colloid depends on either of the two phases involved. The colloidal system is often called a solution and is classified in two ways. These are: (1) Mode of dispersion of the dispersed phase in dispersion medium, i.e. reversible solutions and irreversible solutions. (a) Reversible solutions: In this type of solutions, the dispersed phase is dispersed spontaneously in the dispersion medium because of thermal energy. In this type of solutions, redispersion also occurs easily. (b) Irreversible solutions: In these solutions, no spontaneous dispersion occurs and are thermodynamically unstable. The irreversible sols will be thrown out of the dispersion medium from the colloidal state to the macrostate. (2) The other type of classification based on solvent affinity of the dispersed phase. These are (a) lyophilic and (b) lyophobic. (a) Lyophilic sols: Lyophilic sols are those which have spontaneous tendency to pass into the colloidal state, hence these solutions are reversible. The other characteristics are like (i) The surface tension of these solutions is lower than that of the dispersion medium in which the particles are dispersed. (ii) These sols show very weak Tyndall scattering effect. (iii) Viscosity is much higher than that of the dispersion medium. (iv) These sols are thermodynamically stable. (v) They are not easily precipitated by addition of electrolytes. (vi) These sols are solvent loving. Due to the presence of a number of polar groups in the molecules of lyophilic sols, these are extensively hydrated. Examples are starch, gelatin, glue, etc. (b) Lyophobic sols: These sols are solvent repelling sols. These sols do not have spontaneous tendency to pass into the colloidal state and are irreversible in character. The other characters of these sols are stated as: (i) Surface tension is usually the same as that of the dispersion medium. (ii) The lyophobic sols are often coloured. They show the Tyndall effect.

3.32

TOXICOLOGY

(iii) Viscosity is about the same as that of the dispersion medium. (iv) They are thermodynamically unstable. (v) They are precipitated more easily by addition of even a little electrolyte. (vi) The colloidal particles are not hydrated to a large extent. For example: gold solution, silver solution, etc.

3.8

ELECTROCHEMISTRY

Substances like metals viz. iron, copper, silver, mercury and non-metals like water, solutions of salts, acids, etc., allow the current to flow through them. These are called conductors. But there are other substances, most of the non-metals do not allow the current to flow through them, so these are called non-conductors or insulators. The conductors are broadly divided into two classes: 1. Metallic conductors or electronic conductors in which electricity passes through without producing a chemical change. 2. Electrolytes or electrolytic conductors in which electricity causes a chemical reaction. The substances in their aqueous solutions are called non-electrolytes when they do not allow the current to flow through them. For example, alcohols, oils, sugar solution, starch solution, etc. The main differences between electronic conductors and the electrolytic conductors are as follow: Electronic conductors 1. In electronic conductors the electricity is carried exclusively by the transport of electrons without the transfer of matter of all. 2. There is no chemical change when current is passed.

3. The electrons flow from a higher negative potential to a lower one.

4. With increase in temperature the conductivity of electronic conductors, decreases.

Electrolytic conductors 1. It involves the actual transfer of matters (ions).

2. By the passage of electricity there occurs a chemical change i.e. decomposition of matter. It is called electrolysis. Electrolysis occurs only on the electrodes and not throughout the bulk of electrolyte. 3. The current enters into the electrolyte through positive electrode or anode and leaves through negative elctrode or cathode. 4. With increase in temperature the conductivity increases.

FUNDAMENTALS OF CHEMISTRY

3.8.1

3.33

Electrode Potential

When a chemical equilibrium is not reached in the overall cell reaction, then there can be an electrical work as the reaction drives electrons through an external circuit. The flow of electricity from one electrode to another electrode is possible only when there is a potential difference between the two electrodes. This potential difference is called the electrode potential or cell potential. It is shown in Fig. 3.4. The electrochemical cell consists of two electrodes (metal) and the electrolyte. Generally, the negative electrode (anode) is placed at the left and positive electrode (cathode) on the right of the cell. When the metal electrode is in contact with an electrolyte, some metal ions enter into the electrolyte solution due to a tendency called Nernst electrolytic solution tension, leaving behind electrons on the electrode as M ® M +n + ne– This electrode is negative and called anode. On the other hand, the positive metalic ions from the solution enters into the electrode by taking electrons from the electrode. So, it is now positive electrode and called cathode. Mn+ + ne– ® M Due to electrostatic force in the vicinity of the electrode any further transference of metal ions does not take place. Thus, the positive charge and negative charge remain close to the metal surface forming a double layer. This is called Helmholtz electrical double layer. Because of the Nernst’s electrolytic solution tension there is a difference in electrode potentials. E = Eo – where • • • •

RT a ln Red nF a Oxd

R is the uviversal gas constant, equal to 8.314510 JK–1 mol–1 T is the temperature in kelvin. (Kelvin = 273.15 + °C) a is the chemical activities on the reduced and oxidized side, respectively F is the Faraday constant (the charge per a mole of electrons), equal to 9.6485309 * 104 C mol–1 • n is the number of electrons transferred in the half-reaction. • [Red] is the concentration of oxidizing agent (the reduced species). • [Ox] is the concentration of reducing agent (the oxidized species). • E is the electrode potential • Eo is the standard electrode potential The electrode potential difference depends on the rates of transfer of ions from the metal to the solution and the discharge of ions from the solution on the metal. The electrode which has the tendency to lose electrons (oxidised) is called

3.34

TOXICOLOGY

oxidation potential and the tendency of the electrode to gain electrons (reduced) is called reduction potential. This is shown in the Fig.3.4. Measurement of electrode potentials: The potential difference of the double layer formed at an electrode is known as single electrode potential. For example, let us take an oxidation electrode potential, say Zinc-Zinc ion electrode. Then Zn ® Zn++ + 2e– Let EZn is the electrode potential of Zn electrode. Then

EZn = EoZn –

where EoZn is constant and is equal to

RT a Zn ++ ln nF a Zn

RT In k nF

where K is the equilibrium constant. EZn = EoZn –

or

RT a ln oxidant nF a reductant

since aZn = 1 (solid zinc). RT ln aZn++ nF Similarly, for reduction electrode potential copper-copper ion electrode Cu++ + 2e– ® Cu

Then

or

EZn = EoZn –

ECu = EoCu –

RT a Reductant ln Cu nF a Cu ++ Oxidant

ECu = EoCu +

a ++ RT ln Cu (aCu = 1) nF a Cu

RT ln aCu++ nF In the electrochemical series the elements are arranged in decreasing order (downwards) of their standard electrode potential. In the electrochemical series negative sign indicates that the reduced form has a greater tendency to get oxidised and leave electrons. For example, Zn+2 + 2e– Zn (s) E0 = –0.76 Positive sign indicates that the oxidised form has greater tendency to get reduced and take electron. Cu E0 = 0.80 Cu+2 + 2e– Hence, Zn has the greater tendency to lose electrons.

Then

ECu = EoCu +

FUNDAMENTALS OF CHEMISTRY

3.8.2

3.35

Electrochemical Cell

The redox reaction in solution is studied in terms of electrical measurement in a device called electrochemical cell. This electrochemical cell consists of two electrodes in contact with an electrolyte. The electrochemical cells are mainly of two types (a) Galvanic cell, and (b) Electrolytic cell. (a) Galvanic cell: A galvanic cell is an electrochemical cell in which the free energy of a chemical process is converted into electrical energy, i.e. electricity is produced due to spontaneous reaction occurring inside it. Direction of Electron Flow Cathode Anode

Reduction

Oxidation

Electric current flow

Fig. 3.4 Galvanic cell.

The chemical equation of the redox reaction in Galvanic cell is Zn | Zn++ || Cu++ | Cu. (b) Electrolytic cell: The electrolytic cell is one in which external electrical energy is used to carry out a chemical reaction, i.e. non-spontaneous reaction is occurring inside it. In both the electrochemical cells, if the two electrodes share the same electrolyte (single compartment) then salt bridge is not required, but in case of different electrolytes (two compartments) the salt bridge is required to complete the electrical circuit and cell reaction proceeds. To illustrate this cell reaction we may take Daniel cell (galvanic cell) which consists of a Zn electrode immersed in a ZnSO4 electrolyte solution and a copper electrode dipping in CuSO4 solution. These two are kept in two separate chambers and connected by a salt bridge. Now, each chamber, i.e. one electrode and its electrolyte is regarded as a half-cell. The electrode reactions in the Daniel cell are shown in Fig. 4(b). Zn

Zn+2 + 2e–

Cu

Cu+2 + 2e–

Zinc has a greater tendency to ionize to Zn+2 than copper so that Zn+2 ion goes into solution leaving behind two electrons on the Zn electrode. Thus, Zn electrode is –ve, called anode. On the other hand, at the copper electrode, copper ions from

3.36

TOXICOLOGY

the solution are deposited by accepting two electrons each from the electrode so they are +ve, called cathode. At anode At cathode Overall reaction

Zn(s) ® Zn+2(aq) + 2e– +2

–

Cu (aq) + 2e +2

®

Zn(s) + Cu (aq) ®

Oxidation reaction.

Cu(s)

Reduction reaction.

+2

Zn (aq) + Cu(s).

–Zn +Cu

Salt Brige CuSO4

ZnSO4

Fig. 3.5

Daniel cell.

The electrochemical cell may be reversible or irreversible. In a reversible cell, the chemical reaction inside the cell proceeds in either direction depending on the direction of electric current flow but in an irreversible cell chemical reaction cannot be reversed under the same condition as earlier said. In a reversible cell each half-cell is also a reversible. The thermodyamic relations are only applicable to the reversible cell.

3.8.3 EMF of a Cell and Free Energy Change The thermodynamic relations are applicable to reversible cell only. The chemical process occurring in any galvanic cell is exothermic. The electrical energy of a reversible cell was measured by the decrease of free energy of the cell, i.e. equivalent to the heat of chemical reaction occurring in the cell. DH nF where E is the electrical energy (EMF), DH is the heat of reaction. nF is the charge of 1 gm mole of the substance. In the Daniel cell, the cell reaction is

DH = –nFE or E = –

Zn | ZnSO4 || CuSO4 | Cu

Zn + Cu++ ®

Zn++ + Cu

Helmholtz found that the output of the electrical energy is not equivalent to the heat of reaction but equivalent to the net available work of the process i.e., to the decrease of free energy (–DG). Then,

FUNDAMENTALS OF CHEMISTRY

–DG = nFE From Gibbs-Helmholtz equation, it is found that –DG = –DH – T

FG ¶(DG) IJ H ¶T K

3.37 ...(1)

...(2) p

Putting the value of equation (1) in equation 2, it is

FG ¶(– nFE) IJ H ¶T K F ¶E I where n and F are constants. nfE = –DH – Tnf G J H ¶T K DH F ¶E I + Tnf G J E= – H ¶T K nF

nfE = –DH – T

p

p

Then

...(3)

p

This relation is universally employed for the e.m.f. of a cell. (¶E/¶T) is the temperature coefficient of the e.m.f. of the cell. (i) When (¶E/¶T) = 0, then the electrical energy is equal to the heat of the reaction. (ii) When (¶E/¶T) > 0, i.e. positive, the EMF of the cell increases with temperature and the electrical energy is greater than the heat of reaction. (iii) If (¶E/¶T)p < 0, i.e. negative, the electrical energy is less than the heat of reaction of the cell. From the equation 1, we can conclude that DG + 0 –

3.9

E – 0 +

Cell reaction Non-spontaneous equilibrium spontaneous

CHEMICAL KINETICS

Study of chemical kinetics deals with the speed of chemical reactions under given conditions of temperature, pressure and concentration. The practical importance of the chemical kinetics are as under: (i) to predict how quickly a reaction mixture approaches equilibrium (ii) to optimize the rate of reaction by appropriate choice of conditions (iii) to understand the mechanisms of reactions, they are analysed into a sequence of elementary steps (iv) to know how different factors influence the progress of the reactions, and (v) to get the energy relations between the reactants and products, which are being governed by thermodynamics but not by the time or the intermediate states.

3.38

TOXICOLOGY

There are many reactions in which velocities cannot be measured, as the reaction is very fast. For example, the instantaneous reactions like explosion reactions and most of the ionic reactions. Because these do not involve breaking of any bonds in the reactant molecules and formation of new bonds in product molecules which are the important factors for a chemical reaction. Ag+ + Cl– ® AgCl (time required for the reaction is 10–6 sec). Here, no bonds are to be broken, hence, it is almost instaneous reaction. On the other hand, there are many reactions in which velocities are very slow. Hence, in between the very fast and very slow reactions, there are reactions for which the rate can be measured easily. For example, decomposition in gaseous reactions, hydrolysis of liquid phase reactions, mutarotation of glucose, etc. In chemical kinetics, the chemical reactions are classified into two categories. 1. Homogeneous reactions occur entirely within one phase, and 2. The heterogeneous reactions occur in more than one phase, for example, transformation takes place on the surface of a catalyst.

3.9.1 Rate of a Chemical Reaction Infact, a chemical reaction involves breaking of bonds in reacting molecules and formation of new bonds in product molecules. Since the number and nature of bonds are different in different substances, the rates of chemical reactions differ a lot from one another. The rate of a reaction is defined as the amount of chemical change occurring per unit time. It depends on the concentration or pressure of the reactants. Therefore, the rate is generally expressed as the decrease in concentration of a reactant or as the increase in concentration of a product per unit time. Thus, for the reaction A ® B The rate is

-d[A ] , where – [A] decreases the concentration of reactant or it dt

-d[ B] , where + [B] increases the concentration of product. dt The unit of the rate of reaction is gm mole per litre per second (mol L–1 S–1).

can be expressed as

3.9.2 Factors Influencing Rates of Reactions The rates of a reaction are influenced by a number of factors as: • Nature of the reactant • Concentrations of the reacting species • Temperature of the system • Surface area of reactants

FUNDAMENTALS OF CHEMISTRY

3.39

• Presence of catalyst • Exposure to radiation Nature of the Reactant

Generally, a chemical reaction involves the rearrangement of bonds between the reacting species to form product, i.e. breaking of old bonds and formation of new ones. Consequently, the nature and the number of bonds in the reacting species greatly influence the rate of the reaction. For example, by comparing the Redox titration of oxalic acid Vs. potassium permanganate and potassium permanganate Vs. Mohr’s salt. (i) 5C2O42– (aq) + 2MnO42– (aq) + 16H+ (aq)

® 10CO2 (g) + 2Mn2+ (aq) + 8H2O

(ii) 5Fe+2 (aq) + MnO4– (aq) + 8H+ (aq)

® 5Fe+3 (aq) + Mn+2 (aq) + 4H2O

The second reaction is much faster than the first because in the second reaction, Ferrous ion is a simple ion so bond breaking system is not involved, whereas oxalate ion has a number of covalent bonds which have to be broken in the oxidation reaction. Concentration of the Reacting Species

The rate of a given reaction increases with increased concentration of reactants. As the reaction proceeds, the concentrations of the reactants decrease with time, the rate of the reaction keeps on falling with time. Temperature of the System

In most of the chemical reactions the rate of a reaction increases with rise of temperature. As in the case of oxidation, reaction of oxalate ion which is a very slow reaction, heat is necessary. In most cases, a rise of 10°C in temperature, the rate of a reaction in a homogeneous reaction increases by approximately 2 to 3 times. Surface Area of Reactant

In heterogeneous reaction, the surface area of reactant has much significance, i.e. as the particle size decreases, surface area for the same mass increases. Hence, the smaller the particle, the faster is the rate of reaction. Presence of Catalyst

Catalyst is a substance which can accelerate or retard the rate of reaction but it is not consumed in the overall reaction. The action of a particular catalyst is specific for a particular reaction. For example, manganese oxide can catalyze only the decompositions of potassium chlorate to give oxygen while a particular enzyme can catalyze a particular biochemical reaction only.

3.40

TOXICOLOGY

Exposure to Radiation

There are certain reactions in which the rate of reaction increases by absorbing a radiation of specific frequency. Such reactions are called photochemical reactions. For example, hv H2 + Cl2 ¾¾ ® 2HCl + Energy

3.9.3 Order of a Reaction Order of a reaction is the quantitative dependence of its rate on the concentrations of reacting species. The order of a reaction is defined as the number of molecules whose concentrations determine the rate of the reaction at a given temperature. For example, if the rate of a reaction depends on the first power of the concentration of reactant then it is said to be a first order reaction. A ® Product -d[A] = kCA where k = Rate constant dt Similarly, for a second order reaction, the rate is proportional to the product of two reactant concentrations or the square of the concentration of a reactant. It is given by A + B ® product ...(1) Rate = kCACB 2 A ® Product Rate = kCA2 ...(2) We can define the higher order reactions in a similar way, as for third order reaction

Rate =

Rate = kCA3

Rate = kCACB2 Rate = kCACBCC

Rate = kCA2CB, and so on For nth order reaction Rate = KCn as

If several reactants A, B, C ... etc. are involved, then the rate of the reaction is –

dC = kCaA CBb CCc CDd ......... dt

Then the order of the reaction would be n = a + b + c + d + .... Thus, the order of reaction is defined as the sum of the powers to which the concentration terms are raised in order to determine the rate of reaction.

FUNDAMENTALS OF CHEMISTRY

3.41

The order of a reaction may not always be a whole number. There are reactions in which the order is fractional, i.e. n = 1/2, 3/2, etc. There are certain reactions in which the rate of reaction is independent of concentration. These are called zero order reactions and generally this type of reactions occur in a heterogeneous system.

3.9.4 Molecularity of a Reaction The molecularity of a reaction is defined as the number of molecules or atoms which take part in the rate determining step, i.e. the slowest step of a stoichiometric equation. If the rate determining step involves one, two or three molecules then the reactions are said to be unimolecular, bimolecular or trimolecular. Molecularity is a theoretical concept and is always a whole number while order can be fractional one. Differences between order of reaction and molecularity. Order of reaction 1. It is an experimentally determined qunatity 2. It may have fractional, zero and whole number. 3. It is obtained from the rate for the overall reaction. 4. It cannot express anything about the mechanism of the reaction. 5. It is equal to the sum of the exponents of the molar concentrations of the reactions in the rate equation. 6. Its magnitude can be changed, e.g. in order to pseudo first order reaction.

Molecularty 1. It is a theoretical concept. 2. It is always a whole number. 3. It is obtained from the rate determining step, i.e. slowest step. 4. It gives the facts about reaction mechanism. 5. It is the total number of species in the rate determining step.

6. Its magnitude cannot be changed.

In earlier days, no distinction was made between the order and molecularity of a reaction. The terms unimolecular, biomolecular, etc. are used for first order, second order, etc. reactions, respectively. But actually, there is no correlation between the order and molecularity of a reaction. For example, all bimolecular reactions are of the second order but all second order reactions are not necessarily bimolecular, e.g. second order is a bimolecular reaction. By changing the condition bimolecular reaction may be pseudo first order reaction.

3.42

TOXICOLOGY

3.9.5 Photochemical Reactions The energies needed for chemical reaction are in the range 104–10–5 calories per mole, approximately. According to the distribution law, some molecules at any instant would possess sufficiently large amount of energy and these suffer chemical change in an ordinary thermal process. But many reactions can be initiated by the absorption of light (visible and UV) having wavelengths from about 10000 Å to 1000 Å are called photochemical reaction. The energy in this range varies from 1 ev to 10 ev or 23 to 230 kilocalories per mole. The occurrence of thermal reactions is always accompanied by a free energy decrease. But there are many photochemical reactions in which an increase of free energy is involved due to the absorbance of photons, which may increase the free energy of the reactants sufficiently to make DG negative. For example, the photosynthesis of carbohydrate through chlorophyll and sunlight. Laws of Photochemistry

Grothus-Draper law and the Stark Einstein law are the two basic laws for photochemistry. Grothus-Draper law: This law states that only those radiations which are absorbed can be effective in producing the chemical change. The photon will be absorbed if there will be some change within the molecule (electronic, atomic or molecular motion) which is not forbidden by quantum restrictions and which corresponds to the energy contained in the photon. The extent of absorption of radiation is expressed by Beer’s law and Lambert’s law. Beer’s law: This law states that when a beam of monochromatic radiation is passed through a solution of an absorbing substance, the rate of decrease of intensity of radiation with thickness of the absorbing solution is proportional to the intensity of incident radiation as well as the concentration of the solution. I = I0 10–k1cx

k1 = 2.303al

a1 = molar extinction coefficient, ‘c’ is the concentration of the solution. Lambert’s law: This law states that when a beam of monochromatic radiation passes through a homogeneous absorbing medium, the rate of decrease of intensity of radiation with thickness of absorbing medium is proportional to the intensity of the incident radiation. I = I0 10–ax ‘a’ is the extinction coefficient. Stark-Einstein law: This law states that one photon is absorbed by each molecule responsible for the primary photochemical process. It can be interpreted as only one molecule is activated by each quantum of radiation. Even though a reactant molecule absorbs one photon, the excited molecule does not form products. Therefore, the number of reactant molecules producing

FUNDAMENTALS OF CHEMISTRY

3.43

specified primary products (atoms or ions) for each photon absorbed is expressed in terms of quantum yield (f), i.e. the measurement of the efficiency of a photochemical process. This is called primary quantum yield. As a result of one successful initiation, many reactant molecules might be consumed. The overall quantum yield (f) is the number of reactant molecules that react for each photon absorbed. f= Energy

number of molecules reacting number of quanta of radiation absorbed

E = N0hu or

N 0 hc l

N0 ® Avogadro number = 6.02 ´ 1023 h ® Planck’s constant = 6.625 ´ 10–27 ergs/sec. C ® Velocity of light = 2.998 ´ 1010 cm/sec. Then

E=

1196 . ´ 108 ergs/mole l

The energy E which activates one mole of the reactant, i.e. the energy corresponding to Avogadro number of photons is called one einstein. Primary Processes in Photochemical Reactions

This process follows the steps like: 1. The first step in a photochemical process is the absorption of energy of the radiation by the molecule. A + hu ® A* (excitation) 2. The energy obtained from a photon leads to an electronic transition. A* + A ® A2 (dimerisation), A* ® A + hu¢ (fluorescence). 3. The excited molecule re-emits the absorbed energy in order to come to stable state, fluorescence (single excited state) phosphorescence (triplet excited state) may occur. A2 ® 2A (thermal). Broadly, there are four distinct possibilities of the excitation of the molecules: (a) NOCl + hu ® NOCl* NOCl* + NOCl ® 2NO + Cl2 The molecule is excited by the photon energy and it may retain its energy until it can be used chemically by combination with another molecule. (b) HI + hu ® H + I H + HI ® H2 + I I + I = I2 This is due to the direct decomposition of the molecule.

3.44

TOXICOLOGY

(c) By ionization process, i.e. when the molecules are in excited state (unstable), the molecule would dissociate producing atoms or radicals. (d) At the unstable state, the molecule breaks up into atoms or radicals. The fragments of dissociation are produced with different kinetic energy. The products of dissociation may start secondary chemical changes or chain reactions as Cl2 + hu ® 2Cl Cl + H2 ® HCl + H H + Cl2 ® HCl + Cl and so on. Photochemical equilibrium: The absorption of light by the reactant in the forward process will increase the speed of the forward reaction, but will not influence the rate of reverse thermal process.

ºA Light

2A

Thermal

2

The dimerization is carried out photochemically with light and the opposite change, the conversion of dimers into monomers is a thermal process. Fluorescence: In this process the emitted radiation has a frequency less than that of the absorbed radiation. The absorbed energy is released within 10–8 seconds but it may come out in successive stages. A + hu ® A* A* ® A1 + hu¢ A1 ® A + hu² The emission in fluorescence shall cease as soon as the light source is removed. Phosphorescence: The absorbed energy is released in more than 10–8 seconds and the emission in phosphorescence will continue for some time even if the source of light is removed. Chemiluminescence: The light is emitted as a result of chemical reaction at ordinary temperature. The emission occurs at the expense of some amount of heat of reaction.

3.10

FUNDAMENTAL REACTIONS AND THEIR MECHANISM

All types of chemical reaction involve the existing bond breaking and formation of new bonds. The reactions of the inorganic compounds are the reactions of the ions and are characterised by their reversibility. On the other hand, reactions of organic compounds are molecular in nature, and the atoms of the molecules are firmly bound by covalent bonds. Generally, the organic reactions are based on the fundamental concepts of energetics or thermodynamics. The organic chemical

FUNDAMENTALS OF CHEMISTRY

3.45

reactions may be stepwise reaction or a concerted reaction. Both these reactions may proceed through intermediates or transition state, respectively. The detailed path under taken by the reactants in order to get converted into products is the mechanism of the reaction. Thus, the study of bond breaking and making, its time or order, sequence of steps, the details of electron movement and the relative rates of each step constitutes the study of reaction mechanism. The basic processes in reaction and reaction intermediates is bond fission which may occur in two ways.

3.10.1 Bond Fission In organic chemical reactions, generally the covalent bonds undergo the bond breaking and bond formation processes. A covalent bond is formed by the equal contribution and sharing of a pair of electrons between two atoms of the molecule. fission of such bonds may occur in two ways: (a) Homolytic bond fission or Homolysis. (b) Heterolytic bond fission or Heterolysis. Homolytic Bond Fission

A covalent bond between two atoms A and B may be shown as A–B ÛA:B In a molecule having covalent bond, if one atom (B) is more electronegative than other atom (A), then the bond is polar. If both the atoms of a molecule have same electronegativity, then the bond is non-polar. In case of a homolytic fission the non-polar bond breaks and each fragment, A and B, retains equal number of electrons. If the number of electron is one then the radical is known as free radical which is unstable so it is highly reactive and because of non-polar nature, the free radicals do not have any preference for reaction sites rich or poor in electrons. homolytic

A — B ® A : B ¾ ¾¾ ¾® A• + B• (Free radicals). fission Here each separating group takes one electron. Formation of free radical requires certain energy which should be more than the bond energy of the existing covalent bond. This energy is generally taken from heat, light or catalyst. Commonly the homolytic fission occurs in gaseous reactions and few in case of other phases. The two common types of reactions of free radicals are (1) radical addition and (2) radical displacements. The combination of free radicals results in radical coupling. homolytic

• • For example, CH3 – CH3 ¾ ¾¾ ¾® CH3 + CH3 (free radicals) fission

CH3• + CH3• ® CH3 – CH3 (radical coupling)

3.46

TOXICOLOGY

Heterolytic Fission

When a polar bond undergoes heterolytic fission the pair of electrons remains with one of these fragments (more electronegative), i.e. both electrons go with one group. homolytic

+ – A : B ¾ ¾¾ ¾® A + B : fission

Thus, the heterolytic fission results in the formation of a cation and an anion. The carbon atom carrying a positive charge is called carbonium ion (or carbocation), while the carboanions are negatively charged species containing a carbon atom. For example, homolytic

+ – (i) H3C : Cl ¾ ¾¾ ¾® CH3 (carbocation) + Cl (anion) fission

homolytic

– + (ii) H3C — H ¾ ¾¾ ¾® H3C : (carbanion) + H (cation). fission

Heterolytic fissions are most commonly observed in solutions because the energy used up in heterolysis of a bond can be partly compensated by solvation of the ions. Since the carbonium ions (carbocations) and carboanions (carbanion ions) are charged intermediates they will be preferentially attacked by electron rich or electron deficient reagents, respectively.

3.10.2 Factors Affecting Acid Base Strength An acid donates a proton and a base accepts a proton. The strength of acids and bases is measured by the extent to which they lose or gain protons, respectively. In these reactions acids are converted to their conjugate bases and bases to their conjugate acids. The basicity of a species depends on the reactivity of the unshared pair of electrons in accepting the proton. The more spread out (dispersed, delocalized) is the election density arising from the presence of the unshared pair of electrons, the less basic is the species. Thus, the conjugate acid will be strong. The charge and electron density can be delocalized by the following ways: (i) By extendend p bonding (resonance). (ii) By inductive effect. (iii) By presence of vacant ‘d’ orbitals. (iv) Steric effect and H-bonding. (v) Hybridization effect.

FUNDAMENTALS OF CHEMISTRY

3.47

3.10.3 Inductive Effect The induction of polarity or dipole, in an otherwise non-polar bond, by another is known as inductive effect (I effect). The effect which operates in the presence of an attacking reagent is called temporary effect. The effect which operates in the absence of an attacking reagent is called permanent effect. In the inductive effect, the development of fractional charge in one bond may induce a similar polarity in an adjacent bond, which in turn may propagate it further. The inductive effect is a permanent effect in the ground state of the molecule and usually operates through single bonds. Usually the inductive effect is negligible beyond fourth carbon atom. The inductive effects are two types: (a) –I effect (b) +I effect. –I Effect

The atoms or groups having greater electron affinity (greater electro-negativity) than hydrogen atom are said to have -I effect. For example, –NO2, –OH, –OCH3, –Br, –CI, –F, –CN, –I, –COOH, etc. Let the compounds be like –C2++d – C1+d – Cl–d

–d –C3+++d – C2++d – C+d 1 – Cl

–C4 – C3+++d – C2++d – C1+d – CI–d At –C4, the inductive effect is almost negligible and at –C1 it is more. +I Effect

The atoms or groups having lesser electron affinity than hydrogen, i.e. the atoms or groups those can release the electrons (more electropositive) to the adjacent carbon atom are said to have +I effect. For example, –H, –D, –CH3, –CH2–CH3, –CH (CH3)2 – C (CH3)3, etc. The +I effect of these groups is due to electron releasing nature of alkyl groups. Application of Inductive Effect

(i) Strength of acid: Increase of +I effect will decrease the acid strength +I effect increases H COOH < CH3COOH < C2H5COOH < C3H7COOH decrease in acid strength. Increase in –I effect will increase in acid strength Increase in –I effect Acetic acid < Iodoacetic acid < bromoacetic acid < chloroacetic acid increase in acid strength.

3.48

TOXICOLOGY

(ii) Strength of base: Increase in +I-effect will increase in base strength. +I-effect increases NH3 < CH3 NH2 < (CH3)2 NH < (CH3)3 N Base strength increases Increase in –I-effect will decrease in base strength. (iii) Effect on bond length: Usually the bond length decreases with increase in both inductive effect. Decrease in (–) Inductive effect CH3F, CH3CI, CH3Br, CH3I (iv) Dipole moment: increases.

Increase in bond length As the inductive effect increases dipole moment Increase in (–) I effect CH3I, CH3Br, CH3Cl Increases in dipole moment

3.10.4 Electromeric Effect Electromeric effect (E-effect) involves complete transfer of electrons of a multiple bond to more electronegative atom of the p bond in the presence of an attacking reagent. It is a temporary effect and brought into play instantaneously at the demand of an attacking reagent. :

+ – Polar ¾¾® > C – C < (i) > C = C < ¬reagent :

– + Polar (ii) > C = C < ¬reagent ¾¾® > C – C
C=CC –C
C = C < + CN

:

– >C–C
C – C < (i) > C = C < ¾Br

Br CN

(ii) > C = O < ¾HCN ¾ ¾® > C – OH

3.10.5

Resonance and Resonance Effect and Tautomerism

In many cases, it is not possible to describe the electronic structure of a species adequately with a single Lewis structure. As exemplified by dinitrogen oxide N2O.

:

®

–

+

:

+

:NºN–O: :

:

–

:N=N=O:®

Resonance: If for any given compound two or more structures can be written diferring only in distribution of electrons or lone pair of electrons neither of the structures would explain the behaviour of that compound rather a hybrid of them explains the behaviour of that compound and that hybrid compound possesses less energy than any one. This phenomenon is know as resonance.

H

H :

:

:

:

C:H

:

H:C

:

H:C :C:H

C

:

:

H –d

C

:

(1) H : C : C : H

+d H :

:

H +d

:

–d H

or

:

CH3 – CH3

Examples:

H

H

H

H

H

H

(I)

(II)

(III)

3.50

TOXICOLOGY

Thus, it is a case of functional isomerism. It is considered dynamic isomerism. Inter-conversion of tautomers is hetrolytic in nature, involving the migration of an atom or group from a carbon to anouther atom with necessary rearrangement of linkages. If the migrating group is a cation, tautomeric transformations are known as cationotropic if an anion it is anionotropic. The most common tautomerism involves the migration of a proton and is known as prototropic transformation. If the hydrogen atom travels from one to another of the two polyvalent atoms linked together, the system is dyad. If the hydrogen atom travels from first to third in a chain, the system is a triad and so on. e.g., H–CºN C ¬N–H Hydrogen cyanide Hydrogen isocyanide Two polyvalent atoms (C and N) ® Dyad (2) Triad System

(1) Dyad System

R — CH — C — R

1

R — CH — C — R

H O Keto form

1

O—H enol form

Acetoacetic Ester CH3 — C — CH — COOC2H5 — O

CH3 — C = CH — COOC2H5 — OH

H

Keto form (92%)

enol form (8%)

Stability of enolic form is ascribed to the formation of intramolecular hydrogen binding. CH3 — C = CH — C — O C2H5 O —H

... O

Characteristics of Tautomerism

(1) Tautomers are discrete chemical entities, capable of isolation under suitable conditions, frequently they give rise to separate series of stable derivatives. (2) Tautomerism if caused by the migration of a group or atoms between two polyvalent atoms of the same molecule. It is thus reversible intramolecular transformation. (3) Tautomers differ from each other in stability. The less stable form is called labile form. (4) It is a dynamic equilibrium.

FUNDAMENTALS OF CHEMISTRY

3.10.6

3.51

Reaction Intermediates

Energy is needed to break bonds, while energy is released during bond formation. When reactants collide with sufficient enthalpy of activation and with the proper orientation, they pass through a hypothetical transition state in which some bonds are breaking while others may also be forming. The energy of a reaction Vs. the progress of the reaction is plotted on a potential energy diagram. The progress of the reaction is expressed as reaction coordinate and is measured in terms of bond breaking and bond forming. If the product releases more energy than the reactant, then the reaction is exothermic; while, in case the product releases less energy than the reactant, then the reaction is endothermic. That is, if DH is negative then reaction is exothermic and DH is positive, the reaction is endothermic. From the diagram it is clear that the rate is faster if the transition state is lower, while the rate is slower if the transition state is higher.

Potential Energy or Enthalpy

Transition State (HTS)

+

DH = HTS – HR D Reaction = HP – HR

HR HP Reaction Progress

Fig. 3.6

Reaction progress.

Potential Energy

A reaction intermediate is also a transient species formed during a reaction and corresponds to an energy minimum on the potential energy diagram. Intermediate Intermediate Ea HR

Ea DH

HP

HR HP Reaction Progress

Fig. 3.7

Formation of intermediates.

3.52

TOXICOLOGY

The number of intermediate compounds formed determines the steps involved in a chemical reaction. If no intermediate forms the reaction is one step. If one, two or three intermediates form, then the reaction is two steps, three steps or four steps, respectively and so on. A vast majority of organic reactions takes place via the formation of intermediates. There are four different intermediates (short lived) through which the reaction proceeds. 1. Carbonium ions (or Carbocations): Carbonium ions are positively charged species containing a carbon atom having only six electrons in three bonds. C+

The carbocations differ in stability depending on the nature of the groups attached to the positively charged carbon atom. The order of stability can be predicted conveniently by either of the (i) resonance (ii) inductive and (iii) hyperconjugation effect. The order of stability of carbonium ion is as R3C+ > R2C+ H > RC+ H2 i.e. 3° > 2° > 1° Alkyl groups (hyperconjugation) CH2 = CH – CH2+ « C+H2 – CH = CH2 (stabilised by resonance) Cl – CH2 – CH2+ > Cl – CH2 – CH2 – C+H2

> Cl – CH2 – CH2 – CH2 – C+H2 (inductive effect)

Carbonium ion is formed by heterolytic fission. 2. Carbanions: Carbanions are negatively charged species containing a carbon atom with three bonds and an unshared pair of electrons. C:

(Carbanion) It is also formed by heterolytic fission. A carbanion is stabilized by (i) Resonance, and (ii) +I-effect. The order of stability of carbanion is as CH3 – CH2– > (CH3)2 CH– > (CH3)3 C–, i.e. 1° > 2° > 3° 3. Free radicals: Free radicals are species with at least one unpaired electron. This radical has total 7 (seven) electrons. C

(Free radicals)

It is formed by homolytic cleavage. The free radical is stabilized by the resonance factor analogous to carbonium ion.

FUNDAMENTALS OF CHEMISTRY

CH2

CH2

·

·

CH2

·

R3 C > R2 C H > R1 C H2

3.53

CH2

i.e. 3° > 2° > 1°

4. Carbene: Carbenes are neutral species having a carbon atom with two bonds and two electrons, i.e. total six electrons. These are two kinds (i) Singlet

C

In this, the two electrons have opposite spins and are paired in one orbital. (ii) Triplet

C

In which the two electrons have the same spin and are in different orbitals. This is formed by a-elimination which may be stated as the elimination of both groups from the same carbon atom.

R

C

H Cl

–H + Base

¬¾¾®

R R

– C

Cl -

:

R

Cl

¬¾ ¾®

R R

C:

One of the most important reactions of carbenes is their addition to an alkene to yield a cyclopropane and the process is called cyclopropanation.

3.10.7

Classification of Reactions

Broadly five types of change take place during the organic chemical reactions. 1. Addition reaction: When two molecules combine to yield a single molecule. Addition frequently occurs at double or triple bond and sometimes at small size rings. C2H4 + Br2 ® C2H4Br2 2. Elimination reaction: This is the reverse of addition reactions. Two atoms or groups are removed from a molecule. Removal of the atoms or groups from different atoms produces another bond between these atoms. Removal of atoms or groups from the same atom is called =-elimination which produces a carbene. If the atoms or groups are taken from adjacent atoms and, 1st and 3rd atoms then these are called >-elimination and C-elimination, respectively, producing a multiple bond and a ring structure, respectively.

TOXICOLOGY

(i)

C

—

H

H

a-elimination

Cl

¾ ¾¾¾¾ ¾®

b-elimination

—

C=C

Br

—

—

—

—

(ii) — C — C ¾ ¾¾¾¾® H

C:

Br

—

3.54

C g -elimination

C—C

—

—

—

(iii) — C — C — C — ¾ ¾¾¾¾®

3. Substitution (displacement) reaction: The reaction in which an atom or group of atoms is replaced by another atom or group. Depending on the nature of attacking reagent the substitution reaction may be nucleophilic or electrophilic substitution reaction. A – X + N u ® N u – A + X– (Nucleophilic Substitution) (Nucleophile) A – X + El+ ® El – X + A+ (Electrophilic Substitution) (Electrophilic) 4. Rearrangement reaction: Bonds in the reactant are scrambled as in conversion of a compound to an isomer.

R

:

O R

¾® ¾ R CN HR

C=N OH

5. Redox reaction: These reactions involve transfer of electrons or change in oxidation number. A decrease in the number of H atoms bonded to C and an increase in the number of bonds to other atoms such as C, O, N, CI, Br, F and S signals oxidation. D 3CH3CHO + 2MnO4– + OH– ¾ ¾ ® 3CH3COO– + 2MnO2 + 2H2O

3.10.8 Types of Attacking Reagent Chemical attacking reagents have been classified into two types, namely electrophiles and nucleophiles. 1. Electrophiles: Electrophiles or electron loving are those reagents that are positively charged and sometimes are neutral (electron deficient atom). These are electron deficient chemical species. Due to the electron deficiency, it always attacks at the centre of high electron density.

FUNDAMENTALS OF CHEMISTRY

3.55

(a) Positive electrophiles: These are +vely charged species, for example, NO2+, Br+, Cl+, RN2+, Ag+, CH3CH2+ H3O+, etc. (b) Neutral electrophile: These have at least one electron deficient, i.e. free radicals. For example, R•, BF3, AlCl3, FeCl3, SOCl2, SO3, carbenes, etc. 2. Nucleophiles: Nucleophiles or electron repelling are those reagents that are negatively charged, i.e. electron-rich chemical species. Due to the presence of a pair of free electrons, it always attacks at the centre of low election-density. These are: (a) Negative nucleophiles: These are –vely charged reagents like F–, Cl–, CN–, CH3COO–, C2H5O–, OH–, R–, etc. (b) Neutral nucleophiles: These are neutral but possess an electron-rich atom, ..

..

..

..

..

..

i.e. H2 O . . , N H3, R O .. H, R N H2, R2 N H, R O .. R, etc. 3. Ambient nucleophiles: When a nucleophile has electron-rich centre on both sides, it is known as ambient nucleophile such as CN–, NO2–, since CN – can act as a nucleophile from carbon side as well as nitrogen side: For example, R – X + CN – ® R – C º N R – X + CN– ® R – N º C Nucleophilicity Order

The nucleophilicity order based on electronegativity or basicity of the nucleophile. It increases with the increase in electronegativity of the nucleophile. Increase in nucleophilicity F– < Cl– < Br– < I– Increase in electronegativity.

3.10.9

Conjugation and Hyperconjugation

Conjugation: If the single and double bonds are present alternately in a molecule, it is said to contain double bonds in conjugation and the molecule is called conjugated molecule. CH2 = CH – CH = CH2 (1, 3, Butadiene) The double bonds in a conjugated system do not behave as an isolated double bonds. In case of addition with Br2 molecule they result in a mixture addition products, as CH2 = CH – CH = CH2 + Br2 ® Br Br Br Br ½ ½ ½ ½ CH2 – CH = CH – CH2 + CH2 = CH – CH – CH2 (Major Products)

3.56

TOXICOLOGY

Thus, conjugation effect in molecules results in large deviations from their usual behaviour. Hyperconjugation: Hyperconjugation is defined as the conjugation ability of sigma (s) electrons of a-hydrogen atom with unsaturated system when a H—C bond is attached to an unsaturated system. H

H

H—C—C=C H

+

H

H H

H

H—C=C—C

H

H

H H H

+

H

H —C=C—C H

–

H

–

H H

H

H—C=C—C +

H

–

H

Since s electrons are less polarizable than p or n electrons, the contribution of the ionic forms involving s bonds will be less significant than that of ionic forms involving p and n electrons.

EXERCISE 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

What is quantum theory of radiation? Define the quantum numbers and explain them. How do the electrons fill in the orbitals? Describe briefly about the periodic table and the periodic properties of elements. What are the reasons behind the formation of chemical bonds? Differentiate between ionic and covalent bond. What do you mean by conjugate acid-base pair? Explain the common ion effect. What is solubility product? What is thermodynamic equilibrium? Explain the second law of thermodynamics. What is phase rule? Explain it for one-component system. What are the electrochemical cells? Calculate the e.m.f. of a cell. Differentiate between order and molecularily of a reaction. What are the absorption laws? What do you mean by colloidal solution? Explain the reaction intermediates and define the different reactions.

CHAPTER

"

Toxic Inorganic and Radioactive Elements 4.1

INTRODUCTION

There are three types of inorganic element, based on their physical and chemical properties, these elements may be grouped as metals, metalloids and non-metals. Many of these elements are very essential for animals and plant lives for their growth and metabolic activities. Besides, carbon, hydrogen, oxygen and nitrogen, there are twenty (20) elements have been identified which are very essential for biosphere. The seven major mineral elements calcium, potassium, sodium, phosphorus, magnesium, chlorine and sulphur are the integral parts of amino acids, nucleic acids and structural compounds. The remaining thirteen (13) elements are required in minute quantity. Therefore known as microonutrients or trace elements. These elements are iron, iodine, copper, zinc, manganese, cobalt, molybdenum, selenium, chromium, nickel, vanadium, silicon and arsenic. For example, iron is the part of haemoglobin, cobalt is on chloroplast, zinc is an essential component of at least 150 enzymes, etc. Similarly, there are many elements which are very toxic to the animals and plant lives. The elemental forms of some elements are extremely toxic to the biosphere. A number of metals form very toxic ions. Metals differ from other toxic elements because they are very susceptible to speciation. For example, hexavalent chromium is highly toxic, whereas trivalent chromium is an essential element (trace). The speciation or biochemical form of the metals determines the toxic behaviour of that metal or other element. The degree of toxic action of the metal may involve an interaction between the free metal ion and the toxicological target. Ligand binding is probably the most important chemical process in metal toxicity as it forms complex ions and chelates.

4.2

TOXICOLOGY

4.2

FACTORS INFLUENCING THE METAL TOXICITY

Toxicity of a metal is influenced by a number of factors besides the amount and frequency of toxicant exposure to an organism. The factors influencing the toxicity of a metal are: • Interaction with essential metals. • Speciation or different chemical form of the metals • Formation of metal-protein complexes. • Sensitivity of an organism to that metal. • Immune status of the organism Interaction with Essential Metals

The interaction of toxic elements or metals with essential metals occurs when the metabolism of a toxic metal is similar to that of the essential element (Goyer, 1995). The toxic metals which are influenced by homeostatic mechanism, do interact with the essential metals. For example, lead, calcium and iron do interact with each other as they are influenced by homeostatic mechanism. Similarly, cadmium and iron also interact with each other. Speciation of Metals

Metal toxicity is also dependent on the speciation, i.e., the different forms of metals which is determined from valency state and ligand binding nature. For example, non-ionized compounds are lipophilic and pass readily across biological membranes unaltered by their surrounding medium. The organic forms of metals differ in toxic properties from the inorganic metals. For example, alkyl mercury is more toxic than mercuric chloride. Mercuric chloride affects kidneys whereas alkyl mercury affects nervous system. Formation of Metal Protein Complexes

Many proteins and enzymes are the suitable target of toxicity. Many toxic metals get attached to haemoglobin or serum albumin and are transported through bloodstream and then distributed between red cells and plasma. Transferrin is a glycoprotein that binds most of ferric iron ( Fe+3), Al +3, Mn +2, etc. in blood plasma. Proteins also play a protective role by reducing the toxic activity. For example, ferrin serves as a metal detoxicant, because it easily binds a variety of toxic metals including Fe, Cd, Zn, Be and Al. Ceruloplasmin is a coppercontaining glycoprotein oxidase in plasma which is able to convert ferrous iron to ferric iron. This ferric iron then binds to transferrin and is transported into the bloodstream. Sensitivity of an Organism to Metal Toxic

The organisms with high sensitivity are more susceptible to metal toxicity even for low concentration. Some organisms are very sensitive to a particular metal toxicity whereas others are very resistant to the same substance.

TOXIC INORGANIC AND RADIOACTIVE ELEMENTS

4.3

Immune Status of the Organism

For metals that produce hypersensitivity reactions determine the immune status of an individual. Chemical allergy is an immunologically medical adverse reaction to a chemical resulting from previous sensitization to that chemical. The metals like mercury, gold, platinum, beryllium, chromium and nickel induce the immune reaction in a body. There are four types of immune reaction in a body. There are four types of immune response and these are: • Immediate hypersensitivity. • Immune complex hypersensitivity. • Cytotoxic hypersensitivity. • Cell mediated hypersensitivity. In the immediate hypersensitivity reactions, the antibody reacts with antigen to result as in urticaria, conjunctivitis, etc. The thrombocytopenia occurs due to cytotoxic hypersensitivity reactions. Immune complex hypersensitivity occurs when soluble immune complex forms deposits within tissues producing an acute inflammatory reaction. Cell mediated hypersensitivity also known as delayed hypersensitivity reaction which is mediated by thymus-dependent lymphocytes and usually occurs 24 to 48 hour after exposure (Goyear and Thomas 2001).

4.3

COMPLEXATION AND CHELATION

Most of the transition metals are capable to form complex ions with electron donor functional groups on ligands. The ligands may be charged or uncharged electron donors. Based on the number of donor atoms on the ligands, these may be monodentate, bidentate or polydentate. When polydentate lignads combine with a metal ion to form a stable ring-like structure is called chelation. For example, a polydentate ligand called amino acid glycine combines with copper (II) ion to form a stable chelate. Generally, the chelation with four or more membered ring is very stable.

H H

N *

H

H C

O C

*O

H

–

O*

C O

C H

Cu

+2

Glycinate anions

O

Cu O

H C

N* H

C

H

H +

H

C N

–

H

O

H

O

H N

C

H Copper chelate

H

4.4

TOXICOLOGY

The ligands which are able to form a chelate ring are called chelating agents. In toxicology the chelating agents are organic ligands which can either break or prevent the binding of metallic ions to tissues. Generally, these ligands have donor atoms such as O, S or N atoms which can donate electrons and form a stable complex compound. Thus, complexation and chelation methods are used to detoxify the toxic effects of heavy metals. The important characteristics of ideal chelating agents for toxicology are: • The chelating agents should be water soluble. • They should be non-degradable, i.e., having resistance to biotransformation. • They should have access to the site in the body where the metal ions are bound. • Capable to form non-toxic complexes with toxic metals and should have low affinity towards essential metals. • They should be easily eliminated from the body. • They must be stable at the body’s pH value.

4.4

METAL TOXICITY WITH MULTIPLE EFFECTS

Metals are probably the oldest toxin known to humans. Many metals form both inorganic as well as organic forms which have the toxic effects on living organism. Inorganic forms of most metals tend to be strongly bound by protein and other biological tissue. As a result, it increases bioaccumulation and inhibits excretion. But the organic form of mercury has more toxic effects than the inorganic form of mercury. There is a strong affinity between the electron-donor groups and metals for binding in the protein or biological tissues. These metals tend to accumulate in target organs, and toxic effect is observed when the concentration of the metal in the organ exceeds the threshold level. Liver and kidneys are the most affected organs by metal poisoning as these two organs are the largest (liver, then kidney) screening organ for detoxification. Some important individual metals and their multiple toxic effects are discussed in detail below:

4.4.1 Arsenic (As) Chemistry Arsenic is a metalloid and member of group Vb of the periodic classification. Arsenic undergoes multiple electron transfer reactions. Arsenic is widely distributed in the environment, including plant and animal tissues. The variable chemical behaviour of arsenic is due to its existence as both trivalent and pentavalent compound. Thus, it forms a variety of inorganic and organic compounds of different toxicity to living organisms. The most common inorganic trivalent arsenic compounds are arsenic trioxide (As2O3), arsenic trichloride

TOXIC INORGANIC AND RADIOACTIVE ELEMENTS

4.5

(AsCl3), arsenic hydride (AsH3) and sodium arsenite. Arsenic hydride (AsH3) is extremely poisonous. The pentavalent inorganic compounds are arsenic pentoxide, arsenic acid, lead arsenate and calcium arsenate. These pentavalent inorganic compounds are used as pesticides. Arsenic both trivalent and pentavalent species combine strongly with sulphur and carbon as organic compounds. The oxidation of arsenite to arsenate is slow at natural pH value approximately ranging from 6.5 to 7.5. But oxidation reactions are faster in strong alkaline or acidic conditions. Toxicokinetics The stable, soluble inorganic arsenite and arsenates are readily absorbed by the intestinal tract and muscle tissues. Skin and pulmonary systems are the major routes of exposure. Arsenate is excreted faster than arsenite, mostly through urine because of its poor affinity for thiol groups. Thus, arsenate is less toxic than arsenite and does not inhibit any enzyme system. Biotransformation Arsenic compounds in the environment are vulnerable to chemical and biological transformations. Biochemically, arsenic acts to coagulate proteins, forms complexes with co-enzymes, and inhibit the production of ATP. Arsenic readily undergoes alkylation and arylation in the environment. The methylation of arsenic compounds involves both tri- and pentavalent states of arsenic. The methylation of arsenic takes place in liver. These methylated arsenics are less toxic and more readily excreted than inorganic form of arsenic. Because methylated arsenics are more soluble and have less affinity for thiol groups. In the metabolic process arsenic substitutes with phosphorus with adverse metabolic effects. In this process arsenate inhibits ATP synthesis by oxidative uncoupling reactions as shown: H H e

2–

H

C

PO3

HO

C

H

H

C

O

at sph

o

Ph Ar

sen

ite

(A

sO

3

Glyceraldehyde 3-phosphase

2–

PO3

H

C

O

HO

C

H

O

C

O

PO3

PO3

Leads to ATP synthesis

2–

H

3–

)

H

C

O

HO

C

H

O

C

O

2–

Spontaneous hydrolysis No ATP synthesis

2–

AsO3

Fig. 4.1 Inhibition the production of ATP by arsenite.

4.6

TOXICOLOGY

Toxic Effects Toxicity of arsenicals varies with valency state. Arsenite is more toxic than arsenate. The trivalent arsenic compounds are the principal toxic forms and inhibit the enzyme activity. But pentavalent arsenic compound has little effects on enzyme activities. Arsenites bind strongly to thiol groups and tissue proteins such as carotin in skin, nail and hair. Systemic toxicity has been reported in persons having extensive acute dermal contact with solutions of inorganic arsenic (Hostynek et al. 1993). Arsenic affects mitochondrial enzymes and impairs tissue respiration (Brown et al. 1976). Inhibition of mitochondrial respiration results in decreased cellular production of ATP and increased production of hydrogen peroxide, which might cause oxidative stress, and production of reactive oxygen species as mentioned in the Figure 4.1. Chronic exposure to inorganic arsenic compounds may lead to neurotoxicity of both the peripheral and central nervous system, respiratory distress, damage to kidneys and respiratory tracts.

4.4.2 Beryllium (Be) Chemistry Beryllium (Be) is a group 2 A element and is probably the first metal in the periodic table to be notably toxic. Coal combustion is the major source of beryllium in the environment. Toxicokinetics Beryllium is largely absorbed in gastrointestinal tract because of the acidic nature of stomach. In the acidic condition, beryllium is highly soluble and present in ionized form. Biotransformation Beryllium is distributed to all tissues. Beryllium is highly found in skeleton. It is thoroughly screened by the liver. But high dose of beryllium can pass or transfer to the bones. Toxic effects Beryllium has a number of toxic effects, contact dermatitis is the common beryllium related toxic effect. Skin ulceration and granulomas have resulted from exposure to beryllium. Acute pulmonary disease occurs from inhalation of aerosols of soluble beryllium compounds. The most damaging effect of chronic berylliosis is long fibrosis and pneumonititis. Beryllium also decreases the fidelity of DNA synthesis. The organs like liver, kidneys, heart, and spleen are adversely affected by chronic berylliosis.

4.4.3 Cadmium (Cd) Chemistry Cadmium is one of the “big three” modern heavy metal poisons. The other two heavy metals are lead and mercury. Cadmium is the second member of group II b – Zn, Cd and Hg in the periodic table. The stable state of cadmium in the natural environment is Cd (+2). The two outer ‘S’ electrons in cadmium are the only ones involved in bonding and the + 2 oxidation state of the element is the only one exhibited in its compound upto pH 8. Cadmium is an

TOXIC INORGANIC AND RADIOACTIVE ELEMENTS

4.7

oxyphilic and sulphophilic element and it undergoes multiple hydrolysis at pH values encountered in the environment. Because of its strong affinity for sulphydryl groups, leading to increase in the lipid solubility, bioaccumulation and toxicity. Cadmium is a soft metal, with low melting point and high electropositive metals. Toxicokinetics Cadmium is poorly absorbed through gastrointestinal tract. Absorption of cadmium is increased by dietary deficiencies of calcium and iron. Low dietrary calcium stimulates synthesis of calcium-binding proteins (CaBP) which may aggravate cadmium toxicity. Absorbed cadmium may be eliminated from the body through urine. Cadmium is transported in blood by binding to red blood cells (RBCs) and albumin. Biotransformation Cadmium accumulates in liver and kidney through its strong binding with cysteine residues of metallothionein. Since metabolism of cadmium is closely related to zinc metabolism, metallothionein binds and transports both cadmium and zinc. Cadmium imparts moderate covalency in bonds and high affinity for sulphohydryl groups as per the following reaction.

HS

HS

H

H

O

C

C

C

H

NH3

+ Cysteine

SH

Metallothionein

+

Cd

+2

O

–

Cd

S

S

Metallothionein

+

2H

+

Toxicity Cadmium accumulates in organs and has a long shelf-life about 10 to 30 years in humans. About half of the total cadmium in the body is found in the organs like liver and kidneys. Acute toxicity may result from the ingestion of high dose of cadmium chloride, cadmium oxide fume and cadmium carbonate which are more toxic than less soluble cadmium sulphide (Klimisch, 1993). Cadmium in the body is known to affect several enzymes. Chronic obstructive pulmonary disease and emphysema and chronic renal tubular disease are caused due to low level exposure of the organism to cadmium for a long period.

4.4.4 Chromium (Cr) Chemistry Chromium (Cr) is a transition metal having variable covalency ranging from +2 to +6 state. Out of these oxidation states, only Cr+3 and Cr+6 forms are of biological significance. The most important oxidation state of Cr is +3 which forms large numbers of kinetically inert complexes. Chromium (+6) exists only as oxy species such as CrO3, CrO42– and Cr2 O72– and is strongly an oxidising agent. Chromium (+3) and (+6) are classified as hard acids, thus chromium is one of the least toxic of the trace elements.

4.8

TOXICOLOGY

Toxicokinetics

Chromium is found in small quantities in RNA of few organisms. Chromium is not a significant contaminant of plant tissues. Chromium is readily transferred through food but there is no indication of bioaccumulation. Unlike other metals, chromium does not concentrate strongly in specific tissues. In most species, food is probably a more significant source of chromium than water. Uptake is often temperature dependent and thus there is a seasonal cycle in chromium levels in natural populations (Karbe et al., 1977). Generally, rate of uptake of chromium is the greatest in young individuals and this rate decreases with increase in age. Biotransformation

Metal ions that biological system can use must be abundant in nature and relatively soluble in water. Abundance restricts the available metals to those of atomic number less than 40. The chromium (+6) known as chromate is more toxic than chromium (+3). Sodium chromate (Na2 CrO4) salts are main source for occupational exposure as these salts are the principal substances for the production of all chromium chemicals. These salts are easily water soluble and readily absorbed into the bloodstream through the lungs. An increase in blood, chromium is related to increased chromium red blood cells. Chromates readily cross cell membranes on anion carriers as they are isostructural with sulphate and phosphate anions. In the body at stomach acidity, chromium (+6) is readily reduced into chromium (+3) form as shown in equation, whose gastrointestinal absorption is less than 1% which can be excreted through urinary tract. Cr O42– + 8 H + + 3e– ® Cr +3 + 4 H2 O. Toxicity

Chromium is not acutely toxic to humans because of the high stability of natural chromium complexes in abiotic matrices. The major effect from ingestion of high levels of Cr(+6) is acute tubular and glomerular damage. Hexavalent chromium has some mutagenic properties. The chromium salts like calcium chromate compounds have induced high levels of chromosomal aberrations in cultures of mammalian cells. Evidence of kidney damage is reported from low level chronic exposure of Cr(+6) (Wedeen 1991). Allergic chromium skin reactions readily occur with exposure and are independent dose (Proctor et al., 1998). Occupational exposure to chromium may cause asthma (Bright et al., 1997). The toxicity of chromium (+6) and (+3) to aquatic organisms is generally low. Sublethal /chronic effects of chromium intoxication include decreased growth and body size.

4.4.5 Copper (Cu) Chemistry Copper is generally considered one of the eight essential metals required for metablism of life. The other essential metals are cobalt, zinc, iron,

TOXIC INORGANIC AND RADIOACTIVE ELEMENTS

4.9

magnesium, manganese, molybdenum and selenium. Copper is widely distributed in nature on the free state and in sulphides, arsenides, chlorides and carbonates. Copper belongs to third transition metal series. Copper has the variable valency of +1, +2 and +3 but Cu (+2) is most common and Cu(+1) is a soft acid. Toxicokinetics

Copper is absorbed in gastrointestinal tract by homeostatic mechanisms. Copper is involved in the natural selection of aerobic cells and the evolution of metalloproteins and metalloenzymes. Most copper is stored in liver and bone marrow, where it may be bound to metallothionein. Several copper-containing proteins have been identified in the body. Ceruloplasmin, a blue protein in mammalian serum accounts for over 95% of the circulating copper in mammals. In the biological process, copper is co-ordinated to nitrogen, oxygen and sulphur ligands. Thus, the dominant role of copper in biological systems is its ability to stabilize sulphur radicals. Copper-metallothionen accumulates in lysosomes, facilitating the biliary excretion of copper. Biotransformation

Copper interacts strongly with sulphur forming relatively stable insoluble sulphides. Being an intermediate acceptor between soft and hard acids, copper complexes with nitrogen and sulphur containing ligands. Copper is a component of all living cells and is associated with many oxidative processes. The copper superoxide dismutase undergoes reduction to form hydrogen peroxide. Impairment of the function of several metalloenzymes, including type A oxidases, type ‘b’ monamine oxidases and of the type B oxidases, cytochrome Coxidase enzymes is responsible for the various diseases associated with copper deficiency (Chan et al., 1998). Molybdenum influences tissue levels of copper. Toxicity

Copper is not acutely toxic to humans but highly toxic to most of the aquatic plants and animals. Copper deficiency in humans initiates chronic copper intoxication. The major route for copper to enter human body is drinking water. The concentration of more than 3 mg /L will produce gastrointestinal symptoms including nausea, vomiting and diarrhoea (Pizaro et al., 1999). Copper is not very toxic to humans because it has intermediate co-ordinate character. Thus, it does not interfere with sulphur containing proteins.

4.4.6 Iron (Fe) Chemistry Iron is also one of the essential metals for humans. There are two oxidation states on which iron normally occurs, the ferrous form (Fe+2), and the ferric form (Fe+3). Its chemical behiviour is influenced by its ability to form complex ions with sulphides, sulphates, oxides, and chlorides. The ferrous form (Fe+2) forms weaker complexes than the ferric forms. From the ecotoxicological

4.10

TOXICOLOGY

point of view, these two forms are important in terms of deficiency and acute exposures which influence the mechanisms of toxicity. Toxicokinetics

Iron is absorbed about 2 to 15 per cent from the gastrointestinal tract. Since the iron has the ability to form complex with sulphides, the disposition of iron in the body is influenced by a complex mechanism to maintain homeostasis. Iron absorption is regulated by quantity and bioavailability of dietary iron and rate of erythrocyte production. Absorption of iron in the body occurs in two steps. Absorption of ferrous form occurs from the intestinal lumen into the mucosal cells and transfer from the mucosal cells to storage sites. The elimination of absorbed iron takes place only 0.01 per cent per day through urine and sweat. Biotransformation

Most of the absorbed iron is bound to haemoglobin, about 10% to myoglobin and iron containing enzymes and the remains are bound to iron storage proteins ferritin and hemosiderin. Both ferritin and hemosiderin maintain intracellular iron in the body. A portion of iron taken up by the cells of reticuloendothelial system enters a labile iron pool available for erythropoiesis. Liver is the organ where excess iron is synthesised into ferritin which in turn is converted into hemosiderin by lysosomes. Toxicity

Acute iron toxicity occurs from accidental ingestion of iron containing medicines which may cause metabolic acidosis, liver damage and coagulation defects. Chronic iron toxicity occurs due to excess exposure. Iron in reticuloen-dothelial cells enters a labile pool of iron available for erythropoiesis which may cause disturbances in liver function, diabetes mellitus and cardiovascular effects.

4.4.7 Manganese (Mn) Chemistry Manganese is also an essential metal for humans. Manganese chemistry is appreciably more complex than iron because of its greater number of valencies from +1 to +7. The most common valencies are + 2, + 4 and +7. But in biological system manganese (+ 2) and (+ 4) are more significant. To some extent (Mn+3) also plays important role in biological system. Mn (+ 3) in present in free radicals, thus they have more deleterious effects on the biological systems. Manganese (Mn) is a cofactor of many enzymatic reactions involving cholesterol, phospho-rylation and fatty acids synthesis. Manganese is present in all living cells. Toxicokinetics Manganese generally concentrates in mitochondria, and also found in tissues like liver, kidneys, pancreas and intestines. Manganese is absorbed about 5% or less in gastrointestinal tract. Manganese is found in all living cells. Manganese readily crosses the blood-brain barrier and enters into the cells.

TOXIC INORGANIC AND RADIOACTIVE ELEMENTS

4.11

Biotransformation

Manganese (+3) is the oxidative state in superoxide dismutase and it interacts with Fe+3 state. Biological half-life in the body is 37 days. Manganese is eliminated in the bile and is reabsorbed in the small intestines. Toxicity

Acute exposure of manganese causes a disease called manganese pneumonitis. In the chronic inhalation exposure to manganese dioxide affects the nervous system of humans. It produces a neuropsychiatric disorder characterized by irritability, difficulty in walking and speech disturbances. It also causes liver cirrhosis. The persons which are affected by the excess manganese exposure tend to recover slowly.

4.4.8 Mercury (Hg) Chemistry Elementary mercury is the only metal that is a liquid at room temperature. It is the third member of the group II b triad of the periodic table of elements. The vapour from the liquid mercury referred as vapour mercury which is more toxic than liquid mercury. Mercury (Hg) exists in three oxidation states. Hg(O), Hg (+1) and Hg(+ 2) are readily interconverted in the environment. From the toxicological point of view, mercurials are classified as: • Elemental mercury. • Inorganic mercury compounds • Organomercury compounds. Organomercury compounds are more toxic than inorganic mercury compounds and/or elemental mercury. Methyl mercury (CH3 Hg +) is the most important organomercury compound and has adverse toxic effects on human health. In the inorganic mercury compounds, mercury (II) chloride (HgCl2) is very toxic. The effects of exposure to HgCl2 are aggravated by its high water solubility and relatively high vapour pressure. Toxicokinetics

The mercury vapour is absorbed from inhaled air by the pulmonary route to the extent of about 80 %. Inorganic mercury compounds are absorbed through the intestinal tract and in solution through the skin. Mercury is easily dissolved in bloodstream and then diffuses to all tissues in the body. Mercury vapour is a monoatomic gas which is highly diffusible and lipid soluble whereas the inorganic mercury compounds (HgCl2 ) have low water solubility and are poorly absorbed from gastrointestinal tract. Kidneys contain the greatest concentration of inorganic mercury. Organic mercury compounds have greater affinity for the brain and central nervous system than the inorganic mercury compound. Excretion of mercury occurs through urine and faeces.

4.12

TOXICOLOGY

Biotransformations

Mercury forms in the environment a group of organo-mercury compounds. These are divided into two categories: (i) those in which mercury is amphiphilic and (ii) those in which mercury is liphophilic. Methyl mercury is an amphiphilic which undergoes biotransformation to divalent mercury compounds in tissues by cleavage of carbon-mercury covalent bond. Biological methylation could be due to enzymatic or non-enzymatic processes. Mercury (II) has a strong affinity for sulphydryl groups in enzymes, proteins, haemoglobin and serum albumin. Thus, biological methylation occurs by enzymatic processes. Toxicity

In liver cells, methyl mercury forms soluble complexes which are secreted in bile. The kidney is the primary target organ of Hg(+ 2). Chronic exposure to inorganic mercury (II) particularly HgCl2 causes proteinurea. Mercury affects largely to the metabolic processes of brain. Mercurous mercury is less toxic than methyl mercury. The major human health effects from exposure to methyl mercury are neurotoxic effects in adults (Bakir et al. 1973).

4.4.9 Lead (Pb) Chemistry Lead is a member of the group IV elements and has stable (+2) and (+ 4) oxidation states. It is a ‘P’ block metal. Pb(+2) compounds are predominantly ionic and Pb (+ 4) compounds tend to be covalent. It forms organo-derivatives. Lead forms alkyl and aryl compounds. Most of the lead (+ 2) salts are water insoluble. Lead is present in all biological systems. It is toxic to most living organisms at high exposures. Lead dioxide and lead sulphate salts are also very useful Toxicokinetics

Anthropogenic inputs of lead into the atmosphere is quite high, thus there is every opportunity for exposure of the general population relatively abundant. Absorption of lead through the respiratory tract is the most common route of human exposure. Lead absorption by the lungs depends on the volume of air respired per day, state of lead (vapour or solid) and the size distribution of lead containing particles. The compounds like lead oxide, lead carbonate, lead halides, lead phosphates and sulphates are inhaled by humans. More than 90% of the lead in blood is in red blood cells. Lead in bone may contribute as much as 50% of blood lead, so that it may be significant source of internal exposure to lead. The fraction of lead increases in bone with age. The lead absorption decreases with increased levels of calcium in the diet and vice versa. The major route of excretion of absorbed lead is the urinary system. Lead accumulation on total tissues, including brain, is proportional to maternal blood lead levels (Goyer, 1996).

TOXIC INORGANIC AND RADIOACTIVE ELEMENTS

4.13

Biotransformation

Lead tends to accumulate in bone throughout life with a half-life of lead more than 20 years. Organoleads are less stable because of the weak lead-carbon bond. Generally, aryl lead compounds are more stable than alkyl lead compounds. The most common biochemical effect of lead is inhibition of the synthesis of heme, a complex of a substituted porphyrin and Fe+2 haemoglobin and cytochromes. The largest soft tissue accumulations of lead are in liver and kidney. Lead has a great affinity for sulphydryl groups. Thus, lead inhibits the enzymatic activities that have the sulphydryl groups. Toxicity

The toxic effects from exposures to inorganic lead form a continuum from subtle or biochemical effects to clinical or overt effects (Goyer, 1990). The critical effects or most sensitive effects in infants and children involve the nervous system (ATSDR, 1999). Lead adversely affects a number of systems which include irritability, restlessness, dullness and memory loss. Lead exposures increase the hypertension in humans. Besides, central nervous system, the other target organs are the gastrointestinal, reproductive and skeletal systems. Lead causes reversible damage to the kidney through its adverse effect upon proximal tubules. Lead has multiple haematologic effects. EDTA (ethylene diamine tetraacetic acid) and British Anti Lewisite (BAL) are used to remove or for treatment of lead poisoning.

4.4.10 Nickel (Ni) Chemistry Nickel is placed in group VIII in the periodic table. Nickel can exist in different oxidation states from +1 to +4 compounds. Nickel (+2) states are most common. Nickel is found in abundance on the earth’s crust as oxides, carbonates, silicates with iron, magnesium and as sulphides, arsenides and tellurides. Nickel is also considered an essential metal for humans. Nickel has competitive interactions which are more prevalent with copper than zinc. Toxicokinetics

Nickel (+2) forms stable complexes with inorganic and organic ligands. Nickel is absorbed through inhalation followed by dermal exposure. Almost 35% of inhaled nickel is absorbed into the blood from the respiratory tract (WHO, 1991). The concentration and particle size of nickel regulate the deposition, absorption and elimination of nickel particles in the respiratory tract. Biotransformations

Nickel has a central function in metabolism. Nickel, when administered in acute excess interferes with detoxification activities. It also interferes drug metabolism of the liver by altering both the synthesis and the degradation of cellular heme and the liver glutathione levels.

4.14

TOXICOLOGY

Toxicity

Nickel compounds are carcinogenic to humans. Acute toxicity arises due to competitive interaction with five major essential metals such as calcium, cobalt, copper, iron and zinc. The order of lung toxicity corresponds to the water solubility of various compounds, with nickel sulphate being most toxic, followed by nickel sulphide and nickel oxide (Dunick et al., 1989).

4.4.11 Zinc (Zn) Chemistry Zinc is a member of the group IIb of the periodic classification of elements. It is a nutritionally essential metal. It does not inhibit multiple valency. Only +2 oxidation state is present. It forms complex with ammonia, amines, halide ions and cyanide. Zinc is a cofactor for more than 200 metalloenzymes belonging to six major categories—such as oxidoreductase, transferases, hydrolases, lyases, isomerases and ligases (Cousins, 1996). Toxicokinetics

Zinc is absorbed in gastrointestinal tract through food and is homeostatically controlled. In blood, zinc is attached to albumin. Zinc is excreted from the body through urine and faeces. Bile is the major route of zinc excretion. The greatest concentration of zinc on the body is in the prostate which is a zinc-containing enzyme. Liver is the main organ where zinc is concentrated. Biotransformations

Zinc plays a vital role in the biosynthesis of nucleic acids, RNA polymerases and DNA polymerase. Zinc is a functional group of several proteins that contribute to gene expression and regulation of genetic activity. Zinc is involved in the healing processes of tissues in the body. More than 200 different metalloenzymes have been identified. Zinc is required for optimal vitamin A metabolism. Like calcium, the metabolism of zinc is also required for normal calcification of bone (Leek et al., 1988). Toxicity The toxicity of zinc arises from its synergistic and/or antagonistic interaction with particularly cadmium heavy metal. Zinc deficiency causes the problems like delayed healing, susceptibility to infections, neuropsychological abnormalities, dermatitis, suppression of enzymatic activities and poor immune response.

4.5

TOXIC RADIOACTIVE ELEMENTS

The process of spontaneous disintegration accompanied by emission of radiation is known as radioactivity. Radiations are of three types: alpha (a), beta (b) and gamma (g) rays. Their characteristic properties are as follows:

TOXIC INORGANIC AND RADIOACTIVE ELEMENTS

4.15

Alpha = rays

1. These carry two units of positive charge and are four times as heavy as hydrogen atom, full notation 42He. 2. Its velocity is 10,000 miles per second with high ionisation power of the air. 3. Relatively low penetration power. 4. It has luminescence effect. Beta > rays

1. These are identical with the electron carrying one unit negative charge and negligible mass, the full notation is –10 e. 2. Move faster than a particle with 1,60,000 to 2,40,000 km/sec velocity. 3. Low ionisation power of air and low luminescence effect. 4. More penetration power. Gamma C  rays

1. These are the secondary effects of atomic disintegration with no charge and mass. 2. These are formed from energy rearrangements within the nucleus after emission of an a or b particle. 3. Very high penetration power. 4. It ionises the air due to secondary effect. Radioactive Decay Kinetics

The rate of disintegration of a radioactive element is independent of temperature, pressure and of any external conditions. The rate of radioactive disintegration states that “A constant fraction of a given radioactive element disintegrates in a unit time. As the total amount of the radioactive element goes on decreasing with time, the disintegration amount in a unit time also decreases.” Radioactive disintegration follows first order rate equation. The law of radioactive decay says the rate of decay is proportional to the present amount of radioactive element. It is represented by the equation. X ®Y No ® number of atoms present (X) present originally N ® number of atoms present at a given time‘t’. Then rate of decay is

dN = l (N) dt l = decay constant or disintegration constant –

(1)

4.16

TOXICOLOGY

dN 1 dN × or – ldt = dt N N Integrating equation (2)

Then

l=–

z

z

dN = – ldt + Constant N In N = – lt + C when t = 0; N = No; C = ln No Putting these values in equation (4), we get ln N = – lt + ln No

(2)

(3) (4)

(5)

N = – lt No (6) or N = N0e–lt The half life period of a radioactive element is the time during which half the weight of a given sample of the element disintegrates. This value is constant so it is possible to characterise each element by this value.

or

ln

N0 after time T half of the amount 2 disintegrates. Putting this value in equation (6), we get It is represented as in equation N =

or

1 = e–lt or ln 0.5 = – lT 2 2.303 log 0.5 = –lT

(7) (8)

0.6931 (9) l From this equation it is clear that half life period of a given radioactive element is independent of initial amount of the element. Average life (t) is the reciprocal of decay constant of radioactive element. T=

1 (10) l Soddy-Fajan Group Displacement Law Radioactive disintegration takes place in successive stages and each daughter element produced is also radioactive. The half life period of each stage is different. The Group Displacement Law states that “The emission of an alpha particle results in the formation of an element which lies two places to the left and the expulsion of a beta particle results in the formation of an element which lies one place to the right in the Periodic Table.”

t=

TOXIC INORGANIC AND RADIOACTIVE ELEMENTS

4.17

Nuclear Stability or Radioactivity Theory It has been found that most of the stable nuclei are non-radioactive. Some important characteristics of the radioactive theory are 1. Nuclei whose neutron to proton ratio (N/P) lies outside the stable belt (N/p > 1 or N/p < 1) undergo spontaneous radioactive disintegration. A low values of proton the slope of the curve is 45° indicated that N/P ratio is unity (N/P = 1) which are very stable nuclei (up to P £ 20) like calcium. For radioactivity there are two conditions. (i) If N/P > 1 then it will emit b particle. (ii) If N/P < 1 then it will emit a particle. Radioactive nuclei P = 83 Number of neutrons

N/P > 1

N/P = 1

N/P < 1 2 P=

0

Number of protons

Fig. 4.2

Neutron-proton diagram for stable nuclei.

2. All nuclei with protons up to 83 are stable. More than (P > 83), are all radioactive nuclei. 3. Nuclei with even number of protons and neutrons are generally more 235 stable than those of odd 235 U are used as the fissionable 92U numbers. So material. 4. Magic numbers, i.e. nuclei with 2, 8, 20, 50, 82 or 126 protons or neutrons are exceptionally more stable than other nuclei. Artificial Radioactivity or Radioisotopes Artificial radioactivity in which nuclei (two) undergo a change artificially by bombarding, i.e. nuclear reaction produced by bombardment with nuclear radiation like. 14 7 N

1 + 42 He ® 17 8 O + 1 H (with a particle)

7 3 Li 23 11 Na

+ 11H ® 84 Be + g (with proton) 24 24 + 10 N ® 11 Na ® 12 Mg + e – (with neutron)

9 4 Be

+ g ® 84 Be + 10 n (with g rays)

4.18

TOXICOLOGY

4.5.1 Radioactive Toxicants in Aquatic Environment Various amounts of radiation may enter and affect the aquatic environment. The radioactive radiations may enter the water body from both anthropogenic and natural sources. The anthropogenic sources include the following: 1. Uranium and thorium mining and refining. 2. Use of radioactive materials in nuclear power plant. 3. Use of radioactive materials in medical research laboratory and industrial activities. 4. Use of radioactive materials in nuclear weapons. These are shown in nuclear fuel cycle (Fig. 4.3). The natural sources include the cosmic rays and terrestrial sources like geological formation. It has been established that the average natural radioactivity in the waters is much more than the artificial radioactivity. The majority of human exposure is an unavoidable background radiation from the above sources. Radium-226 is found in groundwater from geological formation whereas it is in surface water from the anthropogenic sources. The radioactive elements decay by emitting alpha (a) beta (b) or gamma (g) radiations caused by transformation of the nuclei to lower energy states. As the chemical properties of radioactive materials essentially remain the same as their stable counterparts, they are readily absorbed by the organisms through food and water and get accumulated in blood and certain vital organs like the thyroid gland, the liver, the bone and muscular tissues. Uranium and thorium mines

Refining plant

U

235

enrichment

Fraction of fuel assemblies

Plutonium Nuclear reactor Spent fuel

Repositories

Low level wastes

Spent fuel

Commercial burial

Decommissioning of reactor

Fig. 4.3 Nuclear fuel cycle.

TOXIC INORGANIC AND RADIOACTIVE ELEMENTS

4.19

When dealing with the environmental effects of radiation, the understanding of most important factors is essential. The factors like the dose of radiation and exposure to which type of radioactive waste water are to be studied. The dose is commonly measured in terms of rads (rd) and rems. The radioactive waste waters are classified into three categories as follows: (a) Low level radioactive waste: It contains sufficiently low concentrations so that there is no significant health hazards. These radioactive wastes can be liquid, solid or gaseous which are produced in high volumes. Low level wastes has been buried and monitored in near-surface burial areas in which the hydrologic and geologic conditions are thought to severely limit the migration of radioactivity. (b) High level radioactive wastes: They are extremely toxic and a sense of urgency surrounds their disposal. These are liquid or solid wastes having a very high level of radioactivity. Storage of high level waste is the best solution and eventually some sort of disposal programme must be initiated. (c) Intermediate level wastes: The concentration level of radioactivity in these wastes are at a medium level between the high level and low level wastes. They can be disposed of like low level wastes but after giving proper treatment. Effects of Radioactive Toxicants: The radioactive materials affect the aquatic environment in two ways such as: 1. By entering the normal pathways of mineral cycling and ecological food chains. Certain marine organisms have the capacity for accumulating radionuclides from water. This biomagnification may cause objectionable radioactivity in living organisms. The different types of radiations have different penetrations and as a result do variable damages to the living tissues. 2. Through emission of radiation, the radioactive toxicants affect the other materials. These radioactive toxicants can be moved long distance by biospheric phenomena.

4.5.2 Toxicokinetics and Effects of Radioactive Elements The intensity of a radioactive substance is measured in SI unit of becquerels (Bq) gray (Gy) and sievert (Sv). The absorbed dose of radioactive element is defined as the mean energy ‘e’ imparted by ionizing radiation to matter of mass ‘m’ (ICRU, 1993). D = e/m D = absorbed dose e = mean energy deposited in mass. m = mass.

4.20

TOXICOLOGY

Generally, the absorbed dose is expressed in Gray. The Gray is equal to the amount of radiation causing 1 kg of tissue to absorb 1 joule of energy. Different kinds of radiation do different amounts of damage to living tissues for the same amount of energy. The SI unit sievert (Sv) takes account of different ways in which same amount of energy can be imparted to tissues. The safe annual exposure of the general public is usually given as 5 mSv. This can be well explained from the given example (i) A dose of 20 Sv = a dose of 20 Gy of b emission. (ii) A dose of 20 Sv = a dose of 20 Gy of g emission. (iii) A dose of 20 Sv = a dose of only 1 Gy of a particle. Thus, it indicates that alpha (a) particles have about 20 times the effect of b or g radiation for the same number of Grays. Some radioactive isotopes are especially more dangerous because they follow the same biochemical pathways in the body as stable element do. The ionizing radiation alters chemical species in tissues and can lead to significant and harmful alterations, for example, DNA damage and mutagenesis. Two radioactive elements particularly radon and radium are more concerned as these two have potential toxic effects to the human when it is exposed to ionizing radiations.

4.5.3 Radon and Radium The decay scheme for the entire uranium series which produces daughter radioactive element radium which in turn produces radon. Radon is the alpha (a) emitting short lived decay products radon (parent). Radon is the most damaging form of radioactive nuclei. Alpha particles emitted from a radionuclide in the lung cause damage to cells lining the lung bronchi and other tissues which leads to cancer. Radon enters into the body by inhalation and are deposited on the bronchial airways. Carcinogenesis is related to absorbed alpha dose. Thus, radon can deliver a greater or lesser carcinogenic potential. Radium Radium is a carcinogenic radioactive element and enters humans through occupational exposure. Radium once ingested, it is accumulated and incorporated on the bone surfaces of the body in the same way as that of calcium metabolism.

4.5.4 DNA Damage and Mutagenesis DNA is a double helical macromolecule consisting of the nitrogen bases adenine (A), guanine (G), cytosine (C), and thymine (T). The order in which these bases occur in DNA determines the nature and structure of newly produced RNA. The adenine base pairs naturally with thymine (A: T base pair) while guanine pairs with cytosine (G : C base pair) so that one DNA strand has the complementary sequence of the other.

TOXIC INORGANIC AND RADIOACTIVE ELEMENTS

4.21

Ionizing radiation losses energy and slows down by forming ion pairs (a positively charged atom and an electron). During this radiation energy may directly be deposited in DNA or may ionise other molecules. Closely associated with DNA, hydrogen or oxygen, to form free radicals that can damage DNA. Mutagenesis is a process in which inheritable traits result from alterations of DNA. The substances that cause mutations are known as mutagens. Ionization frequently disrupts chemical bonding in cellular molecules such as DNA. The interaction of ionizing radiation with DNA produces numerous types of damage. These products differ according to which chemical bond is attacked, which base is modified, and the extent of the damage within a given segment of DNA, for example, nitrous acid (HNO2), a chemical mutagen causes mutagenesis to three out of four nitrogenous bases–adenine, guanine and cytosine which contain amino (–NH2) group. In the chemical reaction, nitrous acid replaces amino groups with doubly bonded oxygen atom. Now keto (R2C = 0) groups are formed. These keto groups convert the DNA bases to some other groups. Thus, DNA may not function as usual, causing mutation. The position of a mutagen in DNA and its chemical and physical properties in that context dictate the type of mutations induced (Essigmans and Wood, 1993). Mutagenesis can be the result of several different alteration in the physical and chemical nature of DNA.

EXERCISE 1. What are the factors influencing the metal toxicity? Explain them. 2. Define chelation. What are the important characteristics of ideal chelating agents for toxicology? 3. Explain the multiple toxic effects of the metals–Arsenic and Beryllium. 4. What are different multiple toxic effects of Cadmium and Chromium metals? 5. Defferentiate the toxicokinetics of Iron and Manganese metals. 6. What are the multiple toxic effects of Zinc and Nickel? 7. What are different types of radioactive radiations? Explain the Soddy-Fajan Group Displacement Law. 8 . Explain the different toxicants and their effects on aquatic environment. 9. Discuss the toxicokinetics and the effects of radioactive elements.

CHAPTER

5

Toxic Organic Compounds 5.1

INTRODUCTION

All the organic compounds contain carbon, hydrogen and next to them oxygen abundantly. Carbon has the chelation property to form a large number of organic complex compounds, many of which provide the basic fabric of living organisms. Most of the arthropogenic (synthetic origin) organic compounds are toxic to a greater or lesser extent to the humans. The behaviour of organic compounds is dependent upon their molecular structure much as molecular size, molecular shape and the presence of functional groups which are the important determinants of metabolic fate and toxicity. Molecules with a strong charge are highly polar whereas weak charge molecules have low polarity. Highly polar molecules are easily soluble in water and these molecules are more reactive than low polar molecules. Thus, carbon compounds having the functional groups such as – OH, – CH = 0, > C = 0 and – NO2 are more polar and reactive because due to the presence of heteroatoms, there is a difference in electronegativity between them. For example, oxygen is more electronegative, thus it attracts electrons towards itself so that there is the development charges. Hence, molecules with high polarity tend to enter into chemical and biochemical reactions more actively. In this chapter, the toxicity of different organic compounds like hydrocarbons, organometallic compounds, organometalloid compounds and other organic compounds having different functional groups.

5.2

HYDROCARBONS

Hydrocarbon organic compounds are composed of only carbon and hydrogen. Hydrocarbons are found in all states of matter—gas, liquid and solid. These compounds have low polarity thus they are poor water solubility but are highly soluble in most of the organic solvents. Hydrocarbons may be grouped into three

5.2

TOXICOLOGY

important categories such as: 1. Acyclic saturated and unsaturated hydrocarbons for example, alkanes, alkenes and alkynes. 2. Mono and/or polycyclic aromatic hydrocarbons for example, benzene, naphthalene, 3, 4-benzo (a) pyrene. 3. Mixed hydrocarbons containing combinations of two or more of the above two types, for example, cumene, styrene, 1-(2-propyl) naphthalene, etc. H

H

H

H

C

C

H H

C

C

H

H

H

H C

C

H Ethane (Alkene)

H H

C

H

Alkene (1, 3-butediene)

C

Alkyne (Acetylene)

Benzene

Naphthalene

CH3

CH

Cumene

3, 4-Benzo (a) Pyrene

CH3

CH

CH3

CH

CH3

CH2

Styrene

1- (2-Propyl) naphthalene

The chemical behaviour or fate of alkanes is that they very easily undergo oxidation, substitution and photochemical reaction through free radical mechanisms as per the equations. Oxidation reaction 2 C2H6 + 7 O2 ® 4 CO2 + 6 H2O + heat. Substitution reaction CH3 – CH3 + Cl2 ® CH3 CH2 Cl + HCl. Photochemical reaction hυ CH4 + Cl2 ¾¾ ® CH3Cl + HCl

TOXIC ORGANIC COMPOUNDS

5.3

hυ CH3Cl + Cl2 ¾¾ ® CH2 Cl2 + HCl hυ CH2Cl + Cl2 ¾¾ ® CH Cl3 + HCl hυ CH Cl3 + Cl2 ¾¾ ® C Cl4 + HCl. The alkene favours the addition reaction which is proceeding through heterocleavage of the covalent bond. CH2 = CH2 + HBr ® CH3 – CH2 Br. The alkynes also undergo the addition reaction. H – C = C – H + HCl ® CH2 = CHCl The cyclic aromatic organic compounds favour the substitution reaction.

Cl + Cl2

+ HCl

5.3 TOXICITY OF ACYCLIC SATURATED AND UNSATURATED HYDROCARBONS The high polar organic compounds are more reactive and more toxic than the low polar organic compounds. The polarity of acyclic saturated and unsaturated hydrocarbon varies in the following order. Polarity decreases Alkyne > Alkene > Alkane Toxicity increases

The major exposure route of the acyclic saturated and unsaturated hydrocarbons is through the inhalation. These toxicants cause the effects like eye irritation, skin irritation and narcosis. These alkanes, alkenes, and alkynes are simple asphyxiant which means that air containing high levels of these gases does not contain sufficient oxygen to support respiration. For example, methane, ethene, ethylene, etc. and the simple asphyxiants. Exposure to higher alkane, alkenes and alkynes may damage the central nervous system. Exposure to skin causes dermatitis. But the derivates of these organic compounds are very highly polar and became very toxic to living organisms. Halogen substituted hydrocarbons are very reactive and they produce many toxic effects. For example, alkyl halides and alkenyl halides, are more reactive and toxic than the simple hydrocarbons.

5.3.1 Toxicity of Alkyl Halides Alkyl halide is formed by the substitution reaction. Halide groups substitute the hydrogen on an alkyl group. Since the halogens are in highly electronegative

5.4

TOXICOLOGY

group, alkyl halides become more polar. Thus, the reactivity and toxicity of alkyl halides increase. A number of alkyl halide compounds are formed, for example, chloroalkane, chloroalkene, etc. Of all the alkyl halides, carbon tetrachloride (CCl4) is very toxic through both inhalation and ingestion. It causes harm to the central nervous system, liver and gastrointestinal tract. CH3Cl Chloromethane

CH2Cl2 Dichloromethane

CHCl3 Trichloromethane (Chloroform)

CCl4 (Carbon tetrachloride)

From the biochemical mechanism of carbon tetrachloride toxicity, it is evident that the cytochrome P-450 dependent mono-oxygenase system acts on carbon tetrachloride (CCl4) in the liver to produce trichloromethyl (Cl3 C.) free radical. This free radical combines with molecular oxygen to produce (Cl3 COO ) free radical which is very reactive and react readily with biomlecules such as proteins and DNA (Hodgsen, 1987).

×

Cl Cl

Cl

C

Cl

Cyt. P-450

Cl

C

Cl

Cl O2

Cl

Cl

C

O

O.

Cl

low O2 Bind to lipid CHCl3, Cl2C:, HCOCl, CO

COCl2

Trichloromethyl free radical is relatively stable abducts which may initiate lipid peroxidation and damage the proteins and nucleotides.

5.3.2 Toxic Effects of Alkenyl Halides The alkenyl halide compounds are composed of at least one carbon-carbon double bond and one halogen atom. These compounds are highly polar, thus they are very reactive. They exhibit very wide range of toxicity due to their chemical behaviour. H

Cl C

H

C

(Vinyl Chloride)

H

C

C

H C

H

Br H

C

H

H (2-Bromo-1, 3-butadiene)

TOXIC ORGANIC COMPOUNDS

5.5

These compounds have toxic effects to central nervous system, respiratory system, liver, blood and lymph systems. Vinyl chloride is a carcinogenic compound and its carcinogenicity result from its metabolic oxidation to chloroethylene oxide by the action of the cytochrome P-450 dependent monooxygenase in the liver (Hodgson, 1987). H

Cl + O

C

C H

O

H

Cyt. P-450

H

Cl C

C H

H

This epoxide has a strong tendency to covalently bind to protein, DNA and RNA. The epoxide undergoes a rearrangement reaction to form chloroacetaldehyde. Chloroacetaldehyde is a mutagen and is responsible for mutagenesis. O

H C

Cl

Cl

H

H

C

H Epoxide

H

O

C

C

H

Chloroacetaldehyde

5.4 TOXICITY OF MONO- AND POLYCYCLIC AROMATIC HYDROCARBONS The halide substituted aromatic hydrocarbons are more polar and reactive than simple aromatic hydrocarbons. A large number of halide substituted aromatic hydrocarbons are released into the environment. Some important aryl halides are as in Fig. 5.1. Cl

Monochloro Benzene

Cl

CH3

Cl

Cl

Cl

Cl Cl Hexachloro Benzene

Fig. 5.1

Cl Cl

1-Chloro-2methyl Benzene

1-Chloro naphthalene

Some important aryl halides.

Exposure to most of aryl halides occurs through inhalation of skin contact. Aryl halides affect the liver, respiratory system and irritate eyes and skin. Some aryl halides, for example 1,4-isomer (dichlorobenzene) causes profuse rhinitis, nausea, anorexia, jaundice and liver cirrhosis. Hexachlorobenzene is highly toxic to humans by causing liver necrosis.

5.6

TOXICOLOGY

5.5 TOXIC EFFECTS OF OXYGEN-CONTAINING ORGANIC COMPOUNDS A large number of oxygen-containing organic compounds, are formed in environment which are very toxic. In these compounds, the carbon is covalently bonded to oxygen. Next to carbon and hydrogen, oxygen is abundantly present in these compounds. For example, alcohols, acids, aldelydes, ketones, phenols, esters, ethers and epoxides are very common oxygen containing organic compounds having different functional group (Fig. 5.2). O CH3

CH2

OH

C

CH3

Ethanol

OH

Ethanoic acid (Acetic acid)

OH CH3

CH3

CHO

C

O

CH3

Acetaldehyde

Acetone Phenol

O CH3

O

CH3

CH3

Dimethyl Ether

O CH3

C

C

O CH3

CH2

Acetic anhydride

Fig. 5.2

CH3

C

Dimethyl Ester

O O

O

O CH

CH

CH2

1, 2, 3, 4-Butadiene epoxide

Some oxygen-containing organic compounds.

5.5.1 Toxicity of Alcohol Toxicity is not a big problem with higher alcohols. The exposure of lower alcohols like methanol, ethanol, isopropanol occurs through inhalation and skin absorption. Most of the methanols about 30 to 40% are absorbed in respiratory tract and the remaining are converted on to formaldehyde and subsequently to formic acid in liver as per the following metabolic oxidation reaction. O CH3OH

[O]

H

C

O H

[O]

H

C

OH + H2O

The products cause acidosis which affects the central nervous system and the optic nerve. The formaldehyde in the retina of optic nerve is responsible for

TOXIC ORGANIC COMPOUNDS

5.7

blindness. In cases of acute exposure to methanol may cause cardiac depression and even death. The higher saturated alcohols have some toxicity because of their polarisability. It is found that isopropanol is more toxic than amyl alcohol which is in turn more toxic than butyl alcohol.

5.5.2 Aldehydes and Ketones Aldehydes and ketones are considered in the same group of compounds as both contain the carbonyl (C = 0) group. The difference is that in aldelydes the carbonyl group is attached to a carbon (C) and hydrogen (H) atom at the end of the hydrocarbon chain whereas in ketone it is bonded two carbon atoms in between the first and last carbon of a hydrocarbon chain. For example, O CH3

C

O H

CH3

Acetaldehyde

C

CH3

Acetone

Exposure to aldehydes and ketones may occur through inhalation and skin absorption. Formaldehyde may cause hypersensitivity from prolonged and continuous exposure. The lower aldehydes and ketones are more water-soluble than the higher aldelydes and ketones. Lower aldehydes are sensitive to moisture thus, they may attack moist tissues like mucous membranes of the upper respiratory tract and the eyes. Ketones may act as narcotic and dissolves fats from skin, causing dermatitis. Aldehydes and ketones are irritant of the skin, mucous membrane and eyes. Prolonged exposure to acetaldehyde may cause nausea, vomiting, headache, dermatitis and pulmonary edema. These effects may be delayed. It may also cause chronic respiratory disease, liver damage, unconsciousness and may cause conjunctivitis.

5.5.3 Organic Acids (Carboxylic Acids) O

Carboxylic acid contains C OH functional group which is polar and water soluble. When this functional group is attached to unsaturated carbon, it becomes more reactive and the toxic effect increases. Some organic acids are shown in Fig. 5.3. Carboxylic acids are the oxidation products of alcohols and aldehydes. Formic acid exposure causes irritation to eyes and skin. The exposure of carboxylic acids occur through inhalation, skin absorption, and ingestion. Acetic acid is very corrosive to tissues. Acrylic and methacrylic acids are considered to be more toxic.

5.8

TOXICOLOGY COOH

CH3

CH2

Acetic acid

COOH

CH

Acrylic (Propenoic acid)

COOH COOH COOH Benzoic acid

Phthalic acid

Fig. 5.3

Carboxylic acids.

Acrylic and methacrylic acids corrosive to tissues and irritants to eyes, skin and respiratory tracts. It may be extremely destructive to tissues of the mucous membranes and upper respiratory tracts, eys and skin (Lenga, 1985). In general, the increase of the number of carboxylic acid groups and unsaturated carbon bonds in the carbon skeleton, there is an increase in toxicity and corrosiveness of that carboxylic acid. In addition to that, the presence of hydroxide group at the alpha (a) position, the toxicity of the carboxylic acid increases, for example. (Fig. 5.4). CH2

CH

COOH

>

CH3COOH COOH

COOH

>

COOH OH

CH3

CH

COOH

>

CH3

CH2

COOH

Toxicity increases

Fig. 5.4 Order of toxicity of carboxylic acids.

Exposure to acrylic and methacrylic acid may cause pulmonary edema, damage of gastrointestinal tract and damage of lung.

5.5.4 Acid Anhydride The combination of two carboxylic groups gives rise to carboxylic acid anhydride as per the chemical equation. O CH3

C

O O H + HO

Acetic acid

C

O CH3

Acetic acid

CH3

C

O O

C

CH3

Acetic anhydride + H2O

TOXIC ORGANIC COMPOUNDS

5.9

Acetic anhydride is the most important carboxylic acid anhydride because of its use in various fields like textiles, pharmaceuticals, processing of semiconductors, polishing of aluminium, etc. Acetic anhydride is corrosive to skin, eyes and respiratory tracts. The exposure to anhydride occurs through inhalation and skin absorption. Acetic anhydride causes burning sensation in nose, mouth and throat.

5.6

NITROGEN-CONTAINING ORGANIC COMPOUNDS

There are many organic compounds (natural as well as synthetic) having nitrogen in their components. The main constituents of these compounds are carbon, oxygen, hydrogen and nitrogen. Some important nitrogen containing organic compounds are amines, amides, nitriles, nitrosoamine, nitro compounds, etc. (Fig. 5.5). NH2 H 2N

CH3

CH3

Methylamine

C

N

Acetonitrile Aniline

O N NO2 CH3

NO2

CH3

Nitromethane

N

CH3

Dimethylnitrosoamine Nitrobenzene

O CH3

C

NH2

Acetamide

Fig. 5.5

N Pyridine

Some important nitrogen containing organic compounds.

From the ecotoxicological point of view, nitrogen containing organic compounds are very important as a large number of enzymes and DNA contain nitrogen in their bases. The monoamine oxidases are found in mitochondria of a wide variety of tissues such as liver, kidney, brain, intestine and blood platelets. Enzymatic deamination, i.e., removal of an amino group (– NH2) from a compound occurs in liver. The rate of removal of amino group with the primary amines is faster. Electrons withdrawing group substitution on aromatic ring increases the removal rate of reaction. The lower aliphatic amines are more toxic than higher aliphatic amines. Aromatic amines are more toxic than aliphatic amines.

5.10

TOXICOLOGY

5.6.1 Toxicity of Amines Amines are the derivatives of ammonia (NH3). Amines are divided into two groups such as non-aromatic amines and aromatic amines. When the nonaromatic aliphatic amines contain less than 6 carbon atoms are classified as lower aliphatic amine. The lower aliphatic non-aromatic amines are generally more toxic. These amines are basic compounds which increase the pH value of the exposed tissues by hydrolysis. These amines are exposed through inhalation and skin absorption. The lower amines are corrosive to tissues and may cause necrosis of liver and kidneys. The prolonged exposure may exhibit haemorrhage and edema. In carbocyclic aromatic amines, at least one is an aromatic ring. Aniline is one of the most important aromatic amines which is very toxic with a toxicity rating of 4. It is soluble in lipids. Aniline may be toxic by inhalation, ingestion and skin absorption (Bretherick, 1986). Symptoms of exposure may include headache, drowsiness, cyanosis, mental confusion, convulsions, nervous system effects, blood effects, fatigue, loss of appetite and dizziness (Bretherick, 1986). The most common effect of aniline on humans is methemoglobinemia caused by the oxidation of iron (II) in haemoglobin to iron (III) with the result that the haemoglobin can no longer transport oxygen in the body (Manahan, 1989). The enzymatic reaction is as per the following equation. HbFe (III)

Methemoglobin HbFe (II) Reductase

Exposure to aniline may cause severe irritation of the eyes and skin, methemoglobin formation, prolonged anoxemia, central nervous system depression, haemolysis of red blood cells followed by stimulation of bone marrow, liver effects and jaundice (Sax and Richard, 1989). Aniline undergoes biotransformation to cause methemoglobinemia because pure aniline does not oxidize Fe+2 in haemoglobin to Fe+3. The other aromatic amines like benzidine, pyridine are moderately toxic to humans. The exposure occurs through inhalation, ingestion and skin absorption. Benzidine is a carcinogen. It causes blood haemolysis, bone marrow depression, and damage of liver and kidneys. While pyridine causes anorexia, nausea, fatigue and mental depression. NH2

H 2N

N Benzidine

Pyridine

5.6.2 Toxicity of Amides Amides are formed by treating with ammonium salt of organic acid and glacial acetic acid. Lower amides are easily soluble in water. From the toxicological

TOXIC ORGANIC COMPOUNDS

5.11

point of view acetamide and acrylamide are the most important amides as they are toxic to humans. CH3 COO NH4 ® CH3 CO NH2 + H2O Acetamide Acetamide may cause skin and eye irritation and corneal damage. The prolonged exposure to acetamide may cause severe irritation to mucous membrane whereas acrylamide is very sensitive to air moisture and light (Lenga, 1985). O CH2

CH

C

NH2

Acrylamide

Acrylamide may be toxic by inhalation and ingestion. Acrylamide is acknowledged as a potent neurotoxin. It may also be absorbed through mucous membranes, lungs and gastrointestinal tract (Grant, 1986). It may also cause peripheral neuropathy (Grant, 1986). Acrylamide may cause damage to central nervous system and may cause ataxia and limb weakness. Other symptoms may include erythema, central peripheral distal axonopathies, skin changes, mental confusion, skin ulcerations, dermatitis, gastrointestinal problems, weight loss, inability to stand, collapse, body tremors and hallucinations (Steere, 1971).

5.6.3 Toxicity of Nitriles From the toxicological point of view, nitriles are analogous of highly toxic hydrogen cyanide. The two most important nitriles are Acetonitrile and Acrylonitrile as shown in Fig. 5.6. CH3

C

Acetonitrite

N

CH2

CH

C

N

Acrylonitrile

Fig. 5.6 Some important nitriles.

Acetonitrile is a clear colourless liquid and is incompatible to both acids and bases. It is sensitive to moisture, light and heat. It is soluble in water. Acetonitrile may be toxic by ingestion, inhalation and skin absorption (Lenga, 1985). It causes irritation to eyes, skin, nose and throat. Symptom of exposure may cause nausea, vomiting, abdominal pain, weakness, flushing of the face, respiratory depression, chest pain, hematemeris, unconsciousness and death (Sittig, 1985). It may cause asphyxia, irritation to mucous membranes and respiratory tracts, cyanosis and lacrimation (Lenga, 1985). In severe exposures, it may cause delirium, paralysis and coma (Bretherick, 1986).

5.12

TOXICOLOGY

Acrylonitrite is a clear, colourless to pale yellow volatile liquid containing both nitrile and C = C groups make the acrylonitrile very reactive, thus very toxic to humans. It is also analogs of highly toxic hydrogen cynide (HCN). The exposure occurs through inhalation, skin absorption and ingestion. It is a lacrymator and irritant to eyes, skin and nose (Grant, 1986). Acrylonitrile causes nausea, abdominal pain, cyanosis and causes damages to liver, kidneys, central nervous system and respiratory system. Exposure may lead to neurasthenic syndrome, asthenovegetative syndrome and gastritis. During metabolic processes, acrylonitrile releases cyanide and it inhibits the enzymatic activities for respiration tissues. It is a potential carcinogen. Acrylonitrile may also cause erythema and epidermal necrolysis or necrosis (Hayes, 1982).

5.6.4 Toxicity of Nitro Compounds The organic compounds having – NO2 functional group are known as nitroorganic compounds. Some important nitro-organic compounds are shown in Fig. 5.7. CH3

NO2 ; CH3

Nitromethane

CH2

CH2

NO2

Nitropropane

NO2 HO Nitrobenzene

Fig. 5.7

NO2 Nitrophenol

Some important nitro compounds.

Exposure to nitromethane may cause anorexia, diarrhoea, nausea and vomiting. They may cause some harm to liver and kidneys. But nitropropane is more toxic. It is soluble in most of the organic solvents. It’s exposure may cause irritation of the skin, eyes, mucous membranes and upper respiratory tract, nausea, diarrhoea, vomiting, pulmonary oedema, hepatocellular carcinoma and damage to liver and kidney. Nitrobenzene is very soluble in organic solvents. Ingestion of alcohol aggravates the toxic effects of nitrobenzene. It is used to manufacture of aniline, thus its toxic action is also similar to that of aniline. It enters into the body through all routes such as ingestion, inhalation and skin absorption. It may involve the conversion of haemoglobin to methemoglobin which deprives tissue of oxygen. Symptoms of exposure may include irritation of eyes, skin and mucous membrane, signs of anoxia, cyanosis of lips, nose and ear lobes. It may also cause anaemia, nausea, dermatitis, dyspnea (breathing problem), respiratory failure, black tongue, coma and peripheral neuritis. Death may result from intake of 2 ml of nitrobenzene.

TOXIC ORGANIC COMPOUNDS

5.13

Nitrophenol may be toxic by ingestion, inhalation or absorption through the skin. Its exposure may include irritation of the skin, eyes, nose and throat. It causes consciousness, cyanosis, damage of liver and kidneys, dermatitis, corneal damage and hypothermia. It may cause methemoglobinemia, damage of central nervous system, abdominal cramps and drowsiness.

5.6.5 Toxicity of Nitrosoamines N-nitroso compounds are known as nitrosoamines having N-N = 0 functional group. From the ecotoxicological point of view, these compounds are all carcinogenic. Some important nitrosoamines are in Fig. 5.8.

CH3

N

O

N

CH3

N

O

N

Dimethylnitrosoamine

Diphenylnitrosoamine

Fig 5.8 Some important nitrosoamines.

N-nitrosodimethylamine is incompatible with strong oxidisers and strong bases. It is very sensitive to exposure to light especially ultraviolet light. Different nitrosoamines cause cancer in different organs. Dimethylnitrosoamine cause liver damage and jaundice. All type of nitrosoamine exposure occurs through inhalation and skin absorption. Chronic exposure may cause harm to reproductive systems and cause gastrointestinal haemorrhage, hepatomegaly and abdominal pain.

5.7

PHOSPHORUS CONTAINING ORGANIC COMPOUNDS

Phosphorus is a very reactive element. It is incompatible with air, oxygen, alkalis and reducing agents. Phosphorus exists in four or more allotropic forms: white (or yellow), red and black (or violet). There are many kinds of phosphorus containing organic compounds and different organophosphorous have different degrees of toxicity. Some important organophosphorus are in Fig. 5.9.

H H

P

CH3

P

H

CH3

H

CH3

P

H

CH3

Phosphine

H

O

Methyl Phosphine

P

Phosphine Oxide

H

H HO

P

OH

OH Phenyl Phosphine

Fig. 5.9

Phosphonic Acid

Important organophosphorus.

5.14

TOXICOLOGY

5.7.1 Phosphine and Phosphine Oxides Phosphine is a colourless liquid or gas with slightly soluble in water. It is a highly volatile compound and it is a gas under ambient conditions. Phosphine is very toxic to humans. The structure of phosphine has two lone pairs of electrons which are responsible for high reactivity and toxicity. H

P

H (Phosphine),

CH3

H

P

CH3

CH3 Trimethyl Phosphine

The phosphine oxides are also colourless but these are crystalline solids as shown in Fig. 5.10. O CH3

P

CH3

CH3

Fig. 5.10

Trimethyl phosphine oxide.

The most common phosphine oxides are trielthyl phosphine oxides and tributyl phosphine oxides. O C2H5

P

O C2H5

C4H9

C2H5 Triethyl Phosphine Oxide

P

C4H9

C4H9 Tributyl Phosphine Oxide

Humans are poisoned by ingestion, inhalation and subcutaneous routes. The most common symptoms of chronic phosphine and phosphine oxides exposure are necrosis, anaemia, gastrointestinal effects and burns of skin and eyes. Inhalation of phosphine can cause photophobia myosis, retional haemorrhage, and have effects on central nervous system. The combination of trimethyl phosphine produce (phosphorus pentoxide) P4O10 which is very toxic substance and cause corrosive action on pulmonary tract and respiratory tract as it reacts with moisture in air and produces orthophosphoric acid which is very corrosive. 4 C3 H9 P + 26 O2

® 12 CO2 + 18 H2O + P4O10

Trimethyl phosphine P4O10 + 6 H2O

® 4 H3PO4

Phosphorus pentoxide Orthophosphoric acid

TOXIC ORGANIC COMPOUNDS

5.8

5.15

SULPHUR CONTAINING ORGANIC COMPOUNDS

There are number of sulphur-containing organic compounds prepared by substituting H by alkyl or aryl group. Some important compounds are thiols, thioethers, dimethyl sulphides, diphenyl sulphides, etc. CH3

SH

CH3

Methanethiol

S

CH3

CH2 – SH

Dimethyl Sulphides

SH -Toluenethiol

S Benzenethiol

S

Diphenyl disulphide

Thiols are also known as mercaptans. Their exposure occurs through inhalation and skin absorption. Inhalation of lower concentration causes headache and nausea. High concentration exposure causes increased pulse rate and cyanosis. Chronic exposure may cause unconsciousness, even death, coma and cool hands and feet. The biochemical action of alkyl thiols is cytochrome oxidase poisoning. 1-propanethiol is very toxic to humans. 1-pentanethiol may cause the problems like allergy and contact dermatitis. CH3

CH2

CH2

SH

CH3

1-Propanethiol

CH2

CH2

CH2

CH2

SH

1-Pentanethiol

Benzenethiol inhalation causes severe contact dermatitis. Dimethyl sulphide is also known as thioether. The exposure occurs through inhalation, ingestion and skin absorption. These compounds are allergic and cause homolytic anaemia and dermatitis.

5.8.1 Sulphides and Disulphides Dimethyl sulphides are known as thioethers. The other simple organic compounds of sulphur is carbon disulphide (CS2) and it is very toxic to humans. It is soluble in water. Carbon disulphide may be sensitive to prolonged exposure to air and light. It is highly toxic through all routes of exposure. Acute dose of carbon disulphide may irritate mucous membranes and affect the central nervous system. Symptoms of exposure may include narcotic effects leading to unconsciousness, paralysis, and terminal convulsion. Chronic exposure may cause tremors, auditory disturbances and hallucinations.

5.16

TOXICOLOGY

5.8.2 Organic Esters of Sulphuric Acid Organic esters of sulphuric acid are the derivatives of sulphuric acid in which the hydrogen atoms are replaced by alkyl groups. The replacement of both hydrogen from sulphate yields an ester. These esters are also called alkyl sulphates. O CH3

O

S

O O

CH3

C2H5

O

C2H5

(Diethyl Sulphate)

O S

O

O

O Dimethyl Sulphate (Ester)

CH3 O

S

O OH

C2H5 O

O

S

OH

O

Methyl Sulphuric Acid

Ethyl Sulphuric Acid

Diethyl sulphate is water insoluble and can react vigorously with oxidising materials. These are poisonous by subcutaneous route, moderately toxic by ingestion, inhalation and skin absorption. It is also a carcinogen, teratogen and tumorigen. It may affect reproductive system and cause irritation to eyes and skin. Dimethyl sulphate is a colourless liquid and slightly soluble in water. It can react with oxidising materials. It is extremely hazardous. Dimethyl sulphate is a poison by inhalation, ingestion, intravenous and subcutaneous routes. Like diethyl sulphate, it is also carcinogen, tumorigen and teratogen. Heavier exposure damages the liver and kidneys and causes pulmonary edema. It is a corrosive, irritant to skin, eyes and mucous membranes. Severe exposures may be fatal.

5.9

ORGANOMETALLICS AND ORGANOMETALLOIDS

Certain metals can form organometallic compounds in which the metal atom is bonded to at least one carbon atom covalently in an organic group. Similarly in organometalloid compounds, a metalloid element is bonded to at least one carbon atom in an organic group. These organic forms differ in toxic properties from the inorganic counterparts. Non-ionized alkyl compounds such as dimethyl mercury and tetraethyl lead are lipophilic and pass readily across biological membranes unaltered by their surrounding medium. H5C2 H5C2

Pb

C2H5 C2H5

Tetraethyl lead; Pb(C2H5)

CH3

Hg

CH3

Dimethyl mercury; Hg (CH3)2

The organometallic compounds having either ionic bonds or relatively more polar covalent bonds or with vacant atomic orbital on the metal atom readily undergo hydrolysis reaction. For example,

TOXIC ORGANIC COMPOUNDS

Al(CH3)3

5.17

H2O Al(OH)3 + organic products [O2]

the organic products may be alcohol, aldehyde or acid. The toxicity of several metals is greatly enhanced if they become bound to an organic ligand. For example, organotin compounds having general formula (Rn Sn X4– n). Particularly, tributyltion are extremely toxic. Organotin compounds are exposed through skin absorption. Cl (C4H9)

Sn

(C4H9)

(C4H9) Tributyltin

Organomercury is more toxic than inorganic form of mercury. Mercury in its methylated form is more bioavailable than liquid mercury and passed rapidly along with food chain. Tetraethyl lead exposure occurs through inhalation, ingestion and skin absorption. It is lipophilic and it may affect sevrely the central nervous system. It causes ataxia, psychosis and convulsion. Organoselenium compounds are less toxic than inorganic selenium compounds. Similarly, organotellurium is less toxic than inorganic tellurium compounds.

EXERCISE 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

What are the different important categories of hydrocarbons? Explain the toxicities of Alkyl Halides. Discuss the toxicity of mono- and polycyclic aromatic hydrocarbons. What are the toxic effects of Alkenyl Halides? What are the different organic toxicants containing oxygen on their compound? Explain the toxic effects of aldehydes and ketones. Explain the toxicity of nitrogen-containing organic compounds. What are the toxic effects of Nitriles? Discuss the toxic effects of nitro compounds. Name the important toxicants of phosphorous containing organic compounds. Explain the toxic effects of phosphine and phosphine oxides. What are the toxic effects of sulphur containing organic compounds? Explain the toxic effects of sulphides and disulphides. Explain the toxic effects of organometallics and organometalloids.

CHAPTER

$

Movement and Distribution of Toxins in Environment and Ecosystem 6.1

INTRODUCTION

There are many sources of toxic and hazardous chemicals in the environment. From the dose-response relationship, it is evident that the higher the dose, the greater is the intensity of the effects of a toxic element on the organism. But actually the concentration of toxicant at the site or sites of action (target organ or tissue) determines the intensity of toxicity. The routes used by toxicants to enter the body also play important role in determining toxicity. Generally, toxicants do not pass through the body on a single linear pathway. The major routes of entry for toxicants are respiratory, gastrointestinal and dermal systems. Depending on the chemical form, molecular size, solubility, stability, compatibility and access of the organism to the toxicant, the importance of a particular route may be increased. These various routes are dynamically related to each other, but their relative contribution to the overall fate of the toxicant can vary as a result of both extrinsic and intrinsic factors. After entering the body, the toxicants need to be transported to various targeting organs. The circulatory system is the best suitable transport system because it can easily carry out both water-soluble and lipid-soluble compounds. In summary, the toxicants may be absorbed and transported to the site of action through the circulatory system, quickly effect an adverse action and eventually excreted. Toxicants are removed from the systemic circulation by biotransformation, excretion and storage at various sites of the body. All these activities occur simultaneously in a body.

6.2

TRANSPORT ACROSS MEMBRANES

For entering the body, the toxicants face a number of barriers which include the stratified epithelium of the skin, the cells of the target organs or tissues, thin cell layers of lungs, the capillary endothelium and the gastrointestinal tracts. Among

6.2

TOXICOLOGY

these barriers, the stratified epithelium of the skin is relatively thick and membranes of lungs are relatively thin. Thickness of all these cell membranes varies from 7 to 9 nm. In all cases, the membrane of tissues, cells and cell organelles are collectively known as cell membrane concept. The mechanisms by which toxicants can pass a membrane are as follows (Fig. 6.1). Transport of Toxicants

Passive Transport

Simple Diffusion

Fig. 6.1

Special Transport

Filtration

Active Transport

Facilitate Pinocytosis Diffusion

Transport mechanisms of toxins across membranes.

Membranes consist of bimolecular lipid leaflets which are oriented on opposing sides of the membrane. Phospholipids and cholesterol are the predominant lipids present in the membranes. The lipids present in the membrane really allow the considerable movement of macromolecules. The fatty acids of the membrane also contribute appreciably to fluidity of that membrane. The fluid character of membranes is determined largely by the structure and relative number of unsaturated fatty acids. The more the number of fatty acids, the more is the fluidity character of the membranes. Generally, membranes readily allow the non-ionized form of xenobiotics whereas ionized forms are not easily permeable through the membranes. The other factor partition coefficient which influences the penetration of toxicants into the membrane. The partition coefficient states that the ratio of the concentration of the solute in two immiscible liquid remains constant provided the solute is chemically inert to both liquids at constant temperature. C =K C2

K = Distribution constant (partition coefficient). C1 = Concentration of toxicant in one liquid medium. C2 = Concentration of toxicant in other liquid medium. This partition coefficient will determine the solubility of toxicants in the lipids (concentration in lipid phase/concentration in aqueous phase). From the equation it is evident that higher the partition coefficient, higher is the liphophilicity of the toxicants.

MOVEMENT AND DISTRIBUTION OF TOXINS IN ENVIRONMENT AND ECOSYSTEM

6.3

6.2.1 Passive Transport Passive transport is the most predominant mechanism for most of the toxicants. This mechanism involves two submechanisms known as: (a) simple diffusion and (b) filtration. Simple diffusion Simple diffusion is the most common route by which most of the toxicants pass through the membranes. Most of the xenobiotics are large organic molecules having different degrees of lipid solubility. The rate of transport across membranes correlate with their appropriate water/lipid partition coefficient. Compounds in the ionized form do not move readily in simple diffusion process because the ionized organic compounds are not readily soluble in lipids. The xenobiotics which are weak organic acids or bases they become ionized in solution and cannot pass through lipid dominated membrane. But these ionized forms of xenobiotics are water soluble (hydrophilic). These hydrophilic molecules can readily pass by simple diffusion method through aqueous pores. For example, amino acids are water soluble, whereas the xenobiotics like Dichlorodiphenyl Trichloroethane (DDT) is easily soluble in lipids. In general, the non-ionized organic compounds and high lipid to water partition coefficient compounds can pass through lipid dominated membrane by simple diffusion process. The amount in the ionized or non-ionized form of toxicants depends on the PKa of the potential toxicant and on the pH value of the solution. Henderson-Hasselbalch equations give the relationship between PKa and pH value as: PKa – pH = log PKa – pH = log

[non-ionized] (for weak acids) [ionized] [ionized] (for weak base) [non-ionized]

This relationship will explain the degree of ionization. From the above equations, it is evident that at low pH value, a weak acid is largely non-ionized whereas a weak base is largely ionized. As the pH value increases, the reverse is true for both weak acids and weak bases. For example, at low pH value means under acidic condition, the weak organic acids like benzoic acid can more readily pass through the membrane by simple diffusion process. At relatively high pH value means under basic conditions, the weak organic bases like weak organic acids can more readily pass through the membrane. Filtration Filtration is a process in which transport occurs through pores and aqueous channels in the cell membrane. The transport involves bulk flow of water caused by hydrostatic or osmotic force. Filtration process of transport is restricted to hydrophilic substances with low molecular mass. The different

6.4

TOXICOLOGY

membranes have different pore size. For example, kidney glomeruli and liver have relatively large pore size thus allowing relatively larger molecules to pass through. The pore size of other cells is relatively smaller thus much smaller molecules are permitted to pass through them. Filtration process always required a pressure gradient for transport of xenobiotics.

6.2.2 Special Transport The movement of compounds which are larger in size and insoluble in lipids cannot be explained by simple diffusion or filtration. A number of special transport systems which are responsible for the transport across the cell membranes of many nutrients either of bigger size or insoluble in lipids. For example, the nutrients like sugars, amino acid, nucleic acid, and some other compounds need special transport system. There are three different forms of specialized transport systems such as: • Active transport • Facilitated diffusion. • Pinocytosis. Active transport Active transport occurs against a concentration gradient, i.e., it requires energy for transport. This process is a substrate-specific. It means that saturation by the substrate may occur and thus exhibits a transport maximum. The active transport is selective for certain structural features of chemical. Thus, it has the potential for competitive inhibition between the toxicants and endogenous chemicals because both have similar structure. The mechanism may be important that the substances (proteins) actively transported across the cell membranes presumably form a complex with membrane-bound macromolecular carrier on one side of the membrane. This protein facilitates the movement from one side of the membrane to the other end and on the other side the substance is released. The carrier or chemical then returns to the original surface to repeat the transport cycle. In active transport system, the transportation may occur beyond the point at which concentrations are equal on both sides of the membrane. This process is much faster than the simple diffusion. In this type of transport mechanism, both the toxicants and endogenous chemicals having similar chemical and/or structural similarities can move across the membranes. For example, lead and calcium both have similarities in structures, thus both use active transport system but lead may be more quickly moved across the membrane. Facilitated diffusion It also involves the carrier mechanism like active transport. Facilitated diffusion takes place due to a difference in concentration on both sides of the membrane. This process is also substrate-specific. This process has the same mechanism like active transport but the difference is that this process does not require energy as it moves in the direction of the lowest

MOVEMENT AND DISTRIBUTION OF TOXINS IN ENVIRONMENT AND ECOSYSTEM

6.5

concentration. This process will not occur beyond the point at which concentrations are equal on both sides of the membrane. For example, glucose may be transported from the gastrointestinal tract to intestinal epithelium, from plasma into red blood cells and from blood to central nervous system occurs by facilitated diffusion. Pinocytosis This is a specialized transport system in which the membranes flow around a toxicant and engulf the toxicants. Pinocytosis is the process in which the toxicants are in liquid state. The same mechanism for solids is known as phagocytosis. The organs like liver, spleen and lung have this type of transport system.

6.3

ABSORPTION OF TOXIC COMPOUNDS

Absorption of toxic compounds is a process in which the toxicants cross the body membranes and enter the blood stream. The gastrointestinal tract, the respiratory system and the skin are most important routes through which the toxicants usually enter the body. The other routes of penetration of toxic substances are intravenous administration, rectal and nasal absorption. The toxic compounds penetrate membranes during absorption by the same way as the biological essential substances like oxygen, nutrients, etc. penetrate. For a single vehicle and solvent system, the rate of penetration of nonpolar and non-ionized toxicants follows Fick’s law of diffusion as per the equation. C. A d K = Diffusion constant of penetration. C = Concentration of toxicants A = Surface area available for toxicant transfer d = Thickness of the membrane. The above equation implies that rate of transfer is directly related to the surface area and it gives steady state penetration.

K=

6.3.1 Absorption of Toxicants by Gastrointestinal (GI) Tract The oral route is very important for accidental or deliberate ingestion of toxicants. After oral intake of toxicants, in most of the cases the extent of absorption by gastrointestinal tract is determined by their lipophilicity. The uptake of hydrophilic substances through the pores is relatively small. Absorption of toxicants can take place along the entire length of the digestive tract, even in the mouth and rectum. Many substances can be absorbed rapidly through the wall of the gastrointestinal tract. The absorption is more rapid by the GI than the other routes. There is appreciable differences in pH value within the GI tract which influences the absorption of toxicants. The stomach tends to be

6.6

TOXICOLOGY

more acidic than the intestine. According to Henderson-Hasselbalch equation, the weak organic acids, which are non-ionized and lipophilic, can be absorbed more readily from the stomach than from intestine. Similarly, the weak organic bases which are ionized and lipophobic, can be absorbed more readily from intestine than stomach. All these absorptions occur by simple diffusion mechanisms. The intestine has also greater surface area than stomach, thus it favours absorption at the intestine. The GI tract also has at least one active transport system that decreases the absorption of xenobiotics. For toxicants with structural similarities to compounds normally taken up by the active transport mechanisms. In this case absorption process is enhanced. For example, cobalt is absorbed by the same active transport mechanism that normally transports iron. The number of toxicants actively absorbed by GI tract is low; most enter the body by simple diffusion. Generally, the lipophilic substances are absorbed by simple diffusion process more rapidly. The substances absorbed from the gastrointestinal tract are first transported by the venous blood, to the liver. Liver is the largest screening organ of the body. Thus, in liver, a large part of the toxic substances is either stored or removed from the blood and excreted into the bile. An important aspect of GI absorption is enterohepatic circulation. If the liver excretes the unchanged toxic substances into the bile, the substance may be reabsorbed when entering the intestine and then again excreted to bile. Thus, this process slows down the elimination of the toxic substances from the body. This process is known as enterohepatic circulation (Fig. 6. ).

l rta

in

ve

Po

Bile duct Duodenum

Fig. 6.2

Enterohepatic circulation.

In bucco-enteral circulation, the toxic substances are absorbed in the intestine, subsequently taken up by the salivary glands from the blood and then excreted again by the glands into the oral cavity.

MOVEMENT AND DISTRIBUTION OF TOXINS IN ENVIRONMENT AND ECOSYSTEM

6.7

6.3.2 Absorption of Toxicants by Respiratory Tract The respiratory tract (lungs) is the most important route of entry for toxic gases (e.g., carbon monoxide, sulphur dioxide and nitrogen dioxide), vapours of volatile solvents (e.g., benzene, carbon tetrachloride, etc.) and aerosol. The sequence of respiration involves several interrelated air volumes that define the capacity of the lungs and factors important to particle disposition and retention. The absorption of inhaled gases and vapours occurs mainly in the lungs. Before a gas reaches the lungs, it passes through the nose (trachea), then reaches the bronchi and their branches, the bronchioles, which in turn lead into the alveoli. Trachea acts as a ‘scrubber’ for water-soluble gases and highly reactive gases, thus it partially protects the lungs from potential toxicants. From alveoli the toxicants enter into the bloodstream. The rate of entry of gases or vapours (toxicants) is influenced by the alveolar ventilation rate. For very small particles and gaseous toxicants, absorption takes place in the alveolar region. When a gas is inhaled into the lungs, gas molecules diffuse from the alveolar space into the blood and then dissolve. The greater portion of highly blood soluble gases is transferred to the blood with each breath and little is left in the alveolus. This process will continue till the equilibrium is reached between the gas molecules on the blood to the gas molecules in alveolar space. At equilibrium the ratio of the concentration of toxicants on the blood and in the alveolar space is constant. This solubility ratio is known as blood-to-gas partition coefficient. This partition coefficient (constant) is different for different gaseous toxicants. The more soluble the toxicant, the more time it will take to reach equilibrium in the blood. For highly soluble gases, the principal factor limiting absorption is the rate of respiration. The higher the inhaled concentration of a gas, the higher the gas concentration in blood, but the blood to gas partition coefficient remains constant unless the saturation is reached. Thus, it is evident that the high-soluble toxicants are removed rapidly from the lungs by the blood. For example, chloroform has high solubility and ethylene has low solubility (blood/gas solubility ratio). Therefore, a small percentage of ethylene from total gas of lungs will be removed by the blood circulation. There is little or no evidence for active transport in the respiratory system. The absorption of aerosols depends largely on the size of the particles and water solubility of that toxicant present in aerosol. The particles of 5 mm and larger size are generally deposited in trachea. The particles of to 5 mm are deposited in the bronchi regions of the lungs. The particles less than 1 mm can penetrate to the alveolar sacs of lungs. The overall removal of particles from the alveoli is relatively inefficient. Thus, some particles may remain in the alveoli indfinitely.

6.3.3 Absorption of Toxicants through the Skin The skin is a complex, multilayered tissue which makes it relatively impermeable to many toxic substances. Thus, skin is a good barrier to protect the organisms

6.8

TOXICOLOGY

from their environment. However, it is permeable to a large number of toxicants in solids, liquid or gaseous phases to produce systemic effects. For example, carbon tetrachloride can be absorbed through skin in sufficient quantities to cause liver injury. There are three distinct layers of skin such as epidermis, dermis and hypodermis. (Fig. 6.3). The outer stratum corneum or horny layer, which is the uppermost layer of epidermis is the only layer important for penetration of toxicants. This layer consists of keratin which allows very little water to pass and supresses evaporation. Stratum corneum consists of dead cells and it has no blood supply. The epidermis is a multilayered tissue varying in thickness from about 0.1 to 0.8 mm. The thicker areas of the skin have a higher concentration of keratin than the thinner areas. The compounds which are absorbed through skin will first have to pass across the keratinised skin layer before they can reach the bloodstream. Basal layer Hair

Toxicant Sebaceous glands

Opening of sweat gland

Stratum corneum

Epidermis

Dermis

Hypodermis

Hair follicle

Fig. 6.3

Capillary network

Sweat gland

Cross-section of human skin.

All the toxicants move across the stratum corneum by passive diffusion. The extent of percutaneous absorption of a substance depends largely on the physical and chemical properties of the substance. The absorption of a xenobiotic by skin is known as percutaneous absorption. Polar substances appear to diffuse through the outer surface of protein filaments of the hydrated stratum corneum, whereas nonpolar molecules dissolve in and diffuse through the lipid matrix between the protein filament (Blank and Scheuplein, 1969). The rate of diffusion of nonpolar toxicants is proportional to their lipid solubility and is inversely related to their molecular weight (Marzulli et al., 1965). The absorption of toxicants through the skin varies, depending on the

MOVEMENT AND DISTRIBUTION OF TOXINS IN ENVIRONMENT AND ECOSYSTEM

6.9

condition of the skin. There are solvents which promote passage across the skin. Solvents like dimethyl sulphoxide (DMSO) can facilitate the penetration of toxicants through the skin. The dermis and hypodermis areas of the skin play a very minor role in penetration. The dermis is highly vascular which provides further opportunity to transfer. The hypodermis layer of the skin is highly lipid in nature and serves as a shock absorber. There is no support of active transport system in skin. The stratum corneum is much thicker in humans than in animals. Human skin is usually less permeable for xenobiotics than the animal skin.

6.4

DISTRIBUTION OF TOXICANTS OVER THE ORGANISM

After a substance has been absorbed or administered, the substance is distributed throughout the body mainly through circulatory system and other body fluids (e.g., plasma water, interstitial water and intracellular water). Vascular fluid has the important role in the distribution of absorbed toxicants. Distribution usually occurs rapidly. Initially, distribution will take place by diffusion over the various aqueous compartments. The toxicants do not need to pass across cell membranes and thus fill only the extracellular fluid compartment. The rate of distribution of toxicants to different organs or tissues is determined by blood flow and the rate of diffusion from the blood into the cells of concerned tissues or organs. After absorption, a toxicant may be distributed to the sites where it induces its toxic effect, may be transferred to a storage depot, transported to the organs of detoxification or interaction and eventually excreted. The concentration of a toxicant may be achieved in the blood following exposure depends on the apparent volume of distribution.

6.4.1 Volume of Distribution There are various compartments in the average individual with normal body weight. The total body fluid (water) may be divided into three distinct compartments such as: • Plasma water • Interstitial water • Intracellular water. The plasma water and interstitial water combinely are known as extracellular water. Human plasma accounts for 4% of the body weight or 3 litres in average. But plasma water accounts 53% of total blood volume. The interstitial water accounts for 14 to 15% of the body weight that may be about 10 to 1 litres in average. The intracellular water compries 38 to 40% of the body weight that may be equal to 5 to 6 litres in average. Therefore, the concentration of a toxicant in blood depends largely on its volume of distribution. For example, if the ‘x’ gm toxicant is distributed only in plasma, a high concentration is achieved in the

6.10

TOXICOLOGY

vascular tissue. If the same quantity (x gm) of toxicant is distributed in the interstitial and intracellular water, concentrations will be much lower in the vascular system. Because both of these contain large volume of water, thus dilution of toxicants occurs here.

6.4.2 Accumulation of Toxicants in Tissues Toxicants often stored in specific tissues, either at sites of storage like in liver or kidney, or at the site of action (e.g., haemoglobin). The substances which are binding to cellular components or dissolution in lipids leads to a much higher concentration in the tissues than in the bloodstream. For example, the highly lipophilic compounds like DDT, dieldrin, polychlorinated biphenyls (PCBs) are highly accumulated in body fats. The liver and kidney have a large accumulative capacity, especially for heavy metals. Lead is stored in bones, but manifestations of lead poisoning appear in soft tissues.

6.4.3 Distribution Mechanism of Toxicants There is an important distribution mechanism for xenobiotics binding to the plasma proteins. For example, albumin can bind a large number of different toxic compounds. Cellular components of the blood also contribute to the distribution of toxicants but they play a much less significant role than the plasma proteins. For example, ceruloplasmin is a plasma protein which carries most of the copper metals. Albumin is the most abundant protein in plasma and serves as a depot and transport protein for many endogenous and exogenous compounds. The binding of chemicals to plasma proteins is of special importance from ecotoxicological point of view because if a compound is bound to a blood protein, it is immobilized away from the site of action. The displacement of one toxicant by another more toxicant is possible in this mechanism.

6.4.4 Reversible Binding Mechanisms Many toxic substances are bound reversibly to a variety of biological components. Similarly, there are many toxic and non-toxic substances and metabolites that irreversibly bind to tissue proteins. In the case of liquid-protein reversible interactions, the law of mass action provides a mechanism so that the toxicants can be transported and then dissociated at various tissues. Cf + Bf where

k1 k2

CB

Cf = Concentration of free toxicant molecules. Bf = Free binding sites. CB = Concentration of bound toxicant molecules. k1 and k2 are the rate constants of association and dissociation respectively.

MOVEMENT AND DISTRIBUTION OF TOXINS IN ENVIRONMENT AND ECOSYSTEM

Kd =

CB

6.11

bB

CB

Kd is the dissociation constant = k2 /k1. The dissociation constant equation indicates that the sites with lowest dissociation constant will form the strongest bonds with the toxicants. Therefore, once a molecule binds to plasma protein, it moves throughout the circulation until it dissociates. Dissociation occurs when the affinity of another molecule or tissue component is greater than that of the plasma protein to which the toxicant was originally bound. The binding forces must be strong enough to establish an initial interaction but at the same time weak enough so that dissociation may occur at another site. As long as the binding force is reversible, redistribution will occur whenever the concentration of one site (blood or tissue) is diminished. In general, the organic anions are bound more strongly than organic cations to the plasma proteins. The affinity increases if a lipophilic group is present. Plasma protein binding reduces the concentration of the free compound in the blood which in turn reduces the intensity of toxic effect because there will be non-availability of free compounds in the blood. On the other hand, it also reduces the elimination of a toxic substance and can provide a reservoir of the toxic substances which can be mobilized from time to time.

6.4.5 Irreversible Binding Mechanism The non-specific and irreversible nature of binding of xenobiotics causes competition for the binding sites. The competitive binding for the same sites on a protein can have an important toxicological significance. In this irreversible binding mechanism, the displacement of a less toxic (low affinity) substance by a stronger (greater affinity) toxic substance is facilitated. This displacement interactions may also affect the transport of a metabolite by its carrier protein and it has more harmful effects on the organism. Many metals show competitive binding for the metal binding protein, i.e., metallothionein.

EXERCISE 1. What do you mean by the transport mechanisms of the toxicants? Draw the flow chart of the mechanisms by which toxicants can pass a membrane. 2. Explain the working principle of the transport of toxicants through the membranes. What is partition coefficient? 3. What are different passive transport mechanisms? Explain the simple diffusion mechanism on detail. Write the important significances of this mechanism. 4. Discuss about the special transport mechanism.

6.12

TOXICOLOGY

5. Write short notes on: (a) Active transport mechanism. (b) Pinocytosis. (c) Facilitated diffusion. 6. What is Fick’s law of diffusion? Explain it. 7. Why the absorption of toxicant is greater in intestine? What is enterohepatic circulation? 8. What are the different layers of skin? Explain the mechanism how the toxicants enter through the skin? 9. How do the toxicants enter into an organism’s body through respiratory tract? 10. How do the toxicants distribute over the organism? 11. Explain the distribution mechanism of toxicants over the organism. 12. What is reversible binding mechanism? Differentiate it with irreversible binding mechanism.

CHAPTER

7

Fate of Toxins 7.1

INTRODUCTION

All organims are surrounded and exposed constantly by a number of foreign chemicals or xenobiotics, which may be harmful to the functioning of the organisms. In many cases, it is found that the parent compounds do not confer toxicity to a cell or tissue but rather one or several of their metabolites confer the toxicity to cells or tissue. After a xenobiotic has entered the body through skin, respiratory system or gastrointestinal routes, the higher organisms have the capacity to expel them from the body. But the lipophilic xenobiotics are not easily removed rather these are accumulated in the body. The hydrophilic xenobiotics can be readily excreted in the urine. The elimination of lipophilic xenobiotics mainly depend on their conversion to watersoluble compounds so that they can be easily eliminated from the body. If it is not converted to hydrophilic, then these lipophilic compounds can be readily reabsorbed. Passive reabsorption of lipophilic substances takes place because these substances tend to dissolve in the lipid membranes of the epithelial cells. The living organisms can usually eliminate a xenobiotic in two ways (a) by direct excretion and/or (b) by metabolic transformation of the parent substance. Without metabolic transformation, lipophilic xenobiotics would be excreted by the body so slowly that they would eventually kill the organism. Some lipophilic xenobiotics such as polychlorinated xenobiotics which are difficult to metabolize, poses no harm to the organism. They can remain in the body for many years. The biotransformation is generally catalyzed by enzymes released from liver or from other tissues.

7.2

BIOTRANSFORMATION OF XENOBIOTICS

Organisms have a wide array of enzymes that are capable to metabolize the xenobiotics and endogenous metabolic waste products into the modified

7.2

TOXICOLOGY

chemicals whose toxicity either increased or decreased. These metabolites are more water-soluble compounds, which are more readily eliminated from the body. The degree of elimination of xenobiotics depends on their conversion to water-soluble chemicals, by a process called biotransformation. The process by which a lipophilic xenobiotic compound is converted to hydrophilic compound is known as biotransformation. The biotransformation reactions may be divided into two major pathways such as: 1. Phase-I: Biotransformation which includes oxidation, reduction and/or hydrolysis reaction. 2. Phase-II: Biotransformation which includes conjugation of an endogenous, hydrophilic substance with a polar group in a molecule. The conjugated product is water soluble. Most of the biotransformation reactions are catalyzed by enzymes in the liver and other tissues. For example, cytochrome P-450 enzymes in the liver convert steroid hormones to water-soluble metabolites that may be eliminated through urine or bile.

7.2.1 Phase-I Biotransformation Phase-I biotransformation reactions involve oxidation, reduction and hydrolysis. A phase-I reaction introduces reactive polar functional groups such as – OH, O

– NH2, – SH, – COOH, – NH – OH, C C onto lipophilic xenobiotics. Now the product is more water-soluble than the parent compound and generally more suitable for excretion or further phase-II reaction. A major phaseI biotransformation is oxidation, which may be mediated by cytochrome P-450 (mixed function oxidases), alcohol dehydrogenage, aldehyde dehydrogenase or monoamine oxidase. The phase-I reactions may be discussed further, for example, mixed-function oxidases.

7.2.2 Mixed-Function Oxidases (Microsomal Oxidation) Mixed function oxidation are those oxidations in which one atom of an oxygen molecule is introduced into the substrate while the other is reduced to water as per the below reaction. Product OH Substrate + O2

Mixed-function Oxidases

H 2O

RH + O2

Mixed-function Oxidases

ROH + H2O

FATE OF TOXINS

7.3

Mixed-function oxidation is also known as mono-oxygenation. The monooxygenations of xenobiotics are catalyzed by the key enzyme called cytochrome P-450-dependent mono-oxygenase. The active site of cytochrome P-450 contains an iron atom that can be either divalent (+2) or trivalent (+3) state (Timbrell, 1982). Cytochrome P-450 is found in many tissues but in the liver, it oxidises a number of xenobiotics. It can bind to the substrate and molecular O2 in the mixed function oxidation process in which the substance is oxidized. Epoxidation

Epoxidation is the most important microsomal reaction which is a very stable and environmentally persistent epoxide. It is also highly reactive intermediate of aromatic hydroxylation. In epoxidation, the addition of an oxygen molecule to the unsaturated bond to produce an epoxide. For example, the conversion of benzene to phenol involves the formation of a highly reactive intermediate, an epoxide which is more toxic than the parent compound. Another epoxidation is the oxidation of naphthalene to produce an epoxide which acts as an intermediate for aromatic hydroxylation. O

O2/mono-oxygenase

O

Epoxidation Benzene

Epoxide

H O

O2 /mono-oxygenase Epoxidation Naphthalene

An Epoxide

Like aromatic compounds, many aliphatic compounds, containing unsaturated bonds between carbon atoms also undergo epoxidation. For example, trichloroethylene undergoes oxidation to produce an epoxide as: Cl

H C

C Cl

Cl

O2 /mono-oxygenase

Cl

Epoxidation

Cl

O

H C

C

Cl An Epoxide

The enzyme used here is cytochrome P-450. In all the above epoxidation processes, the toxicities of the epoxides are much higher than the parent compounds. This process is called intoxification. H

H C

H

C Cl

Vinyl chloride

O2 /mono-oxygenase

H

Epoxidation

H

O C

H C Cl

An Epoxide

7.4

TOXICOLOGY

The epoxide formed from vinyl chloride cause liver cancer. In general, the electrophilic character of an epoxide react with nucleophilic groups in biomacromolecules such as proteins and DNA which may lead to damage of these molecules. This may cause cancer. Hydroxylation

Hydroxylation is a reaction in which the –OH groups are attached to hydrocarbon chains or rings. In toxicology phase-I reaction, the hydroxylation is followed by epoxidation. For example, the conversion of benzene to phenol through reactive intermediate, an epoxide is formed. H

O2/mono-oxygenase

O

Epoxidation

OH

Rearrangement Hydroxylation

H Benzene

Phenol

Epoxide

Similarly, naphthalene is converted to naphthol by hydroxylation process.

The epoxidation and hydroxylation together are responsible for making several xenobiotic compounds more toxic through metabolic process. The ultimate carcinogens arising from the metabolic activation of benzo (a) pyrene 7, 8-dihydrodiol 9, 10-oxide as illustrated below. Bezo (a) pyrene 7, 8-dihydrodiol-9, 10 is known as bay-region diol-epoxide and is classified as procarcinogen. The stereoisomer of benzo (a) pyrene 7, 8-diol-9-10-epoxide is fomed in three steps. Benzo (a) pyrene is converted to the 7, 8-epoxide which gives rise to the 7, 8-dihydrodiol through the action of epoxide hydrolase. This is further metabolised by the cytochrome P-450 dependent mono-oxygenase system to the 7, 8-diol-9, 10-epoxides. The last two products are potent mutagens and unsuitable substrates for the further action of epoxide hydrolase. 12

1

11

2

10

3

9 8

Cytochrome P-450

4 7

6

5

Benzo (a) pyrene

O 7, 8 epoxide of benzo (a) pyrene Fig. Contd.

FATE OF TOXINS

7.5

Fig. Contd.

Epoxide hydrolase

O P-450

HO

HO

OH

OH 7, 8-diol-9, 10 epoxides of benzo (a) pyrene

7, 8-dihydrol of benzo (a) pyrene

O, N and S-Dealkylation

Many xenobiotics contain alkyl groups, such as the methyl (– CH3) group attached to atoms O, N, and S. In dealkylation mechanism, the methyl group is replaced by ‘H’. For example, in O-dealkylation of p-nitroanisole the CH3 group is replaced by H to produce p-nitrophenol OCH3

OH O O-dealkylation

+ H—C—H NO2

NO2 P-Nitroanisole

P-Nitrophenol

In aliphatic compound the O-dealkylation is O R—O—CH3

O-dealkylation

(Ether)

ROH + H—C—H (Alcohol)

The product of O-dealkylation (e.g., P-nitrophenol) is frequently used substrate for cytochrome P-450 dependent mono-oxygenase activity. N-dealkylation is a common reaction in the metabolism of carbaryl insecticides, drugs and other xenobiotics. N, N-dialkyl carbamates are readily dealkylated. Like O-dealkylation, here also alkyl group is replaced by H. For example, N, N-dimethyl-P-Nitrophenyl Carbamate undergoes dealkylation process to produce N-methyl-P-nitrophenyl carbamate as follows: O O—C—N

O CH3

O—C—N

CH3 N-dealkylation

NO2 N, N-Dimethyl-P-Nitrophenyl Carbamate

H CH3

+ HCHO NO2 N-Methyl-P-Nitrophenyl Carbamate

7.6

TOXICOLOGY H R—N—CH3

N-dealkylation

H + HCHO

R—N H

Secondary amine

Primary amine

S-dealkylation occurs with a number of thioethers. For example, dimethyl mercaptan undergoes S-dealkylation in which methyl (– CH3) group is replaced by H. CH3—S—CH3

S-dealkylation

CH3—SH + HCHO Mercaptans or Thioalcohol

Dimethyl mercaptan (Thioether)

7.2.3 Non-microsomal Oxidation There are many enzymes other than microsomal monooxygenases involved in the oxidation of xenobiotics. Generally, the enzymes responsible for nonmicrosomal oxidation are located in mitochondria or in the soluble cytoplasm of the cell. Alcohol and Aldehyde Dehydrogenase

Alcohols and aldehydes are oxidized by a number of enzymes such as alcohol dehydrogenase, aldehyde dehydrogenase, dihydrodiol dehydrogenase, etc. Alcohol dehydrogenase (ADH) catalyze the conversion of alcohols to aldehydes or ketones. For example, the alcohols like methanol or ethanol are oxidized to formaldelyde or acetaldehyde respectively which may further catalyzed by aldehyde dehydrogenase (ALDH) to carboxylic acid such as formic acid and acetic acid. NAD R—CH2OH Alcohol

+

NADH + H ADH

+

+

NAD + H2O NADH + H

O R—C

H

ALDH

Aldehyde

+

O

R—C

OH

Carboxylic acid

NADH ® Non-alcohol dehydrogenase In these reactions NAD+ is the preferred cofactor and the alcohol dehydrogenase reaction is reversible, i.e., carboxyl compounds being reduced to alcohols. Alcohol dehydrogenase (ADH) is a cytosolic enzyme present in several tissues including the liver, kidney, lung and the gastric mucosa (Agarwal and Goedd, 1992). The primary alcohols are oxidized to aldehyde whereas the secondary alcohols are oxidized to ketones. Alcohol dehydrogenase is inhibited by a number of heterocyclic compounds such as pyrazole, imidazole and their derivatives. Generally, the alcohol oxidation is considered an activation reaction

FATE OF TOXINS

7.7

because due to oxidation aldehyde is formed which is very toxic and is not readily excreted because of their lipophilicity. Aldehyde Dehydrogenase (ALDH) oxidizes aldehydes to carboxylic acids with NAD+ as the cofactor. The oxidation of aldehydes to carboxylic acid is known as detoxification step because acid is water soluble and excreted readily. Amine oxidases There are three types of amine oxidase namely, monoamine oxide (MAO), diamine oxidase (DAO) and polyamine oxidase (PAO). The monoamine oxidases (MAO) are found in mitochondria, liver, kidney, brain, intestine and blood platelets. A number of xenobiotics are substrate for MAO enzyme. Oxidative deamination of a primary amine produces ammonia and an aldehyde whereas oxidative deamination of secondary amine produces a primary amine and an aldehyde. The aldehydes formed by MAO are usually oxidized further by other enzymes to the corresponding carboxylic acids. CH2—NH2

CHO

COOH

NH3 + H2O2

O2 + H2O

MAO Cl

Cl P-Chlorobenzylamine

Cl

P-Chlorobenzaldehyde

P-Chlorobenzoic acid

Diamine oxidases are enzymes that also oxidize amines to aldehyde. In this case, the preferred substrates are aliphatic diamines in which the chain length is four or five carbon atoms. NH3 + H2O2

O2 + H2O H2N — C4H8 — CH2NH2

H2N — C4H8 — CHO

DAO

Diamines with carbon chains longer than nine are not substrates for DAO, but they can be oxidized by MAO. Diamine oxidase is a cytosolic, copper containing pyridoxal phosphate-dependent enzyme present in liver, kidney, intestine and placenta. Polyamine Oxidases (PAO) are similar to MAO in its cofactor functions which use oxygen as an electron acceptor results in the production of hydrogen peroxide. O2 + H2O

C5H11NH2 + H2O2

O C5H11 — NHCH2 — C Milacemide

NH2

CHO

PAO COOH CONH2 Oxamic acid

CONH2

7.8

TOXICOLOGY

7.3

OXIDATION OF NON-CARBON ELEMENTS

Biotransformation reactions which yield products having a higher toxicity than the parent compounds are referred to as metabolic activation or bioactivation. There are many oxidation of non-carbon element existing. The most important oxidation of non-carbon elements are oxidation of nitrogen (N-oxidation) oxidation of sulphur (S-oxidation), and oxidation of phosphorus (P-oxidation). N-Oxidation N-oxidation can occur in a number of ways, including N-oxide formation, oxime formation and hydroxylamine formation which are considered to be important intoxification mechanism. For example, metabolic activation reaction is carried out in substrate 2-acetylaminofluorene to produce a potent carcinogen product. For example (i) N-Oxidation H COCH3 Cytochrome

N

N

P-450

2-Acetylaminofluorene

OH COCH3

N-Hydroxyl-2-acetylaminofluorine

(ii) O CH3

N

CH3

CH3

N

CH3

N-Oxidation P-450 Dimethylaniline

Dimethyl N-Oxide

(iii) CH3

O C

H 3C

CH3

Trimethylacetophenoneimine

CH3 CH

NH

O C

N-Oxidation

CH

NOH

P-450

H 3C

CH3

Trimethylacetophenoneoxime

S-Oxidation Several sulphur containing xenobiotics such as thiols, thioamides, thioethers, thiocarbamates, and thiocarbamides. Thioethers in general are oxidized by FAD-containing monooxygenase (FMO) to sulphoxides which are subjected to S-oxidation. The thiocarbamate functionally present in numerous agricultural chemicals is converted to S-oxides (Sulphoxides) which can be further oxygenated to sulphones. For example.

FATE OF TOXINS

7.9

(i) O S-Oxidation

CH3 — S — CH3

CH3 — S — CH3

P-450

Dimethyl mercaptan

O S-Oxidation

CH3 — S — CH3

Sulphoxide

O Sulphone

(ii) NCN

NCN

CH2 — S — (CH2)2 NHCNHCH3

N

CH2 — S — (CH2)2 NHCNHCH3

N

S-Oxidation

CH3 N H Cimetidine

N H

CH3

Cimetidine-S-Oxide

NCN

O

O

S-Oxidation

CH2 — S — (CH2)2 NHCNHCH3

N

CH3

N H

O

Cimetidine Sulphone

P-Oxidation P-oxidation involves the conversion of trisubstituted phosphines to phosphine oxides. Similarly, the P-oxidation in parathion yields insecticidal paraxon which is much more effective than the parent compound in inhibiting acetylcholinesterase enzyme. (i)

O 2N —

—O—P

OC2H5

P-Oxidation

OC2H5

cytochrome P-450

S Parathion

O2N —

—O—P S Paraxon

(ii) O —P — CH3 Diphenyl methyl phosphine

P-Oxidation cytochrome P-450

—P— O Diphenyl methyl phosphine oxide

OC2H5 OC2H5

7.10 7.4

TOXICOLOGY

METABOLIC REDUCTION

A number of metals (pentavalent arsenic) and xenobiotics having functional groups, such as azo, nitro, carbonryl, disulphide, sulphoxide, alkene, N-Oxide, quinone are susceptible to reduction. These reduction reactions are carried out by reductase enzymes which are found largely in liver, kidney and lungs. Some intestinal bacteria which contain these enzymes reduce some xenobiotics in the intestinal tract.

7.4.1 Azo- and Nitro-reduction Azo and nitro-reduction are carried out by both bacteria and mammalian nitroreductase systems. These reductions are catalyzed by two liver enzymes such as: cytochrome P-450 and NADPH-quinone oxidoreductase. These reactions are inhibited by oxygen. The azo-reduction reactions are also inhibited by Carbon monoxide (CO). Nitro-reduction by intestinal microflora plays an important role in biotransformation of xenobiotics. (a)

Nitro-reduction

(i) NO2

NO

NHOH

2H Nitrobenzene

NH2

2H Nitrosobenzene

2H Phenyl Hydroxylamine

Aniline

(ii) O HO — CH — CH — NH — C — CHCl2 CH2OH

CH — CH — NH — C — CHCl2 CH2OH

6H

NO2

(b)

O

OH

NH2

Azo-reduction N

N—

NH

CH3

NH — CH3

H3C

H3C NH2

NH2

Hydrazo derivative

O-aminoazotoluene

NH2

NH2 CH3 +

H3C NH2

FATE OF TOXINS

7.11

7.4.2 Carbonyl Reduction The reduction of certain major functional groups in xenobiotics such as aldehydes, ketones and alkenes can be reduced metabolically. Aldehydes reduce to primary alcohol and ketones to secondary alcohol. These reduction reactions are catalyzed by alcohol dehydrogenase (ADH). Alkene reduces to alcohol. The carbonyl reductases are NADPH-dependent, cytoplasmic enzymes of low molecular weight. These are found in liver, kidney, brain and other tissues. O CH3 — C — H

Aldehyde Reduction

Acetaldehyde

CH3 — CH2 — OH Ethanol (Acetyl alcohol)

O

OH

CH3 — C — CH3

Ketone Reduction

Acetone

CH2

CH2

CH3 — C — CH3 2° alcohol

Alkene Reduction

Alkene

CH3 — CH2 — OH Alcohol

Aromatic aldelyde reduction CHO

CH2OH Aldehyde Reduction

Cl

Cl

P-Chloro benzaldehyde

P-Chlorobenzyl alcohol

7.4.3 Disulphide Reduction Some important disulphides are reduced to their corresponding sulphydryl components. For example, the drug disulfiram (Antabuse) are reduced to their sulphydryl constituents. Disulphide reduction by glutathione is a three-step process. The last reaction of which is catalyzed by glutathione reductase. The first step can be catalyzed by glutathione S-transferase. (i) S

S

S

H5C2

H5C2

C2H5 N—C—S—S—C—N

H5C2

N — C — SH

2 C2H5

Disulfiram (Antabuse)

H5C2 Diethyldithiocarbamate

(ii) R — S — S — R¢

Disulphide reduction

R—S—S—H

7.12

TOXICOLOGY

(iii) GSH

XSH

X—S—S—X

XSSG

Disulphide

GSH

XSH

X—S—S—G

G—S—S—G

NADPH + H

+

NADP

G—S—S—G

+

2GSH

GSH ® Glutathione Reductase

7.4.4 Sulphoxide and N-Oxide Reduction The reduction sulphoxides occurs in mammalia tissues. These reactions are catalyzed by Thioredoxin-dependent enzymes which are found in liver and kidney. It has been suggested that a form of recycling occurs involving the oxidation in the endoplasmic reticulum followed by reduction in the cytoplasm. For example, sulindac is a sulphoxide that undergoes reduction to a sulphide, which is excreted in bile and reabsorbed from the intestine (Ratnayak et al,. 1981). (i) O R — S — R¢

Sulphoxide

R — S — R¢

reduction

(ii) O CH

S — CH3 2H H2O

CH

CH3 F

CH2COOH Sulindac

S — CH3

CH3 Sulphoxide reduction

F

CH2COOH Sulindac sulphide

The reduction of N-oxides can be catalyzed by in the presence of NADH or NADPH which are found in liver. For example, tirapazamine (benzotriazine di Noxide) undergoes N-oxide reduction by NADPH-Cytochrome P-450 reductase (Saunders et al. 2000).

FATE OF TOXINS

O

7.13

O

N

N

–

2e

N N

N N

NH2

–

N

2e

N N

NH2

NH2

O Tirapazamine (SR-4233)

SR.4317

SR.4330

7.4.5 Metal Reduction Certain metals like pentavalent arsenic undergoes reduction to produce trivalent arsenic metal containing xenobites. As (V)

Arsenic Reduction

Pentavalent Arsenic

7.5

As (III) Trivalent Arsenic

METABOLIC HYDROLYSIS

Hydrolysis is a process in which H2O molecule is added to the substrate so that cleavage of the molecule takes place. The mammals contain a variety of enzymes such as carboxylesterases, amidese which are found in many tissues like tissue lining the intestines, nervous tissue, blood plasma, kidney and muscles. These enzymes hydrolyse many xenobiotic compounds such as esters, amides, organophosphate esters, acid anhydrides, thioesters and other ester derivative compounds.

7.5.1 Esterases The esterases like carboxylesterases, pseudocholinesterase and paraoxonase play very important role in limiting the toxicity of many xenobiotics. Generally, carboxylesterases catalyze the hydrolysis of carboxylic acid, esters, amides and thioesters. Most of the carboxylesterase activity in liver is associated with the endoplasmic reticulum, although considerable carboxylesterase activity is present in lysosomes and cytosol. Phosphoric acid esters are hydrolyzed by paraoxonase which is also known as both organophosphatase or aryldialkyl phosphatase and as an arylesterase. Phosphoric acid anhydrides are generally hydrolyzed by organophosphatase. The esterases catalyze the following general reactions: (i) O R—C—OR¢ + H2O

Carboxylesterase hydrolysis

RCOOH + R¢ OH

7.14

TOXICOLOGY

(ii) O

R¢

R¢

+ H2O

Carboxylesterase hydrolysis

RCOOH + NH

R—C—S—R¢ + H2O

Carboxylesterase hydrolysis

RCOOH + SH—R¢

R—C—N

R¢¢

R¢¢

(iii) O

(iv) OH

O

O (C2H5O)2P — O —

— NO2 + H2O

Esterase

(C2H5O)2P — OH + NO2

(v) O (C2H5O)2P — S — CH2 — CH2 — S— CH2 — CH3 + H2O O

esterase

(C2H5O)2P — OH + HS — CH2 — CH2 — S — CH2 — CH3

(vi) SH

O CH3 — C — S —

+ H 2O

Esterase

CH3COOH +

(vii) NH2

O CH3 — C — NH —

+ H2O

Esterase

CH3COOH +

7.5.2 Epoxide Hydrolase Epoxide rings of alkenes and arene oxides (oxiranes) are hydrated by enzymes known as epoxide hydrolases which can form during the cytochrome P-450 dependent oxidation of aliphatic alkenes and aromatic hydrocarbons respectively.

FATE OF TOXINS

7.15

In mammals, there are five types of epoxide hydrolase such as microsomal epoxide hydrolase (mEH), soluble epoxide hydrolase (sEH), cholesterol epoxide hydrolase, hepoxilin hydrolase and LTA 4 hydrolase (Beetham et al. 1995). mEH rapidly hydrolyses epoxides on cyclic systems, but sEH has little effect on these compounds. The mEH and sEH can rapidly convert the potentially toxic metabolites to the corresponding dihydrodiols which are less reactive and easily excreted from the body. Thus, epoxide hydrolases are widely considered a group of detoxification enzymes. Alkene epoxide OH

O — CH — CH2

+ H2O

— CH — CH2OH

Epoxide hydrolase

Styrene 7, 8 oxide

Styrene 7, 8 glucol

Arene oxide OH

O

H

Epoxide + H2O

OH

hydrolase

Naphthalene 1, 2 oxide

H

Naphthalene dihydrodiol

7.5.3 Dehydrochlorinase Dehydrochlorinase is an enzyme which plays an important role in the metabolism of many xenobiotic compounds that contain covalently bonded halogens particularly chlorine. Extensive study has been made on Dichloro Diphenyl Trichloroethane (DDT). Dehydrochlorinase catalyzes the dehydrochlorination reaction of DDT and convert it into DDE. In this process, the halogen (chlorine) atom is replaced by hydrogen. For example, H Cl —

—C—

— Cl

dehalogenation

Cl —

—C—

CCl3

CCl2

DDT

DDE

DDE—Dichloro Diphenyl Ethelenedichloride.

7.6 PHASE-II REACTIONS OF TOXICANTS (ENZYME REACTIONS) Phase-II reaction of toxicants involves the conversion of xenobiotic compounds from polar to hydrophilic compounds for rapid excretion. It is also known as

7.16

TOXICOLOGY

conjugation reaction because it involves the introduction of a substrate compound (polar group) with another species that occurs normally in the body. The species that bind the polar groups obtained from phase-I reaction are called conjugating agents. Thus, the conjugation reactions can occur with a variety of substances, usually intermediates on the organism’s metabolism. These intermediates or conjugating agents are glutathione, sulphate, amino acids (glycine, taurine and glutamic acid), etc. The most common conjugation reactions and their respective functional groups involved in the reactions are mentioned in Table 7.1. In most phase-II biotransformation reactions, there is an increase in xenobiotic hydrophilicity, so they can easily be excreted from the body. Table 7.1

Phase-II reaction—Conjugation reactions (Types and respective functional groups).

Types of conjugation reactions

Functional groups

1. Glucuronidation 2. Sulphonation (Sulphation) 3. Acetylation 4. Methylation 5. Conjugation with amino acids

– OH, – COOH, – NH2, – SH, – CH Alcohols, aromatic – NH2, aromatic – OH. both aromatic and aliphatic – NH2, hydrazines. – NH2, – SH, aromatic – OH. – COOH, aromatic – NH2

6. Glutathione conjugation

epoxide – C

–C

O , organic halides (F, Cl, Br, I).

Phase-II reactions are much faster than the phase-I reactions. Therefore, the elimination of xenobiotics depends on the phase-I reaction which is controlled by cytochrome P-450. The introduction of a polar group during phase-I reactions makes it possible for a conjugation reaction in phase-II. For example COOH Phase-I

O

Phase-II

OH

—

OH

O

O—

HO Benzene

Epoxide

Phenol

OH Phenyl glucouronide

7.6.1 Glucuronidation Glucuronidation is the most important pathway of xenobiotic transformation among all the phase-II reactions. Conjugation of a substrate containing a polar group with glucuruonic acid can only place after the glucuronic has been activated. The activated glucuronic acid contains uridine diphosphate glucose

FATE OF TOXINS

7.17

(UDPG) or uridine diphosphate glucuronic acid (UDPGA). Glucuronides are the conjugating agents present in the body. These conjugating agents react with xenobiotics (polar groups) through the action of UDPG and UDPGA. The reaction involves in it is a nucleophilic disubstitution (SN2 reaction) of the functional group of the substrate. For example, O C UDPGA R—OH Xenobiotics with functional (–OH) group

UDP

OH O

OH

Glucuronidation

OR

HO OH

The structure of UDPA is as follows:

Conjugate of xenobiotic with gluceuronide

O C

OH O

OH

OUPGA

HO OH

R may be a benzene ring (Phenyl group). The kind of enzyme that catalyzes this type of reaction is UDP-glucuronosyltransferases. (UGTs), which are located in the endoplasmic reticulum of liver, kidney, intestine, skin, brain, spleen and nasal mucosa. The site of glucuronidation is generally an electron rich nucleophilic heteroatom (O, N & S). A wide variety of reactions are mediated by glucuronosyl-transferases. Glucuronide conjugation products may be classified according to the element to which the glucuronide is attached. These products are O-glucuronides, N-glucuronides and S-glucuronides. The formation of O, N and S-glucuronides is as follows: O-glucuronide formation COOH O O

UDPGA

UDP

UDP-glucuronosyl transferase 1, Naphthol

HO

—

—

OH

OH OH

O-glucuronide

7.18

TOXICOLOGY

N-glucuronide formation COOH —

H UDPGA

NH2

UDP

O

—N

HO

UDP-glucuronosyl transferase

OH OH

2, Naphthylamine

N-glucuronide

S-glucuronide formation COOH UDPGA SH

UDP

O HO

S

UDP-glucuronosyl transferase

OH OH S-glucuronide

Thiophenol

When the functional group through which conjugation occurs is aliphatic alcohols or phenols they form O-gluconide ethers if it is carboxylic acid then it is O-gluconide ester. Primary and secondary aromatic and aliphatic amines form Nglucuronides while free sulphydryl groups form S-glucuronides. These glucuronides are more toxic than their parent compounds.

7.6.2 Sulphation (Sulphate Conjugation) Sulphate conjugation is the most common reaction in phase-II. The sulphate needs to be activated first before the reaction with the substrate can take place. The sulphate esters which are water soluble and readily eliminated from the body as the product of sulphation. The xenobiotics such as alcohols, arylamines and phenols undergo sulphate conjugation through catalyzed enzymatic reaction. Sulphotransferase are responsible for catalyzing the reaction and are found in liver, kidney and lungs. The sulphation requires the prior activation of sulphate ions to 3¢-phosphoadenosine-5¢-phosphosulphate (PAPS). In sulphate conjugation reaction, sulphonate (SO3– ) is transferred from PAPS but not the sulphate ion (SO4– 2) to the xenobiotic compound. For example, (1) O

N N

Phenol

O

P —O

O

N

—

N

—

+

—

—

NH2

—

—

OH

O

—

O

CH — CHOH — CH — CH — CH2O — P — O — S — O PAPS

OSO3H + PAP Phenyl sulphate

O

O

O

—

FATE OF TOXINS

7.19

(2) —

OSO3H

—

OH

CH3 — CHCH2CH3 1

CH3 — CH — CH2OH + PAPS 2, Butanol

Butyl sulphate

The sulphate conjugates of xenobiotics are generally water soluble and excreted mainly in urine. A number of carboxylic acids such as benzoic acid, naphthoic acid, salicylic acid and naproxen are competitive inhibitors of sulphotransferases (Rao and Duffel, 1991). The rate of xenobiotic sulphation depends on the concentration of PAPS. The low concentration of PAPS limits the capacity for xenobiotic sulphation. In terms of conjugation reaction, in general, glucuronidation is a low affinity but high capacity pathway whereas sulphation is a high affinity but low capacity pathway of xenobiotic conjugation. Sulphation is an effective means of decreasing the toxicity effects of xenobiotics. The sulphation reactions are catalyzed by a family of related sulphotransferases that have been classified as: aryl sulphotransferase, hydroxysteroid sulphotransferase, estrone sulphotransferase and bile salt sulphotransferase. Some sulphation reactions are as:

NH2

PAPS

PAP

—

—

(i) NHSO3H

2-Naphthylamine

(ii) O CH2

H HC — C OH 1, Hydroxysaphrole

O

O PAPS

PAP CH2

CH — CH

O

OSO3H 1, Sulphoxysaphrole

7.6.3 Methylation A large number of both endogenous and exogenous compounds can be methylated by several N, O and S methyl transferases. Generally, methylation decreases the water solubility of xenobiotics thus excretion is a slow process. The cofactor for methylation is S-adenosylmethionine (SAM) which donates methyl and is formed from methionine and Adenosine triphosphate (ATP). Though methylation decreases the water solubility of xenobiotics, it is served as detoxication reaction. During the methylation reactions (O, N or S), SAM is converted to S-adenosyl homocysteine.

7.20

TOXICOLOGY

O-Methylation

The O-methylation of phenols and catechols is catalyzed by two different enzymes known as phenol O-methyl-transferase (POMT) and catechol-Omethyltransferase (COMT) (Weinshilboum, 1989, 1992b). A microsomal O-methyltransferase that methylates a number of alkyl methoxy and halophenols. These methylations are inhibited by N-ethyl-maleimide and P-chloromercuribenzoate. COMT plays a greater role in the biotransformation of catechols than POMT plays in the biotransformation of phenols. COMT is found in high concentrations in liver and kidney. The substrates for COMT are dopamine, epinephrine and L-dopa (3, 4-dihydroxy phenylalanine). In methylation process L-dopa is converted to 3-O-methyl dopa and the portion of methyldopa converted to its 3-O-methyl metabolite. For example, (i) CH2 — CH

COO– NH2

CH2 — CH

COO– NH2

SAM

HO

CH2O OH

OH

3, 4-Dihydroxy phenylalanine (L-dopa)

3-O-methyl-L-dopa.

(ii) O

O

NH — C — CH3

NH — C — CH3 SAM

OH Hydroxyacetanilide

SAH

OCH3 P-methoxyacetanilide

N-Methylation

A number of enzymes such as histamine N-methyl transferase, phenylethanolamine N-methyltransferase and indoethylamine N-methyl-transferase are known that catalyze N-methylation reactions. The Histamine Nmethyltransferase (HNMT), a highly specific enzyme that occurs in the soluble fraction of the cell methylates the imidazole ring of histamine and nicotinamide N-methyltransferase (NNMT) which methylates compounds containing a pyridine ring such as nicotinamide and nicotine (Weinshilboum, 1989, 1992b).

FATE OF TOXINS

7.21

(i) CH2 — CH2 — NH2 HN

SAM

N

CH2 — CH2 — NH2 CH3—N

Histamine

N

+ SAH

N-methylhistamine

(ii) SAM

—

SAH

—

N H

N

N

Nornicotine

N CH3

Nicotine

S-Methylation

S-methylation is an important pathway in the biotransformation of sulphydrylcontaining xenobiotics such as thioacetanilide, mercaptoethanol and phenylsulphide. The methylation reaction is catalyzed by the enzyme, thiol-Smethyltransferase. In humans, S-methylation is catalysed by two enzymes called thiopurine methyltransferase (TMPT) and thiolmethyltransferase (TMPT) and thiolmethyltransferase (TMT). TPMT can be inhibited by benzoic acid derivatives but TMT is not inhibited by benzoic acid. The hydrogen sulphide produced by anaerobic bacteria in the intestinal tract is converted by S-methyltransferase to methanethiol and dimethylsulphide. (i) SH

S — CH3 SAM

N

N N

SAH

N

N

N H

N

6-Mercaptopurine

N H

6-methylmercaptopurine

(ii) SAM

Cl

SH P-chlorothiophenol

SAH

Cl

SCH3 P-chloro-S-methylthiophenol

7.6.4 Acylation Acylation involves two steps. In the first step, an activated conjugation agent coenzyme A (CoA) is involved and in the second step, xenobiotic compound is involved in the reaction.

7.22

TOXICOLOGY O

H 2N

NH2 + CoA

NH2

CH3C—NH

Benzidine

Acetylation

The xenobiotic compounds having an aromatic amine (R-NH2) or a hydrazine group (R–NH–NH2) undergo acetylation reaction which is catalyzed by N, O acyltransferase and requires the cofactor acetylcoenzyme A (Acetyl-CoA). The N-acetylation reaction occurs in two sequential steps. In the first step, the acetyl group from acetyl-CoA is transferred to an active site within the N-acetyltransferase. In the second step, the acetyl group is transferred from the acelated enzyme either to an amine to yield a stable amide or to the oxygen of the hydroxylamine to yield a reactive N-acyloxyarylamine. For example, O

O

OH

Ar — N — C — CH3 OH

N-Acyl transferase (1st step)

Ar — N — H + CH3 — C — Enzyme Ar¢NH2 (2nd step)

O

Ar ® Aryl group

Ar¢ NHC — CH3

7.6.5 Amino Acid Conjugation Amino acid conjugation reaction takes in two ways. In one way, xenobiotic compounds containing carboxylic acid conjugated with the amino groups of amino acids present in the body such as glycine, glutamine and taurine. This way needs coenzyme A to catalyze the reaction to form an amide compound. The other way involves the conjugation of xenobiotic compounds containing an aromatic hydroxylamine with the carboxylic acid group of amino acids such as serine and proline. Conjugation with amino acids is a detoxication reaction. COOH

O

C — S — CoA

+ CoA — S — COCH3

+ CH3COOH

Benzoic acid

Benzoyl-CoA O

HN — OH

HN — O — C — CH — CH2OH

—

NH2

+ CH2OH — CH — COO N OH N-Hydroxy-4 amino -quinoline-1-oxide

(Serine)

–

NH2

–

OH + N O

FATE OF TOXINS

7.23

7.6.6 Glutathione Conjugation Glutathione is a very important and crucial conjugating agent in the body. Glutathione conjugation eventually results in the formation of mercapturic acids. Gluatathione compound is a tripeptide which is comprised glycine (Gly), cysteine (Cys) and glutamic (Glu) acids. The glutathione conjugation reactions can take place with a wide variety of substrates containing halogen atoms, for example, dichloronitrobenzene and bromocyclohexane and also with alkenes, alkyl epoxides, aryl epoxides, aromatic hydrocarbons, aromatic nitrocompounds, alkylhalides and arylhalides. Substrates for glutathione conjugation are the xenobiotics that can be biotransformed to electrophiles. The initial reaction is the conjugation of xenobiotics having electrophilic substituents with glutathione which is catalyzed by glutathione transferase. This is followed by transfer of the glutamate by gglutamyltranspeptidase. The addition of glutathione to carbon-carbon double bond is also facilitated by the presence of electron withdrawing groups such as –CN, – CHO, COOR, etc. The displacement of an electron withdrawing group by glutathione occurs when the substrate contains halide, sulphate, sulphonate, phosphate or nitro group attached to an allylic or benzyl carbon atom. For example, (i) Cl

SG Cl

GSH

Cl

HCl

Glutathione transferase

NO2

NO2 1, 2dichloro-4-nitrobenzene

(ii) Cl

OH

O GSH

Chloro cyclohexane

Cyclohexene

1, 2-Oxide

GS

7.24

TOXICOLOGY

(iii) CH2Cl

CH2SG GSH

HCl

Alkyl transferase

(iv) Cl

SG NO2

GSH

NO2

HCl

Aryl transferase

NO2

NO2

(v) O GSH

CH — C — OC2H5 Alkene transferase

CH — C — OC2H5

CH2 — COOC2H5 GS

O

CH — COOC2H5

Dimethylmaleate

(vi) Glutathione transferase reaction and formation of mercapturic acids is as follows: New

draw

COOH

Glutamic acid NH2 — C— CH2 — CH2 — C Glycine acid

NH2 — CH2 — COOH

NH2 O

—

Cysteine NH2 — CH — CH2 — SH Cystenine

COOH Glutathione

COOH

O

CH — CH2 — CH2 — C — NH NH2

CH2 — SH O CH C — NH — CH2 — COOH Glycine

Glutamic acid

FATE OF TOXINS

7.25

Thus, we may write it as O HSCH2CHC — NHCH2COOH NHC — CH2CH2 — C H

NH2 COOH

O Glutathione S transferase

O RSCH2CHC — NHCH2COOH NHC — CH2 — CH2 — CH

NH2 COOH

O glutamyl transpeptidase

RSCH2CH

NH2 COOH

Acetylase

RSCH2CHCOOH O H N C— CH3 Mercapturic acid

The glutathione conjugates formed in the liver can be excreted as such in bite or it can be converted to mercapturic acid in kidney and then excreted in urine.

7.7

BIOACCUMULATION AND BIOMAGNIFICATION

Cells of the organisms have mechanisms for bioaccumulation, the selective absorption and storage of a great variety of molecules including harmful substances. The toxins that are rather dilute in the environment can reach the dangerous levels inside the living cells and tissues through the process of bioaccumulation. The concentration of a substance present in an organism is determined by the factors such as uptake, biotransformation and excretion. The residue depends both on the nature of the substance and the organism. The accumulation is a process by which the amount of a substance present in an organism is increased during lifetime because the uptake is greater than both excretion and biotransformation together. The major sources of bioaccumulation are the surrounding medium and the food. The rate of bioaccumulation can be determined by the equation as follows:

7.26

TOXICOLOGY

d CA = k1CS – k2CO dt

CA ® Concentration of substance in accumulation CS ® Concentration of substance in surrounding medium CO ® Concentration of substance in organism. Biomagnification is a process in which the concentration of a substance (usually harmful) in an organism is higher than that in its food. Biomagnification occurs when the toxic burden of a large number of organisms at a lower trophic level is accumulated and concentrated in a higher trophic level (Fig.7.1). The major source of biomagnification is food chain or food web. Big Fish 1000 PPM

Water 0.1 PPM

Many Plankton 0.1 PPM

Infinite Small fish 400 PPM

Hawk 2000 PPM

Fig.7.1 Biomagnification.

7.7.1 Food Chain Food chain is the linkage of who feeds on whom through which energy, chemical elements and other compounds are transferred from one organism to another organism. The food chain involves a series of organisms and these organisms are grouped into trophic level. Trophic level consists of all those organisms in a food chain that are the same number of feeding levels away from the source of original energy. For example, green plants are one level away from the original source of energy (sun). So it is known as first trophic level. A single food chain should have at least three links to be completed. Food chains occur in all kinds of habitats and communities. The food chain occurs in terrestrial as well as aquatic ecosystems. Very often, a single food chain is linked upto four or five links. Rarely are food chains longer than five links. The food chain is well understood from the Fig. 7.2. In ecosystems, the biotic component consists of three sub-components, namely producers, consumers and decomposers. Producers: These are autotrophic organisms consisting mainly of green plants. Autotrophs are capable of trapping solar radiations through chlorophylls (photosynthetic pigments) and manufacturing food from simple organic substances (CO2 and water).

FATE OF TOXINS

Sun

Hawk

Grass

7.27

Mouse

Snake

Fig. 7.2

Terrestrial food chain.

Consumers: These are hetrotrophic organisms. They are dependent upon other organisms for their nourishment. The consumers that feed only on green plants are called herbivores they are also known as primary consumers (e.g., cattle, elephants, etc.). The consumers that obtain their energy by eating herbivores are known as carnivores or secondary consumers (e.g., tigers, lions, wolves, etc.). There are certain animals that feed on both plants and animals known as omnivores (e.g., bears, humans, cockroach, etc.). There are certain organisms that feed on dead organic matter and are also known as consumers or detrivores (e.g., earthwarms, millipedes, etc.). Decomposers: Decomposers consist chiefly of bacteria and fungi which live on dead organic matter. These organisms break down the complex compounds of dead organic matter and absorb some of the decomposition products and release mineral nutrients. These nutrients are used by green plants for their growth.

7.7.2 Food Web In ecosystem some consumers feed on a single species but most consumers have multiple food sources, e.g., hawk eats both mouse and snake. In this way individual food chain becomes interconnected to form a food web. Food web links are complicated (Fig. 7.3). The energy flow in an ecosystem through food chain is about 80 to 90% of the potential energy as heat. Therefore, the number of links in a sequence is limited usually 4 to 5. The shorter the food chain, greater is the availability of energy. Most terrestrial food chains are shorter whereas aquatic food chains are longer. Biomagnification factor (BMF) is the ratio of concentration of substance in lipid weight predator to that in its prey as: BMF = Clip. Predator/Clip. prey.

7.28

TOXICOLOGY

Hawk Rabbit Grasshopper

Frog

Grass

Snake

Mouse

Decomposer

Fig. 7.3

7.8

Food web (terrestrial ecosystem).

BIOAVAILABILITY AND BIOCONCENTRATION

Bioavailability is the ability of an organism to take up the actual amount of the total quantity of chemicals present in the environment. The fraction of the total chemicals available for uptake of organisms plays an important role in toxicology as they produce adverse effects on the organisms. The uptake of bioavailable fraction of the substance depends both on the chemical species of the element and the nature of the organism at risk. The bioavailable concentration is often estimated on the basis of a series of extraction techniques involving fractional analysis, speciation, sequential extraction, etc. For example, the equatic environment, the free ions of the elements are available for absorption by the organisms. But when an element enters the aquatic medium, there are several factors influencing on the element based on its physico-chemical characteristics in that medium. These factors are pH, Eh, hardness, ionic strength, presence of competitive elements, chelating agents, etc. These factors make an element become water soluble or precipitate in the sediment or sparingly soluble or form complex compounds with other organic and inorganic substances, etc. But only free ions are available for absorption of the organisms. These available substances are called bioavailable substance. In the soil environment, the binding of heavy metals is in the increasing order. Cu < Zn < Pb < Cu. Thus, Cd is readily available for biological tissues to a greater extent than other elements.

FATE OF TOXINS

7.29

Bioconcentration refers to the ccumulation of a chemical substance through uptake from the surrounding medium without consideration of uptake from food. Thus, bioconcentration is the phenomenon in which the concentration of a substance in an organism is higher than that in the surrounding environment. The saturated concentration in the organism is given by CA =

k1 CS k2

CA ® Concentration of accumulation CS ® Concentration of substance in the surrounding medium.

k1 = Bioconcentration factor (BCF). k2

The bioconcentration factor (BCF) can be defined as the ratio of concentration in the organism (CA) to that in the surrounding. Bioconcentration may be defined as the direct non-dietary uptake of chemicals from the surroundings.

7.9

PERSISTENCE AND BIODEGRADATION

There are certain elements or compounds which tend to resist biodegradation and are more persistent. These substances last for long. For example, the compounds containing chloro-, nitro- or sulphate in many synthetic chemicals such as chlorofluorocarbons, plastics, chlorinated hydrocarbons and asbestos are very resistant to degradation. The compounds which are highly resistant to biodegradation are known as recalcitrant compounds. Biodegradation Biodegradation refers to the destruction of organic compounds or the alteration of chemical species by biochemical processes in the environment. Proteins, complex organic compounds and nucleic acids of dead plants and animals are degraded rapidly and completely because they are metabolized by microorganisms prevalent in the environment and these organic compounds are converted to carbon dioxide (CO2) and water. The inorganic substances attached to the organic compounds will be produced as simple salts in the degradation process which is known as mineralization. The by-products of the biodegradation are molecular forms that tend to occur in nature. Biodegradation of xenobiotic compounds that are foreign to living organisms, such as crude oil, synthetic polymers which generally are degraded slowly and partially because the availability of microorganisms to metabolize them is very small. The presence of xenobiotic compounds in the environment may promote the growth of strains of microorganisms that do metabolize these compounds. Microorganisms act as a diverse set of biological catalysts for redox

7.30

TOXICOLOGY

reactions in the environmental systems. Microorganisms produce enzymes that enhance the rate of the reactions. Thus, chemical species are biodegraded or biotransformed when they undergo a reaction induced by a microorganism. Biotransformation refers to metabolization of any substance by the biochemical processes in an organism and get altered its form in this process to another form. Metabolism may be of two types—catabolism and anabolism. In catabolism, the more complex molecules break down to simpler molecules by microbes whereas in anabolism, building blocks of life system are formed from the simpler molecules. Thus, both catabolism and anabolism are reverse processes of each other. The biodegradation of xenobiotic compounds is usually carried out by a cooperating group of microorganisms called consortium. The biodegradation process occurs in several steps and each step is carried out by different microorganisms. The development of microbial cultures with the ability to degrade materials to which they are exposed is described as metabolic adaptation. Biodegradation of xenobiotics depends upon the presence or availability of oxygen. Both anaerobes and aerobes degrade xenobiotics in reductive and oxidative processes, respectively.

-:-4+151. 2. 3. 4. 5. 6. 7. 8.

9. 10. 11. 12. 13. 14.

How does the biotransformation of xenobiotics occur? Explain the phase-I biotransformation of xenobiotics. What is epoxidation? Describe the process of intoxification. Discuss the process of hydroxylation. How do the O, N and S dealkylation occurs in organic compounds? How do the non-microsomal oxidation occur? How many types of amine oxidases? Explain their chemical reactivity. Write short notes on: (a) N-oxidation. (b) S-oxidation. (c) P-oxidation. Explain the metabolic reduction on xenobiotics by the different enzymes. Discuss the metabolic hydrolysis of xenobiotics in the organisms. How does the phase II reaction of toxicants carry out in an organism? Explain in detail. How many types of methylation occur? Explain them. Differentiate between food chain and food web. Define the terms: (a) Bioavailability (b) Bioconcentration. (c) Persistence (d) Biodegradation

CHAPTER

&

Toxicity 8.1

INTRODUCTION

An organism or individual may come in contact with a large number of different chemicals at any given time. During the processes between uptake from the surrounding mediums and excretion from the body, many xenobiotics or exogenous compounds undergo metabolism to highly reactive, electrophilic intermediates. These products may interact among themselves and with the cellular constituents in a number of mechanisms such as absorption, protein binding, biotransformation and excretion of one or both of the interacting toxicants. The biotransformation of a chemical from relatively inert chemicals to highly reactive intermediatory metabolites is known as bioactivation. The toxic responses are usually phenotype manifestations of the toxicants on an organism or individual. Thus, toxicity refers to the effects or response to cause injury to a living organism with reference to the quantity of toxicants administered or absorbed, the mechanism in which the toxicants are administered and distributed, and the type and the severity of effects. It also depends on the nature of the organisms affected and other relevant conditions. There are many causes of illness and disease. The cause may be due to the changes in genetic material, hereditary or otherwise, degeneration in one or more organs. Thus, the intoxication manifests itself in signs of illness varying from restricted local effects to complex syndromes that may cause death of the organism concerned. Intoxication can be considered a sequence of events that starts with the exposure of an organism to the chemicals. The toxic responses by an organism may be classified based on pathological and pathophysiological are as follows:

8.2

TOXICOLOGY

• • • • • • • •

8.2

Function effects Degeneration of organs/tissues (including death) Inflammation Immune-mediated toxicity. Mutagenesis and carcinogenesis. Transplacental toxicity and embryotoxicity. Metabolic disturbances. Endocrine disruption.

LOCAL AND SYSTEMIC TOXICITY

Local toxic effects occur at the site of exposure of the organism to the potentially toxic substance. For example, corrosives, irritants, injuries and/or burns always act locally. Sometimes the local toxic effects are very fatal and may cause death of the concerned organism. For example, inhalation of chlorine gas, hydrogen peroxide and fluorine reacts with lung tissues at the site of contact causing damage which may be fatal. These chemicals can alter the structure of the cell membrane and cause the cell to die. When a group of cells has become non-viable they turn necrotic. Arround the area of necrosis, an inflammatory reaction develops which is accompanied by swelling. If the necrotic tissue has been rejected and the lesion has extended under the basement membrane of the skin or mucosa, an ulcer has formed. Most toxicants or xenobiotics are not highly reactive but are absorbed and distributed around the affected organism causing systemic injury at a target organ or tissue distinct from the absorption site. Thus, systemic effects require absorption and distribution of the toxicants from its entry point to a distant site, at which deleterious effects are produced. The target organ is not necessarily the organ of great accumulation. For example, organochlorine pesticides (DDT) get accumulated in adipose (fatty) tissues to very high levels but does not cause to affect them. Lead concentrated in bone, but its toxicity is due to its effects in soft tissues particularly the brain. Most substances except highly reactive materials produce systemic effects. The chemicals that produce systemic effects do not cause similar degree of toxicity in all organs, instead they have more impact on target tissues only. Some substances produce both local and systemic effects. For example, tetraethyl lead damages the skin at the site of absorption and then is absorbed and transported to the central nervous system (CNS) and other organs.

8.3

IMMEDIATE AND DELAYED TOXICITY

The adverse effects produced by potentially toxic chemicals are likely to be immediate or delayed. Immediate toxic effects can be defined as those that occur

TOXICITY

8.3

or develop rapidly after a single administration of a chemical substance. Generally, the most highly reactive substances produce immediate effects on the organism. Delayed toxic effects are those that occur only after a considerable lapse of time. Among the most serious delayed effects are cancers. Carcinogenesis may take 20 to 30 years after the initial exposure before tumours are seen in humans. The most difficult adverse delayed effects are those that follow years after years exposure in the womb. For example, the vaginal cancer produced in young women whose mothers had consumed diethylstilbestrol during pregnancy in order to prevent a miscarriage. Also delayed neurotoxicity is observed after exposure to some organophosphorus insecticides.

8.4

REVERSIBLE AND IRREVERSIBLE TOXICITY

The toxic effects of many toxicants may be either reversible or irreversible. If a chemical produces pathological injury to a tissue, the ability of that tissue to regenerate largely determines whether the effects are reversible or not. For example, the liver has a great capacity for regeneration, many adverse effects are reversible and complex recovery can occur. There are certain tissues which are not able to regenerate are considered to be irreversible effects. For example, the central nervous system (CNS) in which regeneration of tissue is severely limited. Carcinogenic and teratogenic effects are also considered irreversible toxic effects.

8.5

TOXICITY OF MIXTURES

Our surrounding medium and food have a large number of chemical substances. Toxicity of mixtures arises when an individual or organism is exposed to more than one substance at a time could lead to qualitatively and/or quantitatively different effects. The interaction between two substances sometimes proves to be very complex. The quantitative effects of mixture will be discussed in detail in chapter “interactive effects of toxicants”. Here the qualitative effects of mixture of toxicants will be discussed. The qualitative aspects of combined action of two or more toxic elements can be determined from different points in the toxic process. These are: • Exposure phase • Kinetic phase • Dynamic phase • Physico-chemical interaction. Exposure phase The exposure phase is related to the interactions of the toxicants in the environment and in food among themselves, as a result this interaction leads to form a new substance with different physical and chemical behaviour from the original one. Thus, the new substances have entirely different

8.4

TOXICOLOGY

toxicity to that of the original substances. For example, nitrite and secondary amines react together in the acidic environment of the stomach to form the new product nitrosamines which is carcinogenic. Kinetic phase The substances may greatly affect each other’s kinetics such as absorption, distribution, metabolism and excretion due to the interactions among themselves. For example, due to the interaction of chemicals, the polarity, solubility and lipophilicity character of the toxicant will be changed so that the absorption and distribution system will also be changed. Dynamic phase Two substances with opposite effects on an organ system cause a combined action, of which the outcome is determined by the precise ratio of the substances. For example, DDT causes excitation of the nervous system while barbiturates attenuate the activity of the nervous system. Administration of barbiturate after DDT intoxication reduces the symptoms. (Musch, 1996) Physico-chemical interaction Some toxic substances react with each other in the body to produce another toxic substance or a harmless substance. For example, the chelating agent like hexadentate chelate (EDTA) is used to reduce the concentration of free metal ions and enhance their excretion from the body.

8.6

VARIATION IN TOXIC RESPONSES

The toxic responses vary from species to species, among individuals and different form of lives. Variation in toxic responses can be discussed as: Selective toxicity Selective toxicity refers to the particular toxic element produces injury to one kind of living matter without harming another form of life even though both may exist in intimate contact (Albert, 1973). In the process the living matter that is affected by the toxic elements is termed uneconomic form and the living matter which is not affected is termed economic form. Species differences Different species have different qualitative and quantitative response to the same toxic elements. For example, mice are highly resistant to the hepatocarcinogenic effects of the fungal toxin aflatoxin B1. Dietary doses as high as 10,000 ppb (parts per billion) failed to produce liver cancer in mice whereas in rats dietary doses as low as 15 ppb produced a significant increase in liver tumours (Wogan et al., 1974). Individual differences in response It has been observed that even within a species, large interindividual differences in response to a chemical can occur because of subtle genetic differences. Genetic polymorphism on physiologically important genes may also be responsible for individual differences in toxic responses.

TOXICITY

8.7

8.5

ACUTE TOXICITY

Acute toxicity is that occurs soon after a single, brief exposure to relatively large quantity of a substance. Acute exposures can either be single or multiple exposures occurring within a short time. The acute effects are observed within a few days after exposure and are often such that medical intervention is needed. Some acute exposure may also produce delayed effects. Generally, in acute exposure, the toxicants are absorbed very quickly to produce immediate toxic effects. For example, the acute toxicity occurs after taking excessive quantity of drugs, pesticides, gas leakage from accidental sites, and fires. The symptoms appear soon after exposure are generally severe. There are two types of acute intoxication such as: • Accidental intoxication. • Deliberate intoxication. 8.7.1 Accidental Intoxication

Accidental intoxication occurs unintentionally. Most such cases involve mishaps with chemicals, inhalation of insecticides and nematocides, consumption of drugs and drinking of a product not meant for human consumption. For example, the use of pesticides and nematocides which contain cholinsterase inhibitors may be inhaled while using these chemicals. These inhibitors include both organophosphates and N-methyl carbamates respectively have severe effect on the nervous system. Their acute toxic effects may be the result of binding to and inhibition of acetylcholine-sterase (AChE) an enzyme which is very essential in the nervous system. Once AChE is inhibited which in turn inhibits the hydrolysis process so that acetylcholine accumulated and cause excessive nerve excitation. Inhibition of cholinesterase results from blockage of active site normally occupied by acetylcholine. Both organophosphate and carbamate pesticides are similar to bind to the active site of AChE. In accidents involving chemicals, for example, chlorine gas leakage may cause severe effects on human beings. The symptoms are very acute that the mucous lining of the respiratory tracts (bronchi) is totally damaged causing severe bronchial spasm and the coughing up of considerable quantities of sputum and blood. It may cause death of asphyxia. Similarly, people inside the burning object may damage the alveolar cells known as adult respiratory distress syndrome (ARDS). Inhalation of large quantity of smoke causes bronchial spasm. 8.7.2 Deliberate Intoxication

Deliberate intoxication in which the toxic elements are intentionally administered into the body. For example, the overdose of medical drugs, application of cosmetics on the skin having potential of a chemical to sensitise the skin, application of chemicals on eyes which may cause irritation are the different

8.6

TOXICOLOGY

form of deliberate intoxication. Deliberate autointoxication may be used to kill himself. For example, cyanide is one of the most rapidly acting of all poisons. It is rapidly absorbed through all routes, including skin, mucous membranes and by ingestion of small amount may cause instant death. Overdose of sodium nitropruside drugs is used in treatment of hypertension led to cyanide toxicity. Like cyanide, azide inhibits cytochrome oxidase and produces biochemical lesions. Hydrogen sulphide is also an inhibitor of cytochrome oxidase in vitro and is very poisonous to humans.

8.8

CHRONIC TOXICITY

Chronic toxic effects occur after repeated exposure to a very small quantity of toxicants. The period of exposure is generally longer than 3 months. The length of exposure depends on the intended period of exposure in humans. In this case, the symptoms usually develop gradually. Large groups of individuals may be exposed over long periods of time to considerable lower quality of toxicants which may happen in case of air pollution, water pollution, soil contamination and presence of pesticides, herbicides, etc. in the foodstuffs. Some of the important chronic toxic effects are discussed below.

8.8.1 Carcinogenesis Carcinogenesis is the development of cancer which is characterized by the uncontrolled replication and growth of the body’s own cells (somatic cells). The carcinogenesis involves three phases for the complete development of the cancer. These are—the first phase called initiation phase in which cells are exposed to carcinogenic agents or chemicals. During this phase, an irrevocable step occurred so that the daughter cells of the exposed cell may be able to carry out cell division independently. The second phase known as promotion phase of carcinogenesis in which the initiated cells are stimulated to divide the cells. The last phase or third phase known as progression phase in which the uncontrollable cell division increasingly damages the host and destroys it. Widespread invasion and metastasis, with destruction of the original normal tissue, are predominant in this phase. The role of xenobiotic chemicals in causing cancer is called chemical carcinogenesis. The chemical carcinogenesis arises due to insufficient function of various repair mechanisms such as: • failure of DNA repair • failure of apoptosis. • failure of terminate cell proliferation.

TOXICITY

8.7

Failure of DNA Repair (Genotoxic Process)

Failure of DNA repair refers to the first phase of carcinogenesis, i.e. initiation phase. When an individual is administered by a carcinogen, the individual leads to higher incidence of malignant neoplasms. The majority of carcinogens do this by affecting the genetic material (DNA) during the initiation phase and referred to as genotoxic carcinogens. Carcinogens that react with DNA may cause damage such as adduct formation, oxidative alteration and strand breakage. If these lesions are neither repaired nor injured cells are eliminated, then a lesion in the parental DNA strand may induce a heritable alteration, or mutation, in the daughter strand during replication. Genotoxic chemicals (carcinogens) are those that are capable of damaging or modifying DNA. Most cancer causing substances require metabolic activation and are called procarcinogens, or precarcinogens, proximate carcinogen and ultimate carcinogen to describe the initial inactive compound, its more active products and the product that is actually responsible for carcinogenesis respectively. A procarcinogen is an agent from which one or more biotransformation steps occurred in the organism to produce an ultimate carcinogen. The proximate carcinogens are the intermediate metabolites between procarcinogens and ultimate carcinogens. The proximate carcinogens sometimes act as substrate for the final enzymatic or non-enzymatic reaction leading to the formation of ultimate carcinogens. An ultimate carcinogen is a reactive molecule that enters into a reaction with cellular macromolecules, usually with DNA resulting in initiation step of carcinogenesis. Not all the carcinogens require metabolic activation and those compounds that act as direct acting carcinogens are known as primary carcinogens. Direct acting carcinogens cause tumours at the site of exposure. For example. some direct acting carcinogens are as: O CH3 — O — S — O — CH3 O

Dimethyl sulphate

NH CH2 — CH2 Ethyleneimine

O CH3 CH3

N — C — Cl

Dimethyl carbamyl chloride

In chemical carcinogenesis, the carcinogens have the ability to form covalent bonds with macromolecules particularly DNA. The prominent genotoxic carcinogens are alkylating agents and arylating agents. The alkyl or aryl group acts to attach to DNA at ‘N’ and ‘O’ atoms in the nitrogenous bases that compose DNA. For example,

8.8

TOXICOLOGY O N

HN H 2N

OCH3

N (Guanine)

N H

N

N

Alkylation

H 2N Alk yla tio n

N

N H

OH

CH3 N

N H 2N

N

N

Failure of Apoptosis (Promotion): The Epigenetic Process

A promoter of carcinogenesis is an agent that on long term and repeated administration increases cancer induction following previous exposure to an initiator. The genotoxic chemicals damage the DNA cells so that the levels of P53 protein in cells increase rapidly, may be 5 to 60 fold which may prevent the progression of cells in the GI phase and allow DNA repair to occur before replication or induce cell death by apoptosis, thus prevent carcinogenesis. There are some agents which can arise the incidence of cancer by action in a later phase through non-genotoxic mechanisms are referred as epigenetic carcinogens. If the initiator is followed by repeated administration of a promoter, neoplasia will be observed. Preneoplastic cells or cells with mutations have much higher apoptotic activity than do normal cells (Bursh et al., 1992). If a carcinogen has both properties, initiation and promotion, is known as complete carcinogen. If the carcinogen has only property of initiation is called incomplete carcinogen. Failure to Terminate Proliferation (Progression) Progression is the phase following initiation and promotion. During the progression, neoplasia develops into its terminal forms which ultimately overwhelms the host mainly by invasion and metastasis. The enhanced mitotic activity promotes carcinogenesis due to following reasons: • The enhanced mitotic activity increases mutation through the cell division cycle which shortens the GI phase. Thus, repair of injured DNA is not possible within short time before replication increase the chance of mutation. • During increased proliferation, proto-oncogene proteins may cooperate with oncogene proteins to facilitate the neoplastic transformation of cells. • The proliferation promotes the carcinogenic process is through clonal expansion of the initiated cells to form nodules and tumours. • Cell-to-cell communication through gap junctions and intercellular adhesion through cadtherins are temporarily disrupted during proliferation (Yamasaki et al., 1993). Lack of these junctions contributes to the invasiveness of tumour cells.

TOXICITY

8.9

Dormancy of tumour cells is caused by inhibition of cell division or by a disturbance of the balance between cell division and cytosis. Another aspect of progression is that of tumour vascularization and invasion. This vascularization is controlled by angiogenesis factor and is accompanied by invasion into surrounding tissue and lymph and blood vessels. If cancer cells enter the bloodstream in the form of small emboli, they are destroyed by various blood components. If any emboli is survived in a particular tissue or organ, it will be able to grow in new tissue and subsequently induce blood vessel proliferation.

8.8.2 Mutagenesis Mutagenesis is the phenomenon in which inheritable traits result from alterations of DNA. Various physical and chemical agents known to produce such alterations include ionizing radiation, sulphur and nitrogen mustard, epoxides, ethyleneimine and methyl sulphonate. The substances that cause mutations are called mutagens. The induction of mutations is due primarily to chemical or physical alterations in the structure of DNA that result in inaccurate replication of that region of the genome. The harmful effects of mutations include fertility disorders, embryonic and perinatal death, malformations, hereditary diseases and cancers. There are several ways in which xenobiotic species may cause mutations. However, the process of mutagenesis consists of structural DNA alteration, cell proliferation that fixes the DNA damage and DNA repair. In general, the alterations in the genetic material can be divided into the following categories: • Point mutations • Frameshift mutations • Chromosomal aberrations. • DNA repair and genome mutations. Point Mutations

Point mutations are the smallest unit of mutations in which the transformation of a single-base pair occurs. If the replacement involves the same type of base, it is referred to as base-pair transition. If the replacement involves different type of base, it is called base-pair transversion. For example, replacement of purine to purine, and purine to pyrimidine then it is called base-pair transition and base-pair transversion respectively. The point mutations are carried out in three different ways. There are: (a) Alkylating agents The prominent alkylating agents like alkyl groups such as methyl (CH3) or ethyl (C2H5) attach to DNA. These chemicals yield positively charged carbonium ions (CH3+) or (CH3 – CH2+) that combines with the electron rich bases (N and O) in the DNA. (b) Chemical transformation Nitrous acid (HNO2) is an example of chemical transformation of bases. The three of the nitrogenous bases such as adenine,

8.10

TOXICOLOGY

guanine and cytosine contain the amino group (–NH2), where the nitrous acid reaction takes place. The action of nitrous acid is to replace amino groups with doubly bonded oxygen atoms to form keto groups (C = 0) which convert them to other compounds. As a result, DNA may not function properly and cause mutations. Incorporation of Abnormal Base Analogs The effect of incorporation of abnormal bases which are analogs to the bases cause base transformations and lead to mutations. Some of the base analogs are– bromo uracol, 5-fluorodeoxyuridine, 6-mercaptopurine, etc. Frameshift Mutations In frameshift mutations, addition or deletion of a base in the DNA molecule causes the triplet code out of sequence and errors occur in the DNA functions. For example, the chemicals like acridine causes frameshift mutations. Chromosomal Aberrations Chromosomal aberrations referred to as the GAPS and BREAKS are present in the DNA structure. Gaps are the achromatic lesions in a chromosome which are present due to the loss of DNA. Breaks are the broken ends of chromatids that are dislocated but still contained within the metaphase. The chromosomal mutations arise due to changes in chromosomes through incorrect reincorporation of broken parts. The main type of changes are deletions, translocations, duplications and inversions. Numerical aberrations are a consequence of unequal division of chromosomes and result in a cell with either more or less chromosomes than original. DNA Repair

All types of DNA modification can be considered potential modification. Some of them can lead to death or loss of ability to function normally which may give rise to tumours formation. The cells dispose of DNA repair mechanisms that will attempt to repair the modification of DNA. The DNA modification should be carried out in an error free or a nearly error free mechanism. The enzymes that are able to correct many of the mutations that have occurred to the original DNA molecules exist within the cells. For example, it can be stated that DNA modification induced by mutagens that alter DNA coding by alkylation, can usually be repaired without any error by the protein, methyltransferase that removes the methyl group from O6-methyl guanine and restores the DNA structure in a single step. The other enzymes that repair DNA are glycosylases, DNA-polymerase, etc. Genome Mutations

Genome mutations refer to the change in thin number of chromosomes. Euploidy is used to a multiple of the complete set of chromosomes (monoploid (n); diploid (2n), triploid (3n), etc.) If the numerical changes occur but there is no change in the total number of chromosomes, is known as aneuploidy.

TOXICITY

8.11

8.8.3 Teratogenesis Teratology is the science which deals with birth defects of a structural nature caused by radiation, viruses, chemicals including drugs (Kurzel and Cetrulo, 1981). The chemicals that cause birth defects are called teratogens. Mutations in germ cells (egg or sperm cells) may cause birth defects but teratology usually deals with defects arising from damage to embryonic or fetal cells. Wilson and Fraser (1977) have developed at least six general principles of teratology. These are as follows: 1. Genetic factors: The biochemical effects of teratogens and adverse reproductive effects depend on the genotype of the fertilized ovum and the subsequent stages in development. The variation in response to the same harmful substance depends on the genetic factors. For example, a sedative-hypotonic drug, thalidomide is the most dangerous teratogen. The infants born to women who had taken thalidomide from days 35 to 50 of their pregnancies were born suffering from amelia or phocomelia, i.e. the absence or severe shortening of limbs whereas most of the other mammals, are quite resistant to thalidomide. O

O N

NH O

O Thalidomide

2. Critical periods: Critical period is the expression of reproductive toxicity which depends on the reproductive cycle at which the teratogens cause damage. The embryogenesis involves the cell proliferation, differentiation, migration and finally organogenesis. In general, teratogens may cause structural developmental defects if exposure has taken place during organogenesis. The organogenesis period can be subdivided into periods marking the formation of individual organs. 3. Initiating mechanisms: The teratogens initiate one or more mechanisms resulting in abnormal embryogenesis. The various mechanisms which cause the initial molecular damage are: • Mutations. • Chromosomal aberration. • Disturbances in cell division (mitotic interference) • Changes in nucleic acid composition and protein synthesis. • Nutritional deficiencies. • Deficient or altered energy supply for embryonic and foetal development.

8.12

TOXICOLOGY

• Disturbance of enzyme systems. • Unstructural changes in cell membrane. • Disturbances in the regulation of water and electrolyte balances (changes in osmolarity). 4. Dose-response relationship: Dose-response relationships play an important role in teratology and reproductive toxicolgy. A sufficiently high dose of teratogens may induce toxic effects on reproduction or developmental defects of a structural or functional nature of the organ. But most teratogens appear to have a threshold level below which no malformations are observable. 5. Access to Embryo and Foetus: A complicating factor is that a compound often induces adverse effects in the concerned species. Some xenobiotics may have direct effects, for example, radiations or ultrasound cause direct effect as they pass directly through the material tissue. There are some xenobiotics which may enter into the stage of organogenesis through biochemical transformations or metabolisms. The combination of both direct and indirect effect may lead to embryonic or foetal death, foetal growth retardation or delayed bone formation. 6. Consequences of abnormal development: There are four manifestations of abnormal development such as: death, malformation, growth retardation and functional disorder. The time of organogenesis is the most sensitive time for induction of specific malformations, whereas structural defects are mainly induced in the embryonic period and functional defects are established during the foetal period and later stages of development. Merphogenesis is a complex process, involving cellular proliferation, migration and interaction, ultimately leading to the differentiation and organization of the individual.

8.9 FACTORS AFFECTING TOXICITY OF REACTIVE METABOLITES Some of the important factors which may influence the toxicities of the reactive metabolites. There are three important factors such as: • The level of activating enzymes. • The levels of conjugating enzymes. • The levels of cofactors. The level of activating enzymes Generally, the area of tissue damage is most severe in the regions containing the highest concentration of activating agents. For example, most activation reactions are catalyzed by cytochrome P-450 monoxygenase system which increases the toxicity.

TOXICITY

8.13

The level of conjugating enzymes The conjugating agents are responsible for increasing the toxication process or detoxication process. For example, the conjugating enzyme glutathione transferase whose higher concentrations inhibit the detoxication process, this increases the toxicity. The levels of cofactors The higher the levels of cofactor enzymes, the removal of reactive metabolites are easier. For example, the cofactor enzyme N-acetylcysteine whose higher concentration protects the animals against hepatic necrosis.

EXERC151. Differentiate between (a) Local and systemic toxicity. (b) Immediate and delayed toxicity. (c) Reversible and irreversible toxicity. `2. How do you determine the toxicity of mixtures of toxicants? 3. What are the variations in toxic responses? 4. What is acute toxicity? What are the types of acute toxicity? Explain them in detail. 5. Write short notes on: (a) Carcinogenesis. (b) Mutagenesis. (c) Teratogenesis. 6. What are main causes of chemical carcinogenesis? 7. Explain the epigenetic process in carcinogenesis. 8. What are the reasons for the promotion of enhanced mitotic activity? 9. What do you mean by mutagenesis and how does it occur? 10. What is DNA repair? 11. What are the factors affecting the toxicity of reactive metabolites? 12. Discuss about the chromosomal aberration. 13. Define the terms. (a) Bioactivation. (b) Immediate toxic effects. (c) Epigenetic carcinogens. (d) Merphogenesis. 14. What are the classification of the toxic responses by an organism?

CHAPTER

9

Toxic Effects of Natural and Synthetic Products 9.1

INTRODUCTION

Toxic products are poisons produced from natural or anthropogenic sources. The toxic natural products are produced by organisms whereas the synthetic toxic products are man-made which are generally produced in industries, factories or laboratories. The toxic natural and synthetic products include an enormous variety of materials. For example, the most acutely natural toxic substance is botulism toxin produced by the anaerobic bacterium Clostridium botulinum. The botulism toxin is responsible for many food poisoning deaths. Similarly, the most, acutely synthetic substance carbamates and the organophosphorus insecticides that inhibit the enzyme acetyl cholinesterase which may lead to death of the organism. The toxic natural and synthetic products may be classified into roughly seven categories according to the type of biomolecule they react with. Ecobichon (2001) and Gregus and Klaassen (2001) suggested the classification of toxicants into the following seven categories. 1. Enzyme inhibitors: The toxicants react with different enzymes and inhibit their normal functions. Some toxicants are very harmful to animals and others are to the plants. For example, plants do not have any nervous system and acetylcholinesterase does not play an important role here. Similarly, the essential amino acids are not produced in animals. 2. Disturbance of the chemical signal systems: There are many chemicals which are used to transmit messages at all levels of organization. Some chemical substances disturb this normal functioning of these systems. For example, the nicotine which gives signal much similar to acetylcholine in the nervous system, i.e., it interferes in the normal functioning of acetylcholinesterase.

9.2

TOXICOLOGY

3. The product of toxicants destroy cellular components: Some toxicants may produce active molecules which have the ability to destroy the cellular components. 4. Changes of pH gradients across membranes: Substances like weak organic acids and bases are responsible for changes of pH gradients across the membranes. For example, acetic acid, phenol and ammonia may be toxic because they dissolve in the mitochondrial membrane of the cell. These substances are capable to pick up H+ ion at the more acidic condition outside. The pH difference is very important as it controls the energy production in mitochondria and chloroplast which is severely disturbed by these chemicals. 5. Lipophilic chemicals and their effects: Some lipophilic chemicals like alcohols, petrol, aromatics may dissolve in the cell membrane and increase the toxicity of the substance. 6. Xenobiotics that disturb the ionic balance and osmotic balance: The xenobiotics like sodium chloride may upset the electrolytic balance and osmotic balance which may create severe problems particularly in small babies. 7. The chemicals that destroy tissue, DNA or Protein: The chemical substances like strong acids, strong alkalis, bromine, chlorine gas, etc. are easily soluble in membranes which may destroy tissue, DNA or proteins.

9.2

TOXIC EFFECTS OF SOLVENT AND VAPOURS

Solvents generally refer to organic chemicals of variable lipophilicity and volatility. Solvents are used to dissolve, dilute and disperse the materials that are insoluble in water. In toxicology, the solvent refers to industrial solvents which may cause various toxicological problems to living organisms including humans. These solvents are classified based on their function group such as aliphatic hydrocarbons, halogenated aliphatic hydrogens, alcohols, ethers, esters, glycols, aldehydes, ketones and aromatic hydrocarbons (toluene). The toxicity of a particular solvent depends on the various factors and some important factors are as: 1. Presence of number of carbon atoms. 2. Saturation or unsaturation of organic compound. 3. The structure or configuration of the organic compound such as straight chain or branched chain. 4. Presence and types of functional group. 5. Reactivity of the compound. Most solvent exposures involve a mixture of organic solvents rather than a single compound in our modern environment—in industries in which large quantities of solvent are being used. It is assumed that the toxic effects of these

TOXIC EFFECTS OF NATURAL AND SYNTHETIC PRODUCTS

9.3

mixture of organic solvents are additive because the solvents may also interact synergistically or antagonistically. The gases and vapours of certain chemicals like carbon sulphide, hydrogen sulphide and vapours of aliphatic and aromatic organic compounds are easily inhaled and may be toxic to the organisms. The toxicity of the solvents and vapours depends on the following factors such as: • Toxicity of solvents and vapours. • Exposure route. • Rate of exposure. • Duration of exposure. • Individual susceptibility to solvents and vapours. • Interactions with other chemicals. Few examples of industrial solvents and vapours are studied in this book.

9.2.1 Aliphatic Hydrocarbon The lower aliphatic hydrocarbons such as methane and ethane are the gases present in natural gas. The inhalation of vapours from products containing higher hydrocarbons such as pentane, hexane, heptane and octane which may be present in both straight, chain and branched chain compounds produce central nervous system (CNS) depression, resulting in dizziness and in coordination. Exposure of the skin to pentane or octane liquids causes dermatitis which is due to the dissolution of the fat portions of the skin. Most of the higher alkanes are not regarded as very toxic. Automotive gasoline is a complex mixture of hundreds of hydrocarbons predominantly higher alkanes in the range of more than C8. These are kerosene, jet fuel, diesel fuel, mineral oil and fuel oil. Kerosene is also known as fuel oil no. 1 followed by fuel no. 2 as diesel. The heavier fuel oils no-ranging from 3 to 6 are characterized by increasing viscosity, density and high boiling temperatures. In normal exposure to these gasoline and fuels, toxic effects do not occur normally. They may have the localized toxic effects mainly in the skin and lungs.

9.2.2 Chlorinated Hydrocarbons Aliphatic halogenated hydrocarbons are most widely used as industrial solvents because of their excellent solvent properties. The chlorinated hydrocarbons are generally low flammability. Some of the important chlorinated hydrocarbons are discussed here. Methylene Chloride (Dichloromethane)

Methylene chloride (CH2Cl2) is a common industrial solvent used in food preparation, paint remover, solvent in aerosol products and agriculture. Because of its high volatility, it is present in high concentrations at a particular area. Thus,

9.4

TOXICOLOGY

large numbers of people are exposed occupationally. The important route of exposure of methylene chloride is inhalation. Methylene chloride has only a limited systemic toxicity potential. After inhalation, methylene chloride is metabolized by the cytochrome P-450 mono-oxygenase system to CO2 and CO as follows: O

—

H — C — Cl

NADPH

C

H

—

CYT P-450 O2

HCl Cl

H

HO — C — Cl

CO

—

—

H

Cl

Cl

HCl

O2 CYT P-450

— —

OH

H2O

HO — C — Cl Cl

O C

Metabolism of Methylene Chloride

Cl

H 2O

CO2 + HCl

Cl

Significant levels of carboxyhaemoglobin may occur due to carbon monoxide binding to haemoglobin in the blood. It is generally accepted that tissue hypoxia can contribute to acute central nervous system effects of methylene chloride. Trichloroethylene

Trichloroethylene (Cl2 C = CHCl) is used widely as industrial degreasing solvents and in the dry-cleaning industries. Moderate to high dose of trichloroethylene may cause the depression of the central nervous system (CNS), nausea, confusion, irritation to eyes and nose. Trichloroethylene enters into the system through oral and inhalation route. It undergoes oxidation with cytochrome P-450. Tetrachloroethylene (CCl2 = CCl2)

Tetrachloroethylene is used widely as industrial degreasing solvents, in drycleaning industries, paint and stain remover and chemical intermediate. Tetrachloroethylene is rapidly absorbed into the systemic circulation via oral and inhalation route. This chemical is well absorbed from the lungs and GI tract, distributed to tissues according to their lipid content. It is also oxidized via nepatic P-450s to the lesser extent than trichloroethylene.

TOXIC EFFECTS OF NATURAL AND SYNTHETIC PRODUCTS

9.5

Chloroform (CHCl3)

Chloroform (CHCl3, trichloromethane) is widely used in the production of refrigerant chlorodifluoromethane, chemical intermediates and solvents. It was first used as general clinical anaesthetic but due to some liver injury, it is no longer used as clinical anaesthetic. High concentrations of chloroform with repeated exposure may lead to liver and kidney damage. Under certain conditions, chloroform is heptotoxic and nephrotoxic. These toxicities are potentiated by aliphatic alcohols, ketones, and di- and trichloroacetic acid (Davis, 1992). Chloroform is metabolized by cytrochrome P-450 isozymes to produce phosgene which is responsible for CHCl3’s hepatorenal toxicity as follows: CHCl3

HCl

CYT P-450

O

CCl3OH

O2

H 2O

C Cl

CO2 + HCl

Cl

Phosgene

Carbon Tetrachloride (CCl4)

Carbon tetrachloride is widely used as a dry-cleaning chemical, degreasing agent and in home fire extinguishers. Now its use has been restricted due to its hepatorenal toxicity, carcinogenicity, and contribution to ozone depletion in the atmosphere. Carbon tetrachloride is toxic through both inhalation and ingestion which affect central nervous system and gastrointestinal (GI) tract, liver and kidney. It is likely that the mechanism of liver injury by CCl4 has been investigated in detail (Hodgson et al. 1987). CCl4 is metabolized by Cytrochrome P-450 dependent monooxygenase system in the liver to produce a trichloromethyl free ◊ radical ( CCl3).

CYT P-450

—

Cl — C

—

Cl — C — Cl

Cl —

—

Cl

Cl

Cl

This free radical can bind covalently to lipids and proteins to yield highly reactive Cl3COO•. radical. It may cause structural damage of membranes and inhibition of variety of enzymes.

Cl

+ O2

Cl — C — O — O —

—

Cl — C

—

Cl

—

Cl

Cl

These free radicals and other products from their subsequent reactions may

9.6

TOXICOLOGY

react with oxygen to form peroxides and other cytotoxic metabolites and this process is known as lipid peroxidation (Recknagel et al. 1989).

H C

C

Lipid molecule L

Cl

H

C—C

C

Cl

C

— —

H

— —

Cl + Cl — C — H

Lipid molecule L

Cl

O2

OO H—C

C

Lipid peroxy radical, LOO

Vinyl Chloride (CH2 = CHCl)

Vinyl chloride is known as monochloroethylene is used as anaesthetic and in polymer industries. It polymerizes readily to form polyvinylchloride (PVC). Vinyl chloride is very toxic to humans through inhalation and penetration through skin. It metabolizes through hepatic cytochrome P-450 monoxygenase system to produce epoxide. The epoxide product bind covalently to DNA, RNA and protein to produce mutagenic effects. O CH2 CHCl vinyl chloride

CYT P-450

CH2 — CHCl Chloroethylene oxide

ClCH2CHO Chloroacetaldehyde

9.2.3 Alcohols A large number of aliphatic alcohols have very wide applications as a solvent in different industries, agricultural activities, pharmaceutical fields, etc. The three lightest alcohols such as methanol, ethanol and ethylene glycol will be discussed in detail. Besides these alcohols, diethylene glycol, propylene glycol and glycol ether will also be discussed. Methanol Methanol is also called methyl alcohol or wood alcohol which is widely used as commercial solvent, solvent in paints, varnishes and shellacs. It is also being promoted as a gasoline additive. It is used to prepare formaldehyde and the synthesis of acetic acid. Alcohol toxicity may occur through absorption, inhalation and ingestion. The toxicity of the alcohol in the human body is due to the metabolic oxidation of methanol to form formaldehyde and formic acid.

TOXIC EFFECTS OF NATURAL AND SYNTHETIC PRODUCTS HCHO + H2O

[O] CH3 — OH

9.7

Formaldehyde

2[O]

HCOOH + H2O Formic acid

The products of this reaction cause acidosis. The initial symptoms are a minor central nervous system intoxication and the optic nerve intoxication. The target of methanol within the eye is the retina, specifically the optic disk and optic nerve. The severe metabolic acidosis frequently seen in humans and the susceptibility to methanol toxicity is dependent upon the relative rate of formate clearance. Chronic exposures to lower levels of methanol may result from fume inhalation. Ethanol (CH3-CH2OH) Ethanol is known as ethyl alcohol used as a solvent in industry, pharmaceuticals and in many household products. It is also used as germicide, antifreeze and gasoline additive. The toxic effect of ethanol occurs through absorption and inhalation in lungs, gastrointestinal tract. Metabolically ethanol is oxidized first to acetaldehyde and then to carbon dioxide. Ethanol has a range of acute effects, normally expressed as a function of per cent blood ethanol (Dreisbach and Robertson, 1987). Ethylene glycol (HO-CH2-CH2-OH) Ethylene glycol is widely used as a solvent in industries, a major constituent of antifreeze, cosmetics, chemical synthesis, drying agent, deicers, agent in making polymer fibres and plastics. Ethylene glycol ingestion results in serious poisoning. The most important route of exposure is inhalation. Ethylene glycol as such appears to be non-toxic. But the toxicity of ethylene glycol results from its four major breakdown products such as aldehydes, glycolate, oxalate and lactate.

CH2 — CH2 OH

O

O O2

O2 HO — CH2 — C

HO — CH2 H

OH

Glycoaldehyde

C

OH

Glycolic acid

Ethylene glycol

O

O C—C HO

OH Oxalic acid

O2

O

O

O2

C—C H

OH

Glycoxylic acid

The metabolism of ethylene glycol depends on hepatic alcohol dehydrogenase and it is acutely toxic to humans—kidney failure from the metabolic formation of calcium oxalate.

9.8

TOXICOLOGY OH

OH

Ca

C—C O

Ca O

+2

O

Oxalic acid

C O

O C O

Calcium oxalate

Diethylene glycol Diethylene glycol is widely used as a solvent in industries, as a textile agent, solvent in cosmetic and an additive for inks. The major route of toxicity of diethylene glycol are absorption and inhalation. It is oxidized by alcohol dehydrogenase (ADH) and by aldehyde dehydrogenase. Diethylene glycol causes multiple fatalities from renal failure with symptoms of unilateral facial paralysis, optic neurities with retinal oedema, encephalopathy, and hepatitis. Propylene glycol Propylene glycol is used as a solvent, coolant in cosmetics, food, coolant, antifreeze and in pharmaceutical industries. Propylene glycol is relatively non-toxic. Extremely high dose can cause central nervous system depression, metabolic acidosis, encephalopathy and hemolysis in humans. Glycol ethers Glycol ethers are both water soluble and soluble in organic solvents. Thus, it is used in many oil-water combinations. This property is due to that it exhibits properties of both alcohols and ethers. This dual solubility, makes it a very useful solvent for surface coatings and paint thinners. Toxicity from these compounds generally occurs through inhalation which may damage kidney. Some glycol ethers are hemolytic to red blood cells. The metabolism of glycol ethers to produce alkoxyacetic acid which is the ultimate toxicant. Developmental toxicity (structural anomalies) has been described for several glycol ethers. Glycol ether toxicity varies with chemical structure. With increasing alkyl chain length, reproductive and developmental toxicity decrease, whereas hematotoxicity increases (Ghanayem et al. 1989; Carney et al. 1999 a).

9.2.4 Aromatic Hydrocarbons Benzene

Benzene (C6H6) is chemically the single most significant aromatic hydrocarbon which has excellent solvent properties and high volatility and dries rapidly. It is used as a starting material for the manufacture of numerous products including phenolic, polyester resins, polystyrene plastics, elastomers, etc. Benzene plays an important role in unleaded gasoline due to its antiknock properties. The important route of exposure of benzene is inhalation. Benzene has both acute and chronic toxicological effects. The most important toxic effect of benzene is hematopoietic toxicity. Benzene is a skin irritant and it gives burning sensations, fluid accumulation and blistering. Chronic exposure to benzene can lead to bone marrow damage which may cause anaemia, leukopenia and thrombocytopenia.

TOXIC EFFECTS OF NATURAL AND SYNTHETIC PRODUCTS

9.9

The metabolism of benzene occurs primarily in the liver to produce phenolic conjugates and it is transported via the blood to the bone marrow. H Enzymatic

+O

OH O

epoxidation

Non-enzymatic rearrangement

H Benzene

Benzene epoxide

Phenol

In the second phase conjugation reaction occurs in which phenol is converted to water-soluble glucoronide or sulphate either of which is readily eliminated through the kidneys (Dauterman, 1980). As the bone marrow is rich in peroxidase activity, phenolic metabolites of benzene can be activated to reactive quinone derivatives. These active quinone and their derivatives can cause DNA strand breakage leading to cell mutation. O O

OH OH

(OH) OH OH

OH

O-Benzoquinone

O

Phenol

HO O P-Benzoquinone

Toluene

Toluene (C7 H9) is a colourless liquid and is moderately toxic through inhalation or ingestion. It is used extensively as a solvent in the chemical, rubber, paint and pharmaceutical industries. It has low volatility. Toluene is well absorbed from the lungs and gastrointestinal tract. The toluene is deposited in the tissues having high lipid content. Toluene is a narcotic. The acute symptoms from inhalation include headache, nausea, lassitude, euphoria, dizziness and excitement. Extreme acute exposure lead to coma and even death. The CNS is the primary target organ of toluene. Toluene can be oxidized in presence of hepatic P-450s which catalyzes toluene to produce benzyl alcohol and lesser amounts of cresols. The benzyl alcohol is converted by alcohol deydrogenase (ADH) to benzoic acid which is conjugated with glycine to produce hippuric acid (N-benzoylglycine). It is eliminated through urine.

9.10

TOXICOLOGY O C — NH — CH2 — COOH

COOH

CH2OH

CH3 [O]

[O]

Conjugation with

P-450

ADH

glycine N-Benzoylglycine

The influence of toluene on the metabolism of other P-450 substrates is usually modest.

9.2.5 Vapours Carbon disulphide: Carbon disulphide (S = C = S) does not contain the disulphide group (– SS –) but has two sulphur atoms each separately bonded to a carbon atom. It is a very volatile liquid having boiling point 46°C. Therefore, it caues severe air pollution. The majority of carbon disulphide (CS2) is used in the production of viscose rayon and cellophane, carbon tetrachloride and pesticides. It is also used as a solvent in chemical synthesis and solubilizer for waxes and oils. The primary route of toxicity is the inhalation and acute exposure may cause irritation of mucous membranes and affect central nervous system (CNS) causing depression and restlessnes. Chronic carbon disulphide poisoning by absorption through the skin or respiratory tract involves the central and peripheral nervous systems (PNS) and may cause anaemia. Parkinsonism, asymptomatic CNS and PNS dysfunction, polyneuropathy and encephalopathy may result from chronic carbon disulphide poisoning. Hydrogen sulphide (H2 S) The hydride of sulphur (H2S) is a highly toxic gas. It affects the central nervous system causing headache, dizziness and excitement.

9.3

TOXIC EFFECTS OF PESTICIDES AND BIOCIDES

A biocide is any substance used with the intention of killing living organisms. The U.S. Environmental Protection Agency defines a pesticide as any substance or mixture intended for preventing, destroying, repelling, or mitigating any pest. The ideal and good pesticide is one that is toxic primarily to the target pests and is rapidly inactivated in the environment. Biocide is not used much in the toxicology. For example, mercury salts (Hg+2) may be called biocides because they are toxic for microorganisms, animals and many other organisms whereas DDT is not a biocide because of its specificity towards organisms with a nervous system. Pesticides are almost always xenobiotics. The pesticides have many xenobiotic bonds, i.e., bonds between carbons and halogens, direct bonds between carbons and phosphorus, and between carbons and metals or silicium. Based on presumed selectivity, biocides and pesticides may be classified into several groups such as insecticides, herbicides, fungicides, nematicides,

TOXIC EFFECTS OF NATURAL AND SYNTHETIC PRODUCTS

9.11

rodenticides, mercury salt, aniline, carbamate coumarin, etc. Some important pesticides and their toxic effects will be discussed in this book.

9.3.1 Insecticides The insecticides exhibit a wide range of toxic effects and varying degrees of toxicity. All of the chemical insecticides in use today are neurotoxicants and act by poisoning the nervous system of the target organisms. Generally, the insecticides are not selective and affect the non-target species as readily as target organisms, in the similar way to the higher forms of life. The target sites and mechanisms of action may be similar in all species, only it differs in exposure to different doses. Some important insecticides are as: Organochlorine Insecticides

The chlorinated hydrocarbon insecticides are of intermediate molecular mass and contain at least one aromatic or nonaromatic ring. The organochlorine insecticides include, Dichloro diphenyl trichloro ethane (DDT), aldrin, dieldrin, endrin, taxaphene, chlordane, heptachlor, lindane, mirex, methoxychlor and strobare (Fig. 9.1). The organochlorine insecticides are very effective insecticides because of their properties like low volatility, chemical stability, lipid solubility, slow rate of biotransformation and degradation. But these insecticides are considered to be very harmful environmentally because of their properties like persistence in the environment, bioconcentration and biomagnification in food chains and the acquisition of biologically active body burdens at higher trophic level (Carson, 1962). The organochlorine (chlorinated hydrocarbon) insecticides may be divided into three distinct chemical classes such as dichlorodiphenylethane, chlorinated cyclodien, chlorinated benzene and cyclohexane-related structures. Structure 1.

Cl

CH

Name Cl

DDT.

CCl3

2.

CH3O

CH CCl3

OCH3

Methoxychlor

Cl

3.

Cl

Cl

Cl

Cl Cl

Lindane (a. b HC)x (a - Benzene Hexachloride) contd.

9.12

TOXICOLOGY

Cl

4.

Cl Cl

5.

Cl Cl

H

Aldrin

CCl2 CH2 Cl

H

Cl

H

CCl2 CH2 Cl

H O H

Dieldrin

H

Cl

6.

Cl Cl

Cl

Chlordane.

CCl2 Cl Cl

Fig. 9.1

Structures of some organochlorine insecticides.

Most of the organochlorine insecticides are neuropoisons and exposure to moderate or high doses effects are upon the central nervous system, with symptoms of CNS poisoning including tremor, irregular jerking of the eyes, changes in personality, and loss of memory (Stopford, 1985). Exposure to lindane may cause tremors, ataxia, convulsions, stimulated respiration and prostration. Organophosphorus Insecticides

Organophosphates are phosphoric acid esters or thiophosphoric acid esters. Organophosphate insecticides containing the P = S (thiono) group are not as effective as their analogous compounds that contain the P = 0 functional group in inhibiting acetylcholinesterase (Hodgson, 1987). The first organophosphate insecticide in wide use was tetraethylpyrophosphate. (TEPP) (Fig. 9.2). O

O

CH3 — CH2 — O — P — O — P — O — CH2 — CH3

Fig. 9.2

O

O

CH2

CH2

CH3

CH3

Tetraethylpyrophosphate.

TOXIC EFFECTS OF NATURAL AND SYNTHETIC PRODUCTS

9.13

Organophosphorus ester exposure has a wide range of toxicity including tinnitus, pyrexia, tremor, paralysis, loss of memory, insomnia, restlessness, anxiety, depression and schizophrenia problems. Organophosphates are very toxic because of their inhibition of the acetylcholinesterase activity of nerve tissue. A number of organophosphorus insecticides—including omethoate, trichloronate, trichlorfon, parathion, methamidophos, fenthion, disulphoton and chlorpyriphos—have been implicated in causing organophosphate-induced delayed neurotoxicity (OPIDN) in humans (Abou-Donia and Lapadula, 1990). Some of the most common organophosphate insecticides are listed in Fig. 9.3. Structure

Name

S

1.

Parathion

— NO2

(C2H5O)2P—O—

O S

CH2 — C — OC2H5

(CH3O)2P — S — CH

2.

Malathion

C — OC2H5 O S

3.

(C2H5O)2P — S — CH2 — CH2 — S — C2H5

Disulphoton

CH3 S

4.

(C2H5O)2P — O —

CH

N

CH3

N CH3

Diazinon

S (C2H5O)2P—O—

5.

—NO2 Cl

Chlorothion

O

6.

(CH3O)2 P — O — CH = CCl2

Fig. 9.3

Dichlorros

Some common organophosphate insecticides.

9.14

TOXICOLOGY

The acute intoxication from repeated exposure to organophosphorus esters such as diazinon and chlorfenvinphos cause adverse neurophysiological and psychological effects. Generally, the organophosphates readily undergo biodegradation and do not bioaccumulate. Thus, there is not any serious problem as contaminants of soil and water do not enter the human food chain. Carbamate Insecticides

Carbamate insecticides are esters of N-methyl carbamic acid. The carbamate pesticides are used widely because some are very high biodegradable in comparison to organochlorine and organophosphate pesticides. The toxic effects of carbamate varies with the number of phenol or alcohol group attached to it. The symptoms of acute intoxication by carbamate insecticides are similar to those of organophosphate insecticides, differing only in the dose and duration of exposure. Some of the common carbamate insecticides are given in Fig. 9.4. Structure

Name O

O — C — NH — CH3

Carbaryl (sevin)

1.

CH3

O

CH3

2.

O—C—N N

CH3

N

N

CH3 CH3

Pirimicarb

CH3

O O — C — NH — CH3

3.

CH3

4.

Propoxur (Baygon)

OCH(CH3)2

O

CH3 — S — C — CH — N — O — C — NH — CH3

Aldicarb

CH3

contd.

TOXIC EFFECTS OF NATURAL AND SYNTHETIC PRODUCTS

5.

H 3C

Carbofuran

O

O

H 3C

9.15

O — C — NH — CH3

Fig. 9.4 Some common carbamate insecticides.

Carbaryl has been widely used as an insecticide on lawns or gardens. The toxic effects of carbaryl due to acute exposure are with symptoms of ataxia, tremors, clonic muscle contraction and prostration and incoordination. Generally, carbamate insecticides do not inhibit OPIDN-type neurotoxicity. Carbofuran has a high water solubility and acts as a plant systemic insecticide. The mode of toxic action of carbamate insecticide is inhibition of acetylcholinesterase and reverse reaction is also followed. Botanical Insecticides

Naturally occurring agents of plant origin that contain nitrogen, usually in a heterocyclic ring. These chemicals ranged from highly toxic agents such as cocaine, nicotine, caffeine, etc. Pyrethrins are biosynthesized from pyrethrum to be used as insecticides in the household because of their high degradability and quick “knockdown” action. Some of the common botanical insecticides are as in Fig. 9.5. Structure

1.

Name

Nicotine

N N

CH3

CH3

2.

(CH3)2C

CH3 C—O

CH

O

O CH3

O

Pyrethrin CH2CH

CHCH

CH2

O

CH3 N

N

3.

CH3

N

N

CH3

Fig. 9.5

Some common botanical insecticides.

Caffeine

9.16

TOXICOLOGY

Nicotine is extracted from the leaves of Nicotaina tabacum and Nicotiana rustica by alkali treatment and steam distillation. It is an alkaloid and used as an agent in tobacco. Nicotine is extremely toxic and is readily absorbed through the skin. It may cause muscular fasciculations, convulsions and paralysis.

9.3.2 Herbicides Herbicide is defined as any compound that is capable of either killing or severely injuring plants. Herbicides are generally classified based on their mechanism of toxicity in plants such as: selective, contact and translocated. Selective herbicides are specific toxic to some species, contact herbicides can act when these are in contact on the plant foliage whereas translocated herbicides are absorbed by the plants through soil. Phenolic compounds such as dinitrophenol, dinitroorthocresol, and pentachlorophenol are used as contact herbicides. Some common herbicides are shown in Fig. 9.6. Structure

Name

OCH2COOH Cl

1.

2,4-dichlorophenoxy actetic acid (2,4-D) Cl

Cl

2.

Cl

OCH2COOH

2,4,5-Trichlorophenoxy, acetic acid (2,4,5-T)

Cl

CH3

3.

Cl

OCH2COOH

4-Chloro-O-toloxyacetic acid

Diquat

4. N+

+N

contd.

TOXIC EFFECTS OF NATURAL AND SYNTHETIC PRODUCTS

5.

+

Paraquat

+

H 3C — N

9.17

N — CH3

Fig. 9.6 Some common herbicides.

Chlorophenoxy Herbicides

The chlorophenoxy herbicides such as 2, 4-D and 2, 4, 5-T are systemic herbicides for broad leaf plants that act by excess stimulation of plant growth hormones. These herbicides are very toxic to humans through exposure with acute symptoms including skin, eye and respiratory tract irritation, headache, dizziness, nausea, fatigue nervousness and intolerance to cold. Bipyridilium Herbicides

Bipyridilium herbicides contain two pyridine rings per molecule. Diquat and paraquat are the common herbicides of bipyridyl derivatives. These herbicides are non-selective contact herbicides which can be applied directly to plant tissue to destroy the plant cells rapidly. Paraquat is a very water-soluble contact herbicide that is active against a broad range of plants and is used as a defoliant on many crops. Diquat is a rapid acting contact herbicide used as a desiccant for the control of aquatic weeds. Diquat is less toxic than paraquat. The toxic effects occur through ingestion and the intoxication involves the symptoms that include lethargy, ataxia, hyperexcitability, convulsions, dyspnea, intralveolar haemorrhage, congestion and pulmonary dibrosis.

9.3.3 Fungicides Fungicides include such compounds derived from simple inorganic compounds such as sulphur and copper sulphate through aryl or alkyl-mercurial compounds. The other fungicides are hexachlorobenzene (HCB), dithiocaramates (Maneb, Zineb and Nabam) which are used widely in agriculature. Some common fungicides are given in Fig. 9.7. Structure

Name

Cl Cl

Cl

1.

Hexachlorobenzene (HCB) Cl

Cl Cl

OH Cl

Cl

Cl

Cl

Pentachlorophenol (PCP)

2. Cl

contd.

9.18

TOXICOLOGY O

3.

N — S — CCl3

Captan

O

S

4.

CH2 — NH — C — S — Mn —

Meneb.

CH2 — NH — C — S — S Fig. 9.7

X Some common fungicides.

The dithiocarbamate fungicides have low acute toxicity but HCB, PCP, captan fungicides are very toxic and are considered as teratogens or carcinogens.

9.4

TOXIC EFFECTS OF DRUGS

Medical drugs whose therapeutic and toxic concentrations are very close, it may be necessary to check regularly that the concentration has not become too high. The problems with therapeutic drugs occur due to accidental acute intoxication by children and overdose by adults. The overdose will create problems in the patient’s homeostasis, i.e., both kinetics and biotransformation. Several categories of therapeutic drugs that are frequently used and consider their toxic effects of overdose and misuse, are discussed in this section of the book.

9.4.1 Hypotonics Barbiturates The barbiturates comprise a large group of drugs that have been used as general sedatives and hypotonics. These are the derivatives of barbituric acid. Some of the common hypotonics, tranquilizers, antidepressants, etc. structure given in Fig. 9.8. Barbiturates are administered orally and are metabolized in liver, kidneys and other tissues. Certain barbiturate derivatives like phenobarbital have been used as an anticonvulsant drug for many years. Chronic use of this drug may cause the induction of hepatic microsomal enzymes, which may reduce the effect of other drugs. The tolerance level to barbiturates may increase as much as six times. These drugs may cause depression of central nervous system (CNS), drowsiness, confusion and loss of consciousness. It may also cause respiratory depression.

TOXIC EFFECTS OF NATURAL AND SYNTHETIC PRODUCTS R¢¢

9.19

O

N

R

O R¢

N

N

O

H

Barbituric acid

Imepramine (antidepressants)

H N

CH3 —CH2—CH—NH2

O

O N H

Amphetamine (Benzedrine)

CH3

C2H5 C2H5

Barbital

O

N N Cl

Diazepan (valium)

Fig. 9.8

Some common hypotonics.

Benzodiazepines

The benzodiazepines are non-barbiturate compounds and are widely used as a hypotonic, sedative, tranquillizer or depressants. The ideal hypotonic drug is one that is rapidly absorbed and eliminated over a short period of time. Without producing accumulation in the body, benzodiazepines are relatively safe in overdose and not associated with serious addiction, tolerance development or microsomal enzyme induction. These drugs exert their action on specific benzodiazepine receptor sites in the body. A number of other benzodiazepines such as diazepam (valium) and chlordiazepoxide (librium) are used as anxiolytics. The overdose administration of benzodiazepines may cause drowsiness, respiratory or circulatory depression and occasionally coma. Tricyclic Antidepressants

The tricyclic antidepressants are available in a wide variety of bands including doxepin and imipramine and also in combination with phenolthiazine drugs. Tricyclic antidepressants have three basic pharmocologic actions such as anticholinergic effects, reuptake blockade of catecholamines at the adrengic neuronal site on quinidine-like effects and cardiac tissue.

9.20

TOXICOLOGY

Tricyclic antidepressants are very fatal on overdose situations. The overdose of this drug is very complex and the toxic effects show the symptoms of central nervous system, depression, ataxia, respiratory depression, hypothermia, agitation, lethargy and disorientation.

9.4.2 Narcotic Analgesics Opiates Narcotic analgesic drugs are opiates used in the management of moderate to severe pain. Opiates include drugs derived from opium and exert their action by interacting with specific receptors in the body. Some common narcotic analgesic drugs are shown in Fig. 9.9. N—

1

CH 3

N—

CH 3

8

2 3 HO

4

O

5

7 6 OH

OOCCH3

Morphine

O

Heroin

CH3

O

H3C — C — O — C — CH2 — CH — N (CH3)2 C

Methadone

Fig. 9.9

OOCCH3

O

O— H5 2

C

N — CH3

Meperidine

Some common narcotic analgesic drugs.

There are three major classes of opiod receptor is described as m(mu), k(kappa) and d(delta) and a number of subclasses of these receptors. The most important analgesic mode of action concerns the interaction with m receptors in the brain. Morphine is the main opiate analgesic drug present in opium and heroin is prepared by acetylation of the hydoxyl groups at C-3 and C-6 of morphine. The effects of these drugs include nausea, vomiting, drowsiness, depression of CNS, supression of anxiety and sedation, increase in pain tolerance and respiratory depression. Severe overdose may cause apnea, circulatory collapse, convulsions, cardiac arrest and death. Paracetamol-Aspirin (Non-opiates) Analgesics

Paracetamol and aspirin are the non-opiate analgesic drugs used to manage mild to moderate pain or fever. The chronic use of aspirin may cause gastric irritation

TOXIC EFFECTS OF NATURAL AND SYNTHETIC PRODUCTS

9.21

and bleeding. Overdose of paracetamol is a powerful hepatotoxin that can lead to severe hepatic damage and fulminant liver failure and death due to hepatic failure within 5 to 10 days.

9.4.3 Anticonvulsants or Antiepileptics A wide range of anticonvulsant drugs are used to prevent or reduce the seizures, epileptic fits. The anticonvulsant drugs including carbamazepine, phenytoin, phenobarbitone and diphenylhydantoin are used to control arrhythmias from intoxication by other drugs such as tricyclic antidepressants. Ideally single drug should be used to provide adequate control. Some drugs (phenytoin) used in the treatment of epilepsy may cause interaction with other drugs which can be of serious problems like foetal hydantoin syndrome including cleft palate, hydrocephalus, microcephalus, broad nose, digital thumbs, short neck and various heart defects.

9.4.4 Antipsychotic Neuroleptics Drugs Antipsychotic drugs are used for treatment of patients with psychotic-like symptoms such as schizophrenia. These drugs have adverse side effects including delusions, agitation, delirium, disorientation, hallucinations, disorganized speech and bizarre behaviour. Antipsychotic drugs include chloropromazine, thioridazine and fluphenazine. Now these drugs are not in use because of their adverse effects include Parkinsonian symptoms such as tremor and facial movement disorders, e.g., dystonia, akathisia and tardive dyskinesia. The new antipsychotic drugs include clozapine, rispiridone, olanzapine and quetiapine are used. Clozapine has an associated risk of agranulocytosis and mycocarditics.

9.5

TOXIC EFFECTS OF NATURAL PRODUCTS

The natural products which are produced by living organisms and have toxic effects to other living organisms are called toxic natural products. Toxic natural products are produced from both animals and plants ranging from microorganisms to macroorganisms. For example, mycotoxins are produced by fungi and venom of snakes which are poisonous to other organisms. The terminology related to toxic natural products are discussed as: Poisonous organism: The organism that produces toxins is called poisonous organism. Poisonous animal: The animal that may contain toxin in its tissues that act as poisons to other animals that eat its flesh. Venomous animals: The animal that can deliver toxins to another by means of biting or stinging.

9.22

TOXICOLOGY

9.5.1 Mycotoxins Mycotoxins represent a diverse group of chemicals that can occur in a variety of plant foods. Mycotoxins are toxic metabolites from fungi with a variety of toxic effects. Mycotoxins of most interest are the ergot alkaloids produced by Claviceps sp., aflatoxins produced by Aspergillus sp. and the tricothecenes produced by several genera of fungi, primarily Fusarium sp. Fig. 9.10. NH O

O

O C

O

H

H

O H

O

OCH3

CH3

N—CH3

OH O

H

NH

C

C

C

N

O

C

O

C H

Aflatoxin B1

H N

CH3

Ergotamine

Fig. 9.10 Some mycotoxins.

Ergot Alkaloids

The ergot alkaloids have been associated with the problem to affect the nervous system and to be vasoconstrictors. Sometimes these are implicated in epidemics of both gangrenous and convulsive ergotism. St. Anthony’s fire is an example of convulsive ergotism. Now this problem no longer occur in humans but still occurs frequently in livestock. Aflatoxins

Aflatoxins are the common fungi found as a contaminant of grain, maize, peanuts, etc. Among the various mycotoxins, the aflatoxins are extremely potent hepatocarcinogenicity. Aflatoxin B1 is the most toxic of the aflatoxins, which must be enzymatically activated to exert its carcinogenic effects. Aflatoxin B1 is an extremely biologically reactive compound which may alter a number of biological systems. The hepatocarcinogenicity of aflatoxin B1 is due to its biotransformation to a highly reactive electrophilic epoxide that forms covalent bonds with protein, DNA and RNA. Generally, aflatoxins occur in susceptible crops as mixture of aflatoxins B1, B2, G1 and G2. Trichothecenes

Trichothecenes represent many different chemical entities about 40 or more and are produced by a number of commonly occurring moulds including cephalosporium, fusarium, myrothecium and tricoderma. They are frequently acutely toxic, displaying bactericidal, fungicidal and insecticidal activity causing

TOXIC EFFECTS OF NATURAL AND SYNTHETIC PRODUCTS

9.23

various symptoms including diarrhoea, anorexia and ataxia. Trichothecenes have been implicated in natural intoxications in farm animals and a few in humans.

9.5.2 Microbial Toxins Microbial toxins refer to the toxic substances produced by microorganisms that have antigenic properties. The two major problems regarding toxic substances from microorganisms are their role in causing symptoms of causing microbial diseases and food poisoning. Some of the microbial toxins are tetanus toxin, botulinus toxin and diphtheria toxins. Strains of Shigella dysenteriae bacteria in the body can cause severe form of dysentery because they release a toxin that causes intestinal hemorrhaging and gastrointestinal paralysis. Bacterial toxins may be extremely toxic to mammals and may affect a variety of organ systems, including the nervous system and the cardiovascular system. The most dangerous toxin produced by bacteria outside the body is that of Clostridium botulinum which poisoning symptoms appear within 10 to 12 hrs after ingestion with gastrointestinal tract disorder and neurologic symptoms, paralysis of the respiratory muscles and death.

9.5.3 Animal Toxins The animals that produce toxins may be separated into two groups such as venomous and poisonous. The venomous animals are capable of producing toxins that can deliver during a biting or stinging. For example, snakes, bees, etc. Poisonous animals have poisonous tissues or parts that can become poisonous when other animal eats their flesh. The site of action and metabolism of toxins is dependent on its diffusion and partioning along the gradient between the plasma and the tissues where the components are deposited. The chemistry of animal toxins extends from enzymes and neurotoxic and cardiotoxic peptides and proteins to many small molecules such as biogenic amines, alkaloids, glycosides, terpenes and others. Toxins of Venomous Animals

Snakes are the most notorious venomous animals. The venoms are complex mixtures that include proteins, biogenic amine, histamine, peptides and at least 25 enzymes. Among the most prominent of the enzymes in snake venom are the proteolytic enzymes. Proteolytic enzymes catalyze the breakdown of tissue proteins and peptides. Toxins of snake venom are cardiotoxic or neurotoxic and their effects are usually catalyzed by the peptide hydrolase, protease, endopeptidases, peptidases, proteinases and phospholipase. Arthropod Toxins

There are many arthropods which are poisonous. These include the arachinds (scorpions, spiders, whipscorpions, mites and ticks), myriapods (centipedes, and

9.24

TOXICOLOGY

millipedes), the insects (water bugs, assasin bugs and wheel bugs), blister beetles, lepidoptera and hymenopetra. The scorpions are the oldest terrestrial arthropods and venom of many scorpions contains proteins, peptides, amino acids, nucleotides and salts. The toxins can selectively bind to a specific cells. The stings of scorpions gives rise to localized pain, swelling, tenderness and mild parasthesia. There are about 30,000 species of spiders and their venoms are very complex in nature. Laxosceles are the primitive spiders and are known as brown recluse or fiddle back spiders. Both males and females are venomous. The venom of Laxosceles contains phospholipage, protease, esterase, ribonuclease, collagenase and deoxyribonuclease. The venom has coagulation and vasoconstric properties. After injection of venom, it produces varying degree of thrombocytopenia, hemolysis and hemolytic anaemia. Widow spiders are Latrodectus species. Bites by the widow spiders are described as sharp with occasional pain. The symptoms of widow spider poisoning include localized pain, cramps in muscles, nausea, weakness, sweating and headache.

9.5.4 Plant Toxins Plants have developed various defence mechanisms against the attack of pathogens (viruses, bacteria and fungi) and herbivores. In this evolution process, a large number of toxic chemicals are produced by plants to protect themselves. The quickest way for a plant to protect itself from being eaten is to produce chemicals that are irritating on contact. The plants produce chemicals that include sulphur compounds, lipids, phenols, alkaloids, glycosides and many others and these chemicals produce negative effects on the gastrointestinal, cardiac or nervous system of plant predators. Toxin from plants may affect various organs such as skin, liver, heart, stomach, etc. of the living organisms. Some important and major plant toxins that affect the different organs are discussed below. Skin

There are some plants such as poison ivy (Rhus radicans), poison oak (Rhus diversiloba) and poison sumac (Rhus vernis) have the high potential to cause contact dermatitis as an allergic reaction. The toxic agents in the plant poison ivy is urishikiol which is fat soluble, penetrates the stratum corneum and binds to Langerhans cells in the epidermis. Generally, the allergens of plants tend to be located in the outer cell layers of plant organs. The most common plant allergens consist of pollen. Acute dermatitis is caused by contact with the trichomes of species of Urtica (nettles). Even gentle contact with hairs causes pain and erythema from penetration of the skin by the trichomes. The leaves of certain plants (Dieffenbachia) contain irritating calcium oxalate crystals coated with a trypsinlike inflammatory protein. These may cause contact dermititis.

TOXIC EFFECTS OF NATURAL AND SYNTHETIC PRODUCTS

9.25

Photosensitizers constitute a systemic plant toxin capable of affecting areas other than those exposed. The toxic agent hypercin causes photosensitization and lesions appear after exposure to sunlight (Sako et al. 1993) Liver

The ingestion of species of senecio may cause hepatitis. These species contain a significant concentration of pyrrolizidine alkaloids which are responsible for liver damage in the form of hepatic venoocclusive disease in cattles. The major or toxic alkaloids in Senecio vulgaris is retrorsine and jacobine in Senecio jacobaea. The deaths from mushroom poisoning are due to liver damage following consumption of death cap (Amanita phalloides) which contains two toxic chemicals known as phalloidin and amatoxins. Phalloidin combines with action in muscle cells to interfere with muscle function. Amatoxins inhibit the protein synthesis because it binds with RNA polymerase II-strongly. Nervous System

There are certain toxins produced from plants which cause a variety of central nervous and peripheral nervous system effects, are called nerve toxins. Permanent damage to the nervous system is a serious consequence of excessive neuronal stimulation. Plant derived neurotoxic psychodysleptics affect peripheral neural functions and motor coordination, sometimes accompanied by delirium, stupor, trance states, and vomiting (Emboden, 1979). Many plants that produce amino acids which mimic the action of glutamate on the central nervous system. The excitatory amino acids (EAA) from plants are or more glutamate receptor subtypes which may result in death of neurons. EAA are found in pea family plants. Several members of the mint family contain monoterpenes which can cause tonic-clonic convulsions (Burkhard et al. 1999). Karwinskia humboldtiana is a shrub which produces a toxin to cause paralysis without primary excitation of neurons. The belladonna alkaloids are present in several genera of plants of the family solanaceae. These alkaloids have greater impact on the central nervous system. Kidneys

Bracken fern is the only higher plant to cause cancer in animals under natural conditions. The acute renal failure is the cause of death in poisoning from Cortinarius orellanus.

9.6

TOXIC EFFECTS OF COSMETICS

The most common deleterious effects of cosmetics are occasionally allergic reactions and contact dermatitis. The cosmetics and hygiene products may include deodrants, hair storages, hair dyes, permanent waving solutions, nail polish, shampoos, face cream, cold wave lotion, sunscreen lotion, depilatories, sodium hydroxides and soaps. Cosmetics appear to present little risk of systemic

9.26

TOXICOLOGY

poisoning. These cosmetic products have the toxin agents such as lanolin, colouring agents, paraffin, petroleum, paraben, esters, sorbic acid, phenolic, other organic materials, EDTA formaldehyde, etc. which may cause problems like dermatoconjunctivitis and dermatitis. Formaldehyde used in cosmetics is capable of causing a contact hypersensitivity reaction.

-:-4+151. How do you classify the toxic natural and synthetic products? Explain them in detail. 2. What are the factors influencing the toxicity of a particular solvent? 3. Write short notes on the toxicity of (a) Aliphatic hydrocarbon. (b) Chlorinated hydrocarbon. (c) Alcohols. 4. Explain the toxicity of aromatic hydrocarbons. 5. What are the toxic effects of pesticides and biocides. 6. What do you mean by botanical insecticides? Explain their toxic effects on the organisms. 7. Differentiate the toxicity between (a) Herbicides and fungicides. (b) Organophosphorous and carbamate insecticides. (c) Mycotoxins and microbial toxins. 8. Discuss the toxic effect of drugs. 9. What are the toxic effects of natural products? 10. Discuss about the toxins of plants and animals.

CHAPTER

10

Toxicology of Organs and Organ Systems 10.1

INTRODUCTION

Toxicology of organs and organ systems is the study of adverse effects of drugs, non-therapeutic chemicals and other agents in our environment on the vital organs and organ systems. Generally, the toxic chemicals with the greatest propensity to contaminate or affect humans, whether directly or indirectly through food, water or any other means. The enzymes of biotransformation in an organ play a prominent role in bringing toxicity in organ systems. The metabolic activation of some toxicants or chemicals can take place selectively in certain organs and organ systems. In this chapter the toxicity of some vital organ and organ systems will be discussed. These organs and organ systems are: • Hepatotoxicity (liver). • Dermatotoxicity (skin). • Haematotoxicity (circulatory system). • Neurotoxicity (nervous system). • Toxicity of respiratory system. • Toxicity of reproductive system. • Nephrotoxicity (kidney) • Toxicity of immune system (immunotoxicity). • Cardiotoxicity (heart). • Endocrine toxicity.

10.2

DERMATOTOXICITY (ORGAN–SKIN)

Skin is the largest organ with greatest surface area of the human body, thus it forms an important target organ for many toxicants. The important function of the

10.2

TOXICOLOGY

skin is to protect the body against invading the foreign materials in order to maintain internal homeostasis. Skin is capable of metabolic activity, although these metabolic processes generally proceed more slowly than the rest of the organism. Physiologically, the skin performs the vital functions like thermal, electrolyte, hormonal, metabolic and immune regulation. The skin consists of three layers—the outer epidermis, a keratinized squamous epithelium cells. These cells are tightly attached to each other by desmosomes and to the basement membrane by hemidesmosomes. The underlying layer known as dermis, a dense, fibroelastic connective tissue which supports and nourishes the epidermis. The fibroblasts produce the collagen and elastin fibres that give the skin its tensile strength. The hypodermis which is the innermost layer of the skin having connective tissue containing variable amounts of adipose tissue. Fig. 10.1(a and b). Hair Erector muscle Epidermis

Dermis

Ecrine sweat gland Sebaceous gland

Hair follicle Fat cells Apocrine sweat gland

Fig.10.1(a)

Diagrammatic cross-section of the skin. Stratum corneum Stratum lucidum Stratum granulosum

Stratum spinosum

Stratum basale Melanocytes Basement membrane

Fig.10.1(b)

Diagrammatic cross-section of the epidermis.

TOXICOLOGY OF ORGANS AND ORGAN SYSTEMS

10.3

The epidermis is the only layer that is important in penetration of xenobiotics.

10.2.1 Permeation The ability of xenobiotics to penetrate the skin is very slow because of the existence of specific barrier. The penetration of chemicals through skin (stratum corneum) is also known as percutaneous absorption. If the specific barrier is damaged by vesicants such as acids or alkali, absorption will be enhanced. Stratum corneum is the primary barrier to xenobiotics. The most important factors which can influence the penetration of xenobiotics through the skin are as: • Non-ionized chemicals or substances can penetrate through stratum corneum very easily. • The chemicals which are easily soluble in lipids (lipophilicity) can easily penetrate. • Small molecules can penetrate more easily than bigger one. • Low viscos chemicals can easily penetrate. • Damage to the horny layer as well as oedema increases the permeability to xenobiotics. • The pH value and water content in the stratum corneum greatly influence the penetration ability of xenobiotics. Diffusion through the epidermis depends on the thickness of the stratum corneum and the list of decreasing order of permeability under normal condition is as: footsole > palm > scrotum > forehead > abdomen (Sheuplein and Blank, 1971). Once the substance has penetrated the epidermis, the subsequent uptake of that substance by the vessels is an important factor in its distribution. Fick’s first law of diffusion states that the rate of diffusion or flux (J) is proportional to the concentration of the penetrant (Cs). Thus, J = Kp Cs. Kp = Permeability constant Cs = Concentration of the penetrant Kp = D km/d where D = Diffusivity Km = Partition coefficient. d = Thickness of the skin

10.2.2 Toxic Effects of Xenobiotics of the Skin Dermal exposure to the toxic substances can result in a multitude of disorders. The most toxic effects on the skin can be caused by direct injury or irritation and immunological reaction (allergy). When a xenobiotic substance comes into

10.4

TOXICOLOGY

contact with the skin, it may react with skin cells resulting in skin irritation followed by dermatitis. Dermatitis is an inflammatory condition that can be caused by irritants or allergens. If the chemical substance penetrates the skin and is further distributed, it may cause systemic effects. Some of the most important toxic effects of the skin may be discussed as irritant dermatitis, allergic reactions, phototoxic and photoallergic effects, pigment disorder, urticaria, carcinogenesis and epidermal necrolysis. Irritant Dermatitis

Irritant dermatitis is the most common toxic skin reaction which causes inflammation accompanied by pain. The classification of toxic effect is based on the extent of damage, whether mild or severe. A mild irritant dermatitis in which the damage is limited to the epidermis. It causes hyperplasia in which the proliferation cells in epidermis causes thickening of the skin. In severe irritant dermatitis which is also known as corrosion, the epidermis, the basement membrane and upper dermis have become degenerated (died off). The result is an inflammatory reaction at the transition of necrotic and living tissue. This inflammatory reaction is immediately followed by proliferation of epithelial (hyperkeratosis, hypergranulosis and acanthosis) and connective tissue cells. Contact dermatitis is considered a moderated form of irritant dermatitis (between mild and severe). Eczema, erythema (redness), induration (thickening and firmness), scaling (flaking) and vericulation (blistering) are the common contact dermatitis. Allergic Dermatitis

An allergic dermatitis occurs because some xenobitoics have a greater sensitizing capacity than others to the body of an organism. In allergic dermatitis, the substance first penetrates the horny layer and binds to a certain protein in order to become a complete allergen. Allergic dermatitis is a delayed sensitivity reaction. In hypodermis, the allergen is bound to T-lymphocytes and transported to a local lymph gland. This process is known as sensitization. In general, the low molecular weight chemicals are responsible for causing allergic dermatitis. In allergic dermatitis, only minute quantities of material are necessary to elicit overt reactions. If the skin is exposed to the allergen again and again, the sensitized Tlymphocytes are induced to produce lymphokines which causes inflammation. Phototoxicology

The toxic effect which can be caused by the reaction between the sunlight (UVA-320 to 400 nm) and the toxic compounds known as phototoxicology. After exposure, the skin manifests injury in a variety of ways including both acute and chronic responses. The local phototoxic reactions arise at the site where the skin is in direct contact with the toxic substances. Phototoxic reactions from exogenous chemicals may be produced by systemic or exposure. In systemic phototoxicity,

TOXICOLOGY OF ORGANS AND ORGAN SYSTEMS

10.5

the toxic substance usually enters the body by a route other than through the skin. These substances reach the skin through circulation. On subsequent exposure to sunlight (UV-A-320 to 400 nm) skin reaction may follow. In acute reactions, the skin may appear red and blister within minutes to hours after ultraviolet (UV) light exposure. Photosensitivity

In photosensitization, antigens are formed in the skin under the influence of sunlight which is catalyzed by a photochemical reaction. In most situations, systemic photoallergy is the result of administration of medications. In photoallergic reaction, UV-light is necessary to convert a potential photosensitizing chemical into a hapten which conjugates with a skin protein to produce antigen. Hyperpigmentation and Hypopigmentation The pigment melanin is the important factor for the determination of colour of the skin. Melanin is produced through a series of enzymatic pathways beginning with tyrosine. Some xenobiotics are capable of causing local depigmentation of the skin. Hyper-pigmentation occurs from increased melanin production or deposition of endogenous or exogenous pigment in the upper dermis. The endogenous pigments are melanin and hemosiderin while exogenous pigments are deposition of metals and drugs in dermal tissue. Hypopigmentation refers to loss of melanin or vascular abnormalities. Leukoderma is due to the complete loss of melanin from the skin. Urticaria

Urticaria is accompanied by itching, erosions, lichenification and eczema. It represents an immediate type I hypersensitivity reaction primarily occurred by histamine and vasoactive peptide release from most cells. Localized uticaria may be elicited by certain substances in the area of epicutaneous contact and is generally referred to as contact urticaria and is limited to the skin. Contact urticaria caused by both immunological and non-immunological mechanisms while the most severe forms are caused by exclusively through immunological mechanism. Carcinogenesis

Skin cancer is the most common form of cancer and the major cause of it is sunlight ultraviolet rays. The ultraviolet-B (UV-B) ranges from 290 to 320 nm, damages epidermal cell DNA. The UV-B induces pyrimidine dimers, therefore, eliciting mutations in critical genes. Skin tumors can originate in the epidermis, hair follicles, sweat and sebaceous glands as well as in the dermis and hypodermis.

10.6

TOXICOLOGY

10.3

HAEMATOTOXICITY (ORGAN–BLOOD)

Haematotoxicity is the study of adverse effects of drugs, non-therapeutic chemicals on blood and blood forming tissues (Bloom, 1997). A number of blood cells such as erythrocytes, granulocytes and platelets are produced at a rate of approximately 1 to 3 million per second in an adult. The vital functions of blood is to deliver oxygen to tissues, maintaining vascular integrity and provide many factors to the whole body. These vital functions of blood cells and blood forming tissues are susceptible to toxicants directly or indirectly. The toxic effects include hypoxia, haemorrhage and infection. Primary haematotoxicity refers to one or more blood components are directly affected whereas secondary haematotoxicity refers to the toxic effect is a consequence of other tissue injury or systemic disturbances. Bone marrow is the principal site of haematopoiesis (production of blood cells) and spleen has little contribution in the production of blood cells.The toxicants or xenobiotics have high sensitization capacity to affect the bone marrow results in dysplasia (abnormal production of cells), hypoplasia (decreased production of cells), aplasia (inhibition of cell production) and malignancy of the cells.

10.3.1 Toxicity of Blood Cells The blood cell, particularly erythrocytes (red blood cells) are the major components of the circulating blood which comprises about 40 to 45 per cent by volume. Erythrocytes are the principal vehicles of transportation of oxygen and carbon dioxide from lungs to tissues and vice versa. The toxicants may affect the production of erythrocytes resulting in a disease called anaemia. Erythrocyte production is a continuous process that is dependent on frequent cell division and a high rate of haemoglobin synthesis. Iron deficiency in the body may decrease haemoglobin synthesis and may cause hypochromasia (increased central pallor of RBCs) (Figs. 10.2 and 10.3). The leukon consists of leukocytes (white blood cells—WBC). Leukocytes include granulocyte which may further be subdivided into neutrophils, eosinophils

Heart Arteries Veins

Fig. 10.2 Main components of the circulatory system.

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10.7

Fig.10.3 RBCs.

and basophils. Neutrophils are the largest component of leukocytes. The high rate of proliferation of neutrophils may result in inhibition of mitosis. Such effects by cytotoxic drugs are generally non-specific. Various cytoreductive agents may inhibit DNA, RNA and protein synthesis prior to the miotic. Leukemias are proliferative disorders of haematopoietic tissue that originate from bone marrow. Certain chemicals and radiation can disregulate haematopoiesis, resulting in leukemogenesis. Hemostasis is a multicomponent system responsible for preventing the blood from sites of vascular injury and maintaining circulating blood in a fluid state. Platelets are essential for formation of a stable hemostatic plug in response to vascular injury. The chemical substances or xenobiotics may interfere with the platelet response by causing thrombocytopenia. Some chemicals are capable of affecting both platelet function and number. Thrombocytopenia is due to the decreased production or increased destruction of platelets. Some drugs function as haptens, binding to platelet membrane components and eliciting an immune response.

10.4

HEPATOTOXICITY (ORGAN–LIVER)

The liver is the largest organ in the body and is located between intestinal tract and the rest of the body. The portal vein and hepatic artery supply the blood to and from the liver. The portal vein drains the gastrointestinal tract, spleen and pancreas. It also supplies nutrients and some oxygen. The hepatic artery supplies fully oxygenated blood to the liver. The liver is the first organ to encounter the most xenobiotics, nutrients, vitamins, drugs and environmental toxicants because these substances enter the body through gastrointestinal tract and after absorption, are transported by the hepatic portal vein to the liver. (Fig. 10.4)

10.8

TOXICOLOGY Space of Disse Periportal arttrial capillary

Lymph boundary Lacuna vessel plate

Anastomosing liver cell plates

Sublobular collective vein Central vien Inlet vein Inlet vein

Intralobular bile ductule Bile capillary

Central vien Sinusoid Liver cell plate

Branch of the hepatic artery Intralobular arterial capillary

Bile ductule Boundary plate

Periportal space

Fig. 10.4 Detailed schematic representation of the structure of the liver.

All the major functions of the liver such as metabolic, detoxicating, secretory and excretory can be detrimentally altered by acute or chronic exposure to toxicants. The toxicants may cause cell damage by a number of mechanisms such as: • Enzyme inhibition: Some xenobiotics such as cyanide inhibits the enzymatic function (Cytochrome aa3) which leads to the blockage of cellular respiration and may cause death. • Lipid peroxidation: Lipid peroxidation is caused due to the attack of a free radical on unsaturated lipids (polyunsaturated fatty acids) found in cell membranes. This leads to the destruction of lipids which in turn alter the permeability of membranes, destabilization of lysosomes and inhibit the functions of mitochondria. The chemicals like carbon tetrachloride and white phosphorus are responsible for lipid peroxidation. • Apoptosis: The xenobiotics like calicum influxes into the cell which may damage the tissues. Apoptosis is a programmed cell death. Ischaemia Ischaemia refers to the reduction of oxygen or nutrients supplied to cells due to the reduction of blood flow. This results in cell damage and eventual cell death. Damage to intracellular organelles Damage to intracelluar organelles can result from the alteration of the intracellular Ca+2 concentration which may inhibit Ca+2 adenosine triphosphates (ATPs) resulting in Ca+2 homeostasis. This reaction may lead to rapid cell death.

10.4.1 Types of Liver Injury Most of the biotransformations are detoxication reactions, many oxidative reactions produce reactive metabolites that can induce lesions within the liver.

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10.9

Some toxicants cause direct injury to the liver and others convert the chemicals into toxic substances through metabolic conversion. Liver function is disturbed if there is interference with the hepatocellular metabolic processes or bile secretion. Such interference may take place after acute or chronic exposure to hepatotoxins O H 2N

CH2 Methylene Dianiline

NH2

HC — N

CH3 CH3

Dimethyl formamide

Some of the important liver’s response to injury are as follows: • Fatty liver • Cell necrosis (cell death) • Cholestasis • Bile duct damage. • Cirrhosis. • Hepatitis. • Carcinogenesis. Fatty Liver

The liver holds key position in fat formation. Some toxicants that produce liver injury cause an abnormal accumulation of fats (50%), mainly triglycerides in the parenchymal cells. A normal liver contains 5% fat. This change is also known as steatosis. The metabolic inhibitors ethionine, puromycin and cycloheximide cause fat accumulation without causing death of cells. The other reasons for fat liver are: • Over supply of free fatty acids to the liver. • Interference with the triglyceride cycle. • Esterification of fatty acids. • Secretion of very low density lipoprotein (VLDL). The chemicals like carbon tetrachloride, ethanol, fialuridine, valproic acid, etc. are responsible for the fatty liver. Steatosis is a common response to acute exposure to toxins which may affect the entire acinus. Some xenobiotics cause necrosis of liver parenchyma which is followed by liver degeneration. This liver degeneration may lead to severe effects called hydropic degeneration. Cell Necrosis Cell Death

Cell death may occur by direct cell injury, with disruption of intracellular function, or by indirect injury by immune-mediated membrane damage. Necrosis is characterized by cell swelling, leakage, nuclear disintegration and an influx of inflammatory cells. The necrotic lesions can be caused by a variety of

10.10

TOXICOLOGY

xenobiotics, such as tetrachloroethane, trinitrotoluene, dinitrobenzene and mixtures of chlorinated biphenyle naphthalenes. Cell necrosis is usually an acute injury and may be focal (central, mid zonal, or peripheral) or massive. Focal cell death is characterized by the randomly distributed death of single hepatocytes or small cluster of hepatocytes. Zonal necrosis is characterized by the death of hepatocytes predominantly in periportal (Zone-1) or centrolobular (Zone-3). Apoptosis is another mode of cell death. Apoptosis is characterized by cell shrinkage, nuclear fragmentation, formation of apoptotic bodies, and a lack of inflammation. Cellular Cholestasis Impaired Bile Flow

Cholestasis develops as a result of disturbed transport and conjugation of bilirubin, as a result of bile stasis or damage to the biliary passages. Cholestasis is usually drug induced. The bile duct injury occurs from exposure to xenobiotics like =-naphthyl isothiocyanate. Inflammation or blockage of the bile ducts results in retention of bile salts as well as bilirubin (yellow) accumulation in the skin and eyes, producing jaundice, and spills into urine. Cirrhosis Cirrhosis is characterized by regenerative nodules (clumps of new cells) within fibrotic tissue forming an irregular lobulated (defined) pattern. This progressive disease is characterized by the presence of collagen throughout the liver. Cirrhosis is often associated with liver dysfunction, frequently resulting in jaundice and it is irreversible. Hepatitis Chronic active hepatitis is characterized by extensive portal and periportal inflammation with lymphocyte and plasma cell infiltration, usually in combination with single cell necrosis. Hepatitis is drug induced. Carcinogenesis Chemically induced neoplasia can involve tumours that are derived from hepatocytes, bile duct cells or malignant. The most common type of primary liver tumour are hepatocellular carcinoma, cholangiocarcinoma, angiosarcoma, glandular carcinoma and liver cell carcinoma. The chemicals like aflatoxin, and rogens, thorium dioxide and vinyl chloride are mainly responsible for liver tumour.

10.5

NEPHROTOXICITY (ORGAN—KIDNEY)

The kidneys form the major target organs for a variety of nephrotoxicants. Kidney can be divided into three zones such as cortex, medulla and papilla. The smallest functional unit is the nephron which consists of the glomerulus, the proximal convoluted tubule, the loop of Henle and the distal convoluted tubule (Fig. 10.5 and Fig. 10.6).

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10.11

Cortex Medulla

Capsule Renal artery

Medullary pyramid

Renal vein Renal pelvis

Ureter

Fig.10.5 Diagram of the kidney. Efferent Afferent vessel vessel Glomerulus

Distal tubule Proximal tubule

Bowman's capsule

Collecting duct

Branch of renal artery

Branch of renal vein Ascending limb of the loop of Henle

Descending loop of Henle

To bladder

Fig.10.6 Diagram of the kidney nephron.

Because of the high blood flow to the kidneys, any drug or chemical in the systemic circulation will be delivered to the kidney in significant amounts. Another factor affecting the kidney’s sensitivity to chemicals is that the kidney concentrates and excretes metabolic waste, chemicals and drugs. Thus, it is easily exposed to toxic concentrations of the toxicants. The other factor in nephrotoxicity is the biotransformation of the parent compounds to a toxic metabolite. The most common manifestation of nephrotoxic damage is acute renal failure (ARF) which is characterized by an abrupt decline in glomerular filtration rate (GFR) with resulting azotemia. The chemically induced ARF can be initiated by proximal tubular cell injury, nephrotoxicants also may inhibit cellular proliferation and migration, thereby delaying renal functional recovery.

10.12

TOXICOLOGY

10.5.1 Toxic Nephropathies Nephrotoxicants may cause injury at number of sites along the nephron and produce characteristic clinical syndromes. A wide variety of drugs, environmental chemicals and metals cause nephrotoxicity. For example, mytotoxins, halogenated hydrocarbons, antineoplastics, antibiotics and heavy metals primarily affect proximal tubule, whereas fluoride ions affect Henle loop. Glomerular Injury

Disorders of glomerulus (glomerulopathies) may occur either due to degeneration without inflammatory changes or due to inflammatory reactions called glomerulonephritides. The glomerulus is the initial site of chemical exposure within the nephron. Tubular changes may affect the glomerulus. Blocking of the tubular lumen may cause urinary stasis in the nephron, distension of Browman’s capsule and atrophy and sclerosis of glomerulus. Nephroses may be glomerulonephroses and tubulnephroses. Glomerulonephroses is characterized by the degeneration of the glomeruli due to an increase in intercellular matter. In case of renal amyloidosis (renal medullary injury), a kidney is affected by amyloidosis. Amyloidosis is characterized by damaged glomeruli in which they are enlarged and contain hyaline material called “amyloid”. Proximal Tubule Injury

The proximal tubule is the most common site of toxicant-induced renal injury. The nephrotoxicants like aminoglycosides, cis-platin and metals can cause some form of degeneration accompanied by inflammatory changes, hydropic changes and tubular necrosis. Proximal tubule injury may cause non-lethal dysfunction such as mitochondrial swelling, blebbing of the endoplasmic reticulum and sloughing of proteins of the plasma membrane. Papillary Injury

The renal papilla is susceptible to the chronic injurious effects of abusive consumption of analgesic. The initial target is the medullary interstitial cells which are at risk from exposure to polyene antibiotics, cyclosporine and radiocontrast agents. Distal Tubular Injury

The important components of disital tubular nephron are the loop of Henle, the distal tubule and collecting tubule. They are all involved in the regulation of water, electrolytes and acid-base balance. The functional abnormalities at these sites manifest primarily as impaired concentrating ability and acidification defects. The toxic effects of nephroxicants are renal papillary necrosis and deposition of crystals that may enter the urine.

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10.13

10.5.2 Metal Toxicology Many metals such as cadmium, chromium, lead, gold, mercury, platinum and uranium are nephrotoxic. Metals enter the proximal tubular cells by endocytosis following the binding of the metal or a metalloprotein complex to the brushborder membrane. These metals from protein-metal complexes are released by lysosomal degradation. Low doses of certain metals cause renal tubular acidosis and ultimately death. Metals may also cause toxicity through their ability to bind to sulphydryl group of critical proteins within the cells which may inhibit their normal functions. Mercury

The kidneys are the primary target organs for accumulation of Hg2+. Organic form of mercury such as dimethyl mercury is more toxic than mercuric chloride. The acute nephrotoxicity induced by HgCl2 is characterized by proximal tubular necrosis. Mercury may act directly as a hapten and cause auto-immune diseases. Cadmium

Chronic exposure to cadmium leads to accumulation of Cd11 mainly in kidney. Cadmium damages primarily the proximal tubules. Cadmium in the kidney induces the synthesis of metallothionein in the proximal tubules. Thus, it produces proximal tubule dysfunction and injury is characterized by increasing in urinary excretion of glucose, amino acids, calcium and cellular enzymes. This may lead to a chronic interstitial nephritis.

10.6

NEUROTOXICITY (ORGAN—NERVOUS SYSTEM)

The nervous system may be classified anatomically and functionally. Anatomically, the nervous system may be classified as central nervous system (CNS) (brain and spinal cord) and peripheral nervous system (PNS). Functionally, it is divided as somatic nervous system whose function is consciously controlled and the atonomic nervous system which controls the functioning of the internal organs. The nervous system is protected from the adverse effects of many potential toxicants by an anatomic barrier. The existence of an interface between the blood and the brain is termed “blood-brain barrier”. For central nervous system it is termed blood-brain barrier and for peripheral nervous system it is “blood nerve barrier”. The PNS is less well protected than the CNS. Thus, more toxic effects are observed in PNS than CNS. The systemic exposure to toxicants that inhibit aerobic respiration which cause hypoxia, dysfunction in the myocardium and neurons. The dynamic relationships between the neuronal cell body and its axon are very important because of the responses to axonal and neuronal injuries caused by neurotoxicants.

10.14

TOXICOLOGY

10.6.1 Neurotoxic Effects Neurotoxic effects may be classified based on the site in the body where they occur. In the nervous system, there are four targets such as the neuron, the axon, the myelinating cell and the neurotransmitter system. Neurotoxicants may cause neuronopathies, axonopathies, myelinopathies, synaptopathy or neurotransmitter-associated toxicity. Neuronopathy

Neuronopathy refers to a lesion of the nerve cell body. It is defined as any functional disturbance and/or pathological change in the peripheral nervous system. The loss of neuron is irreversible and includes degeneration of all its cytoplasmic extensions, dendrites and axons. Generally, neurons are highly susceptible to damage from lack of oxygen or glucose. Thus, they are highly sensitive to carbon monoxide, cyanide and azide which block the use of oxygen by inhibition of cytochrome oxidase. There are various kinds of neuropathy caused by different neurotoxicants. Neuronal chromatolysis may be caused by methyl mercury acting on dorsal root ganglion neurons. Ultimately the entire neuron dies. (Fig. 10.7). Ethyl alcohol, lead ions, and inorganic mercury damage the dendritic processes known as dendropathy. Trimethyltin and acrylamide may cause neuronal atrophy and degeneration, and acute toxic peripheral neuropathy. Dendrites Neurilemma cells Myelin sheath

Nodes of Ranvier Nucleus

Cell body (perikaryon)

Axon

Axon terminals

Fig.10.7 Diagrammatic representation of a neuron.

Axonopathies

In axonopathies, the primary site of toxicity is the axon. The chemicals or substances like acrylamide, carbon disulphide, n-hexane, methyl n-butyl ketone and organophosphates cause axonal degeneration in the distal axons of the central and peripheral nervous systems. The longer axons have more targets for toxic damage than shorter axons, thus long axons of CNS (e.g. ascending sensory axons) is more affected by the toxic elements. The toxic effects in which the distal axon is most vulnerable are called central peripheral distal axonopathies. Myelinopathies

Myelin provides electrical insulation of neuronal processes. Myelinopathy is the destruction of myelin sheaths around the axons and is caused by triethyltin, cyanate, dichloroacetate, ethidium bromide and hexachlorophene.

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10.15

Synaptopathies

Many neurotoxicants destroy cellular structures within the nervous system. The following toxic actions may cause due to xenobiotics in synapase: • Interference with synthesis of neurotransmitter. • Alteration of cellular structure. • Impair the process of neurotransmission. • Interrupt the transmission of impulses, blocking of transynaptic communication and block reuptake of neurotransmitters. • Interference with enzymatic breakdown of unused transmitter.

10.7

RESPIRATORY TOXICOLOGY (ORGAN – LUNGS)

The respiratory tract is a very important organ in terms of toxicology as it first contacts for most environmental exposures. Lungs provide large surface area and the thin barrier between air and blood which facilitates the uptake of volatile as well as non-volatile substances. The respiratory tract consists of an airconducting (air transportation) and respiratory (exchange of gas) portions. The air-conducting portion consists of nose, pharynx, larynx, trachea and bronchi and the respiratory portion consists of alveoli. (Fig. 10.8). Trachea Superior lobes Bronchioles Primary bronchi Horizontal fissure Middle lobe Cardiac notch Interior lobes

Terminal bronchiole

Bronchiole

Pulmonary arteriole Alveolar sacs (with external capillary network) Fig.10.8 Diagrammatic representation of the respiratory tract.

The nose is the organ of the respiratory tract that is first exposed by inhaling agents. Larger dust particles are trapped by the hairs in the first part of the nose. The smaller particles settle in the inner part of the nose due to sedimentation or

10.16

TOXICOLOGY

collision. The larynx is the voice box with several cartilage structures. The trachea is the continuation of larynx which divides into two main bronchi leading to the respective left and right lungs. The principal function of lung is gas exchange which consists of ventilation, perfusion and diffusion. The important lung injury is caused by an undue oxidative burden that is mediated by free radicals, NO2, tabacco smoke, etc. The gases and vapours are absorbed over the entire respiratory system depending on solubility and reactivity of the gas with that particular site. Water solubility is the critical factor in determining how deeply a given gas penetrates into the lung. For example, highly soluble gases such as SO2 do not penetrate beyond nose and are non-toxic to animals. The removal of gases is determined by diffusion process. The clearance of deposited particles is caused by nasal clearance, pulmonary clearance, and tracheo-bronchial clearance.

10.7.1 Toxic Responses of the Lung Toxic responses may be acute or chronic. These responses are discussed as follows: Pulmonary Oedema

Pulmonary oedema is an acute toxic response in which thickening of the alveolarcapillary barrier occurs. This toxic response may affect the gas exchange processes (CO2 and O2) in the lung. After exposure to toxicants in which the alveolar-capillary surface is denuded, and in case of modest injury, recovery is readily achievable. Cell Proliferation

After acute injury, regeneration may be taking place by mitotic activity of basal cells, followed by differentiation of the proliferating cells until the epithelium has become normal. When damaged by a toxic agent, the clara cells proliferate and divide. Fibrosis

Pulmonary fibrosis contains increased amount of collagen in the alveolar interstitium, and respiratory bronchioles. Fibrosis increases the rigidity of the tissues. Emphysema

Emphysema is opposite of fibrosis. In emphysema, the respiratory part of the lungs contains cavities due to loss of alveolar structure caused by damage to the alveolar walls and fusing of alveoli. This destruction of the gas-exchange surface area results in a distended, hyperinflated lung that no longer effectively exchanges oxygen and carbon dioxide. Cigarette smoke inhalation is the major cause of emphysema.

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10.17

Pneumoconiosis

It refers to the disease and tissue reaction caused by the inhalation of inorganic dust. When the inorganic dust is the crystalline silica, it is called silicosis. Symptoms of cough and breathlessness occur in this disease. Asthma

Asthma is characterized by inflammation of the lining of the airways and intermittent spasm of the underlying smooth muscle. This disease is characterized by shortness of breath because of narrowing of the large conducting airways (bronchi) due to inhalation of provoking agents. The main symptoms in it include cough, wheeze, chest tightness and shortness of breath. Sulphur dioxide, nitrogen oxides, ozone, ammonia and chlorine are known as irritant gases and mainly responsible for human asthma. Lung Cancer

Lung cancer is the chemically induced tumours in humans. Inhalation of asbestos fibres, metallic dusts like arsenic, beryllium, cadmium, chromium and nickel are mainly responsible for cancer of the respiratory tract. Bronchial carcinoma is the main cause of death from cancer.

10.8

REPRODUCTIVE TOXICITY (REPRODUCTIVE SYSTEM)

Reproductive toxicity refers to the adverse effect of any aspect of male or female sexual function or fertility. The toxicants deteriorate the normal reproductive functions on the developing embryo or foetus or post-natally which may lead to mortality or structural and functional changes. Many xenobiotics and several environmental factors may alter the genetic determinants of gonadal sex, the hormonal detreminants of phenotypic sex, foetal gametogenesis and reproductive tract determination. In general, reproductive toxicity depends on the stage of the reproductive cycle at which the toxicant inflicts harmful effects. Thus, the reproductive toxicity may be subdivided into two ways such as: • Sexual function and fertility in both male and female. • Developmental toxicity to the embryo and foetus. Because of the complex nature of the reproductive process, it is difficult to assess the potential hazard of chemicals to reproduction. The reproductive toxicants may either cause mutations, chromosomal aberrations, altered cell division, changes in protein synthesis, and osmotic and ionic regulation.

10.8.1 Toxic Effects of Chemicals in Reproductive System The effects of different xenobiotics on the reproductive system discussed as: Gonads: Many xenobiotics and drugs target gonads. Alkylating agents, antiestrogens, etc. effectively damage the process of dividing cells. The division

10.18

TOXICOLOGY

of germ cells is also affected, leading to the arrest of spermatogenesis. The germ cells are most sensitive to chemical injury, whereas sertoli cells are observed intermediate sensitivity to chemical inhibition. Location: Location is quite related to pregnant women who are exposed to chemicals at work. In general, the chemicals that have high fat solubility, may be accumulated in breast milk and pass to the baby in potentially toxic amounts. Developmental Toxicity

Developmental toxicity refers to the interference of chemicals with the normal development. This includes embryofoetal toxicity, death, abortion, retard development, structural effects, functional effects, and pubertal development. Effects on CNS

There are certain toxicants which can modify central nervous system (CNS) which in turn alters the secretion of hypothalamic-releasing hormones and gonadotropins so that it supresses the secretion of gonadotropins and ultimately block ovulation.

10.9

CARDIOVASCULAR TOXICOLOGY (ORGAN–HEART)

Cardiovascular toxicology is related to the toxic effects of chemicals or xenobiotics on vascular system, though heart is not the usual target organ for the toxicants. Since the functional effects of heart are frequently of an acute nature, they may lead to abnormal heart function. The toxic effects such as ion homeostasis, altered blood flow, oxidative stress, organelle dysfunction, apoptosis and oncosis are observed because of injury to heart by prototypic myocardial toxicants. (Fig. 10.9) The cardiovascular system has two important parts such as myocardium and vascular vessels (arteries, capillaries, and vein). The important functions of cardiovascular system are to supply nutrients, respiratory gases, hormones, metabolites, to the tissues and carry waste products of tissues and cellular metabolism.

Fig.10.9 Human heart.

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10.19

10.9.1 Cardiotoxicity The chemical induced disturbances in cardiac function consists of chronotropism (changes in heart rate), dromotropism (in conduction), bathmotropism (in excitability) and/or inotropism (in contractility). But the most significant abnormalities are arrhythmias and contractility disturbances. The normal rhythm of the heart is produced continuously recurring impulse starting from sinoatrial node (in right atrium) and then it proceeds to the other areas of the heart in a coordinated way. In arrhythmias, this coordination of heart beat and rhythm are disturbed under the influence of antiarrhythmic agents. Cardiotoxic substances may change myocardial contractility by influencing the excitation-contraction processes. Cardiac hypertrophy is a disease which refers to an increase in heart muscle mass due to increase in the contractile elements and mitochondria. It causes systemic hypertension. Ischemic heart disease is caused by a variety of xenobiotics that disturb the balance of myocardial perfusion and myocardial oxygen and nutrient demand. Cardiomyopathies are related to the disease in which myocardial function has failed and it is chemically induced. Acute toxic effects may cause myocardial necrosis and myocarditis as a result of hypersensitivity reactions. The substances which influence the nervous system can also alter the arterial blood pressure resulting in hypo- or hypertension.

10.10

TOXIC EFFECTS ON ENDOCRINE SYSTEM (ORGAN—ENDOCRINE GLANDS)

Endocrine glands are the collections of specialized cells that produce hormones and secreted into the circulation. The most important function of endocrine system is to regulate the various metabolic processes in the body and give proper maintenance of homeostasis. The chemically induced lesions of the endocrine glands are most commonly encountered in the adrenal glands, followed by the thyroid pancreas, pituitary and parathyroid glands. The major toxic effects are observed as: • It may reduce the function of adrenal glands, to affect the renal functions. • Due to disturbance in thyroid glands, the growth of basal metabolism may be impaired. • Changes in sugar metabolism, which may be caused by reduction of pancreatic function. • Due to certain effects on gonads, it may affect the reproductive system.

10.10.1 Endocrine Toxicity The adrenal cortex of animal is very susceptible to xenobiotics to develop degenerative and proliferative lesions. Many adrenal cortical toxic compounds

10.20

TOXICOLOGY

are lipophilic and thus accumulated in these cells. The adrenal cortical cells have enzymes capable of metabolizing xenobiotic chemicals. These compounds produce necrosis. The adrenal medulla also undergoes a series of proliferative changes. There are few chemicals which selectively inhibit the secretion of thyroid hormone from thyroid glands causing goitre and subnormal function. This is known as hypothyroidism. This may be caused by either lack of iodine deficit in diet or changes in enzymatic reactions that play a role in biosynthesis of thyroid hormone. Similarly, when the thyroid gland is over-reactive, it produces and secretes surplus of thyroid hromones. This is known as hyperthyroidism.

10.11

TOXIC RESPONSE OF THE IMMUNE SYSTEM

Immunity is a homeostatic condition which describes the body defence mechanisms against harmful substances such as bacteria, viruses, parasites and malignant cells which produce infectious diseases. The basic function of immune system is the interaction of xenobiotics with the various immune components of the body and maintain the health of the body well. The toxic effects of a xenobiotic on the immune system can be characterized by qualitative and quantitative changes in the cellularity of the lymphoid organs and bone marrow. The innate immune system is the first line of defence against microorganisms and consists of large physical barrier such as skin and mucous membranes. The adaptive immunity is due to the development of specific response to antigen. Humoral immunity is a response against extracellular or soluble antigens and is initiated by antigen-presenting cells. In addition to innate immunity, there are several soluble components which become activated and secrete a variety of cytokines to protect the body from infection. This complements immunity. Cell mediated immunity refers to the immune response generated by intracellular antigens.

10.11.1 Immunotoxicology Immunotoxicolgy refers to the adverse effects caused by interactions between the various substances and the immune system. For example, drugs, metals, numerous, organic and inorganic chemicals and proteins cause problems like hypersensitivity, autoimmunity, immune suppression and immune enhancement. Immune-suppression effect of some chemicals due to their anti-proliferative effect which lowers the activity of the immune system including surveillance. Nutritional deficiencies also cause selective immunotoxic effects (e.g. zinc deficiencies may be the cause of suppression of cell-mediated immunity). Autoimmunity and all types of hypersensitivity (4 types) responses occur as a result of tolerance losses or induction of sensitivity.

TOXICOLOGY OF ORGANS AND ORGAN SYSTEMS

10.21

-:-4+151. What is dermatotoxicity? Why epidermis layer is important in terms of the penetration of xenobiotics into an organism? 2. Define the terms. (a) Percutaneous absorption (b) Hypochromasia. (c) Apoptosis (d) Amyloid. 3. What are the toxic effects of xenobiotics of the skin? 4. Differentiate between (a) Hyperpigmentation and hypopigmentation. (b) Axonopathy and Myelinopathy. 5. Discuss about the haematotoxicity. 6. What are the different mechanisms through which the toxicants may cause cell damage in liver? 7. What are the different types of liver injury? Explain them. 8. What do you mean by nephrotoxicity? 9. Explain the toxic effects of nephrotoxicants. 10. Discuss about the neurotoxicity. 11. What are the toxic effects of neurotoxicants? 12. What is reproductive toxicity? Discuss it. 13. Explain about the cardiovascular toxicity and its effects. 14. What are the different toxic effects of xenobiotics on the endocrine system?

CHAPTER

11

Biomarkers 11.1

INTRODUCTION

A biomarker may be defined as a biological response to a specific chemical exposure as well as susceptibility to its adverse effects which may help to predict the disease associated with chemical exposure. Biomarkers include measurable biochemical, cytological, immunological, physiological or molecular changes in a biological system directly or indirectly to exposure as well as measurable levels of metabolite in organs of an organism. It is particularly helpful if it can identify exposures before clinically apparent disease occurs. Biological response could apply to anything from binding to a receptor to the functioning of an ecoystem. The biomarkers may be classified as: • Biomarkers of exposure. • Biomarkers of genetic damage. • Biomarkers of susceptibility. • Biomarkers of effect The important aspects of the classification of biomarkers are to assess the toxic effects based on changes in physiological parameters in terms of health status of individual with the interaction to xenobiotics in the environment. Some important aspects of biomarkers are: • Time from which the physiology of an organism is no longer normal. • Find out the time period where the organism is able to overcome the problem. • Find out the time period where the organism is no longer able to overcome the problem. Whether the problem can be overcome by through medicinal help or not. • The point beyond which the changes are irreversible and death is final.

11.2

TOXICOLOGY

To obtain a reliable feedback of the total chemical exposure of individuals, biological monitoring and environmental monitoring must be used to complement biomarkers of exposure. Some examples of biomarkers at various organisational levels are given in Table 11.1. Table 11.1

Biomarkers at different organisational levels.

Organisaional level • Biochemical response • Effect on individual • Binding to a receptor • Physiological alteration

11.2

Biomarker Induction of mono-oxygenases Behavioural changes Nonylphenols binding to oestrogen receptor. Feminization of embryos.

ENVIRONMENTAL AND BIOLOGICAL MONITORING

Environmental monitoring aims to estimate exposure to genotoxic agents which are based on measurements of the levels of a compound present in ambient air. This monitoring has limitations that the estimation of external exposure predicts only the approximate dose received by an organism but does not give information about the respiratory minute volume or of actual uptake and metabolism, which varies from person to person. Biological monitoring is a more integrated way of estimating and evaluating an individual’s exposure. It is the better way of estimation of the quantity of a toxic substance in body organs. Because of the individual differences in absorption, bioavailability, excretion and DNA repair capabilities, the biological monitoring may be carried out in two ways such as: • Chemical analysis may be carried out to measure the internal dose of the parent compound or metabolite in blood, urine, etc. • Biological analysis of the critical dose that actually affect the body organs. Biological monitoring is not suitable for substances which produce a contact effect, such as highly irritant chemicals, such as HCl, ammonia vapour, etc. because these chemicals already produce their effects before they are absorbed.

11.3

BIOMARKERS OF EXPOSURE

Biomarkers of exposure are those that indicate exposure of the organism to the chemicals, but do not give information of the degree of adverse effect that this change causes. Biomarkers of exposure easily indicate the presence of a xenobiotic substance or its metabolites may be measured within a compartment of an organism in the absence of any adverse effect. The application of biomarkers of exposure is to predict the dose received by an individual which can then be related to changes resulting in a disease state. The biomarkers of exposure also provide very useful information on the effects of toxicants with time and

BIOMARKERS

11.3

authenticity. Generally, the biomarkers of exposures may be classified into two parts such as: • Biomarkers of exposure to carcinogens • Biomarkers of exposure to non-carcinogens. Biomarkers of Exposure to Carcinogens

Biomarkers of exposure to carcinogen is one of the most important biomarkers which involves detecting the ability of xenobiotics or carcinogens to form adducts with DNA or protein. DNA-adducts may be related to carcinogenesis which can be measured by various sensitive methods like 32P-post-labelling assays and immunochemical assays. Most of the carcinogens are electrophilic in nature which may react with nucleophilic biomacromolecules (DNA) to form adducts. These adducts can be detected by total hydrolysis of the protein to alkylated amino acids (histidine, cysteine adducts). Many carcinogens are alkylating agents. The alkylated nucleic acids are excised from DNA and excreted in urine, while haemoglobin is a useful indicator of cumulative protein modification. This biological test is helpful to detect carcinogens. The presence of adducts can also be detected by the creation of point mutation. Biomarkers of Exposure to Non-carcinogens The oxidative damage and oxidative stress are caused by exposure to a wide range of non-carcinogens such as organic oxidant, ionising radiation and fenton active catalytic metals. These exposures cause damages to proteins, lipids and nucleic acids. The toxic substances like carbon monoxide and dichloromethane form carboxyhae-moglobin in the blood sample and 3.5% carboxyhaemoglobin in the blood sample is generally taken as safe limit exposure to these toxicants. But certain alkylating agents and pesticides form adducts with amino acids in haemoglobin that can be measured from the blood sample. For example, N-aryl pesticides from sulpinic acid amine duct with cysteine-93 of > haemoglobin.

11.4

BIOMARKERS OF EFFECT

Biomarkers of effect are those which demonstrate adverse effects such as biochemical, physiological, behavioral or other changes on the organism. These toxic effects can be recognized as an established potential health impairment or disease (ATSDR, 1994). The biomarkers of effect range from those that are highly specific to those that are non-specific. For example, the inhibition of Aryl Cholinesterase (AChE) is highly specific to the organophosphorus and carbamate pesticides and the inhibition of aminolevulinic acid dehydratase (ALAD) by lead and certain other metals also considered highly specific biomarkers. A list of biomarkers with their specificity is given in Table 11.2.

11.4

TOXICOLOGY Table 11.2 Biomarkers with their specificity. Biomarker

• • •

Inhibition of brain cholinesterase (ChE) Inhibition of ALAD Eggshell thinning

• •

Induction of monooxygenases Induction of metallothionein

Specific Toxicant Organophosphate, Carbamate Insecticides. Lead 1, 1 dichloro-2, 2-bis (P-Chlorophenyl ethylene (DDE), DDT, Dicofol. Polycyclic Aromatic hydrocarbon (PAH) Cadmium

The highly non-specific biomarkers are also well validated whereas effects on the immune system can be caused by a wide variety of toxicants. For example, the induction of monooxygenases is caused by a wide variety of xenobiotics. The haem containing enzymes known as cytochromes P-450 are major components of the defences of organisms against toxic chemicals in their environment. Thus, the induction of monooxygenase activity in fish liver is generally recognized as a useful biomarker of the exposure of fish to any anthropogenic contaminants (oil spills) in the marine environment. The monooxygenase activity is shown by a wide range of species (mammals, birds and fishes), thus the biomarkers, induction of monooxygenase is very useful to many xenobiotics.

11.4.1 Biomarkers of Adverse Effects It is very important to relate the degree of change of biological response due to the adverse effect of toxicants. The relationship between the biomarker response and an adverse effect demonstrates that the organism has been sufficiently exposed) to toxicants to cause a physiological change. For example, when an organism is exposed sufficiently to the environmental pollutants, they may cause damage to DNA. These pollutants are specific genotoxic effects, especially the increase of carcinogenesis, rather than effects on the reproductive process. The another adverse effect that the behavioural changes are found at a higher orgnisational level. The behaviour of an organism represents the final integrated result of a diversity of biochemical and physiological processes. The behavioural parameters are not especially sensitive to exposure to toxicants or chemicals and that biochemical and physiological changes are usually sensitive to the toxicants.

11.5

BIOMARKERS OF GENETIC DAMAGE

Biomarkers of genetic damage are used to assess the damage caused to DNA adducts by environmental pollutants (genotoxic agents). Since the damage of DNA adducts may be mechanistically related to carcinogenesis, the use of genetic markers has become intriguing for molecular epidemiologists. The genetic markers include the alterations in chromosomal structure such as restriction fragment length polymorphism (RFLPs), loss of heterozygosity and

BIOMARKERS

11.5

translocation markers. The interaction of a xenobiotic with DNA and consequent mutation involve different stages such as: • Formation of DNA adduct. • Modification of DNA such as strand breakage. • Structural perturbations to the DNA become fixed. • Alteration of gene function. The importance of genetic biomarkers is mainly the detection of early biological responses so that it can be related the exposure to carcinogens to initiating events in the cancer process.

11.6

BIOMARKERS OF SUSCEPTIBILITY

Biomarkers of susceptibility have an important role in assessing individual differences in susceptibilities to the impacts of chemicals, physical or infectious agents. For example, the people with glucose->-phosphate dehydrogenase deficiency are more susceptible to develop anaemia upon exposure to aromatic amines. Many xenobiotic compounds inhibit the activities of the immune system and thus increase the susceptibility to infectious agents, parasites and cancer. Deficiency of =1-antitrypsin predisposes to developing emphysema. Cytochrome P-450 isoforms are responsible for several instances of altered susceptibilities. Higher affinity to aryl hydrocarbon receptor (AHR) may increase the risk of developing cancer. The people with high metabolizers of debrisoquine have an increased risk of lung cancer. Low level exposure to a cytochrome P-450 lA1 or 1A2 inducer may elevate enzyme activity which may increase the risk of a number of cancers due to increased bioactivation of procarcinogens. For example, exposure to polyaromatic hydrocarbons in cigarette may increase cytochrome P-450 (CYP) activity which may increase the activation of carcinogenic metabolites.

11.7

BIOMARKERS IN PLANTS

It is very important to analyze the impact of environmental pollutants particularly air pollutants on plant functions. Some specific biomarkers have been identified in sensitive plants. For example, in the presence of excess selenium, the Sesensitive plants die because of the incorporation of Se in sulphur amino acids leads to the synthesis of enzymes of lower activity. Similarly, exposure to excess fluor (a mineral containing flourine), plants synthesize fluoroacetyl CoA and then convert it to fluorcitrate that blocks the metabolic pathways by inhibiting the enzyme aconite. The activity of the enzyme peroxidase is used to establish the exposure of plants to air pollution, particularly sulphur dioxide (SO2). In a few cases it is known that excess of a specific chemical will give rise to the production of a metabolite which is different between tolerant and sensitive plants. For example, phytochelatins are synthesized during exposure to a number

11.6

TOXICOLOGY

of heavy metals such as cadmium, copper and zinc and exposure to anions like Se O24–, Se O23– and As O3– 4 .

11.8

SIGNIFICANCE OF BIOMARKERS

The most significance of biomarkers is that they provide very useful and authentic information on the effects of pollutants in the environment. But care must be taken in interpretation of biomarkers that the same chemical may induce different proteins in one species and other with another species. Based on the information of biomarkers, effective remedial action can be taken, thus the monitoring programme has to be very effective. The other important significance of biomarkers is their ability to integrate multiple chemical exposures across an area with numerous chemical contaminants, which is very critical at most chemical waste sites. It has been recognized as the biomarkers are the better tools for predicting environmental and genetic risk which are of great help to take remedial measures. The biomarkers are having great significance in hazard assessment. Because, the basic approach of hazard assessment is to measure the amount of the chemical present and then relate that to the adverse effects caused by a particular amount of chemicals. For example, chemicals such as Polycyclic Aromatic Hydrocarbons (PAH) and many pesticides have very short biological half lives in most species but may have long-term effects. Thus, the biological and chemical monitoring systems should be complementary to each other. The role of biomarkers in environmental assessment is envisaged as determining about a specific environment whether a particular organism or organisms are physiologically normal or not. Both specific and non- specific biomarkers are valuable in environmental assessment. These biomarkers indicate about the exposure to chemicals, and to assess the hazard of all major classes of pollutants and non-specific biomarkers that assess accurately and completely the health of the organism and its ecosystem.

EXERCISE 1. 2. 3. 4.

What is biomarker? What are the different types of biomarkers? What are the important functions of biomarkers? What are aims and objectives of environmental monitouring? How do you monitor it? 5. Write short notes on: (a) Biomarkers in plants. (b) Biomarkers of effect. (c) Biomarkers of exposure.

CHAPTER

12

Evaluation of Toxicity and Risk Assessment 12.1

INTRODUCTION

The general principle of toxicology and ecotoxicolgy is to correlate the quantity of chemicals or toxicants to which an organism is exposed and the nature and degree of consequent harmful effects. Toxicity evaluation is the determination of the potential of any xenobiotics or chemicals to act as a poison, the conditions under which this potential will be felt and the characterization of its action. The dose-response relationships provide the basis for assessment of hazards and risk presented by environmental pollutants. Most of the toxic evaluations can be subdivided into in vivo tests for acute, chronic or subchronic effects and in vivo tests for genotoxicity. There are two major objectives of toxicity evaluation such as: (i) To prepare a toxicological profile of the chemicals or toxicants and to find out whether that toxicant is genotoxic carcinogen, a tetratogen or a nephrotoxic agent. (ii) To identify a dose below (threshold point) which the toxic effects of concerned chemical does not occur. Thus, the general principle of toxic evaluation is to prepare the toxicological profile and the dose without any effect which are the first stages in hazard identification and risk assessment. Risk assessment is defined as the systematic scientific characterization of potential adverse health effects resulting from exposure to hazardous agents or situation (NRC 1994). Thus, risk assessment is a qualitative and quantitative assessment of the probability of deleterious effects under given conditions.

12.2 12.2

TOXICOLOGY

CHEMICAL AND PHYSICAL PROPERTIES (STRUCTURE/ACTIVITY RELATIONSHIPS)

For the toxicity testing, it is essential to obtain the information regarding chemical and physical properties of the concerned chemicals as given below. The structure, solubility, stability, pH, sensitivity, electrophilicity, volatility and chemical reactivity can provide important information for hazard identification. Based on physical and chemical properties, a chemical can enter a living organism by one or more routes of uptake. For example, the most lipophilic compounds absorption from the guts of vertebrates is faster than absorption from the skin. Thus, the toxicity level is usually higher with oral administration than with topical application. The structure-activity relationships are very useful for assessment of complex mixtures. The toxicity estimation of environmental mixtures containing 2, 3, 7, 8-tetra chloro dibenzo-p-dioxin (TCDD) and related chlorinated and brominated dibenzo-p-dioxins, dibenzofurans and planar biphenyls was calculated as the sum of the product of the concentration of each multiplied by its toxicity equivalence factors (TEFs). The different species have different susceptibility to the toxic action of some chemicals. The selective toxicity is applied in this case but taking a limited number of species. Selective ratio =

Median lethal dose for species A Median lethal dose for species B

Median lethal dose is expressed as LD50 which will cause a toxic effect at the 50% level, i.e., the dose that will kill 50% of a population.

12.3

IN VIVO AND SHORT-TERM TESTS

Most of the toxicity testing is carried out on experimental animals because human data is difficult to obtain experimentally because of the deleterious effects. In the experimental testing of the toxicity of concerned chemical, the suspected chemical has been administered into one or more species and then the animal is subjected for acute tests or chronic tests. The results are used by a variety of extrapolation techniques to determine the toxic effects to humans. The validation and application of in vivo and short-term test is particularly important to risk assessment because such tests can be designed to provide information about mechanisms of effects. But these tests require sensitivity (ability to identify accurately), specificity (ability to recognize the specific problem) and predictive value for the toxic end point under evaluation.

EVALUATION OF TOXICITY AND RISK ASSESSMENT

12.3

12.3.1 Acute Toxicity Tests The acute toxicity of chemicals to mammals, birds and other vertebrates is usually concerned with lethality through the estimation of LD50 or LC50. The use of animal bioassay data is a key component of the hazard identification process. The basic principle of risk assessment is that the chemicals that cause tumours in animals can also cause the same effects on humans. LD50 and LC50 In normal toxicity testing, a single dose is given orally to obtain an estimate of acute oral LD50. The LD50 is the estimated dose that when the test chemicals over a range of value is administered directly to groups of test animals, results in the death of 50% of the population over a fixed period of exposure under the defined conditions of the test. It can be obtained by plotting the percentage of mortality against the log of the dose (mg kg–1) Fig. 12.1. Similarly, LC50 is the estimated concentration in the environment that the test animals are exposed for a fixed period that will kill 50% of the population so exposed under the defined conditions of the test. 100 80

% mortality

70 60 50 40 30 20 10

LD5

0

0 10

100

1000

–1

Dosage (mg kg ) log scale

Fig. 12.1 Determination of LD50.

12.3.2 Chronic Toxicity Tests Chronic tests are those conducted over the greater part of the lifespan of the test animal. Chronic toxicity tests are performed to assess the cumulative toxicity of chemicals. These studies usually are performed in rats and mice and extend over the average lifetime of the species. Chronic toxicity assays are commonly used to evaluate the potential oncogenicity of test substances. (Huff, 1999). The maximum doses for use in chronic animal toxicity testing is performed where the basic human pharmacokinetic data are available. The important chronic toxicity tests are carcinogenicity, teratogenicity, mutagenicity and reproductive toxicity.

12.4

TOXICOLOGY

12.3.3 Carcinogenicity Tests Carcinogenicity tests refer to long-term test designed to detect any possible carcinogenic effect of a test substance (toxicants). Recently a new approach has been designed for carcinogenicity testing in which the carcinogens are being administered or exposed to rats and mice for about 6 months to 2 years. This studies on non-rodent species are usually for 1 year. For this purpose, 50 male and 50 female animals per group are dosed with the test agent in that vehicle. All animals that survive the schedule end of the experiment are subjected to autopsy and observations are made. Dose selection is critical in these studies to ensure that premature mortality from carcinogenicity does not limit the number of animals that survive to normal life expectancy. This is called Maximum Tolerated Dose (MTD) determination. The MTD is defined as the highest dose that can be predicted not to alter the animals normal longetivity from effects other than carcinogenicity. Some regulatory agencies have defined MTD as the dose that suppresses body weight gain slightly (10%) in 5 months preliminary test.

12.3.4 Mutagenicity Tests (Ames test) Mutagenesis is the ability of chemicals to cause changes in the genetic material in the nucleus of cells so that changes may be transmitted during the cell division. The best known mutagenicity test is the ‘Ames test’ in which certain bacterial strains of Salmonella typhimurium are used. These strains lack the enzyme phosphoribosyl ATP synthetase, which is required for histidine synthesis. These strains will not grow in the absence of histidine but can be caused to mutate back to the wild type which can synthesize histidine and hence can grow in its absence. The choice of a specific strain will determine the sensitivity of the test. Thus, more sensitive strains such as TA-100 (single point mutations) and TA-98 (frameshift mutations) are used. Strains have also been selected with DNA base repair-deficient showing a low repair rate. The sensitivity of these strains is therefore very high. Since many chemicals are not mutagenic or carcinogenic unless they are biotransformed to a toxic product by enzymes in the endoplasmic reticulum. The value of mutagenicity tests in carcinogens is characterized on the basis of sensitivity, specificity and predictive value. Sensitivity =

Number of carcinogens positive in the test Total number of carcinogens in the test

Specificity =

Number of non-carcinogens negative in the test Total number of non-carcinogens in the test

Productive value =

Number of carcinogens positive in the test Total number of positive carcinogens in the test

EVALUATION OF TOXICITY AND RISK ASSESSMENT

12.5

12.3.5 Reproductive Toxicity Tests Reproductive toxicity is defined as the identification of substances which have an effect on the normal course of reproduction. These substances may exert their adverse effects in the male or female reproductive system during the various stages such as formation of germ cells, conception, embryonic development, foetal stages, etc. A number of animal tests are used to examine the potential of an agent to alter reproduction. Some of the important tests are: • General fertility and reproductive performance (single generation) tests are usually carried out on rats with two or three doses. 20 males are treated with the test compound for 60 days prior to mating and 20 females are treated for 14 days prior to mating. The animals are given the chemical throughout gestation and lactation period. Then animals are kept on constant observation and analysis. The high dose which fails to cause any maternal toxicity, can be considered in low dose of that drug to humans so that there will be no measurable toxicity. This information is derived from animal models and this can be an indication of the harmfulness of a substance to man. • General fertility and reproductive performance (multigeneration) tests of the potential chemicals to disrupt normal embryonic and/or foetal development (teratogenic effects) are also carried out in rodents, usually rats. In this test usually two species are considered, the other non-rodent species is usually rabbits. The test compound is administered into the males and females of test animals from weaning of first generation to third generation. The dose is considered low when there is no toxic effects in the first generation and in case of high dose one-tenth of LD50 will be affected in weaning generation. Similar tests and observations are carried out up to three generations to evaluate information on following end points. • Fertitity index • The number of live births to total births. • Gross deformities at birth • Internal changes at weaning. • Inernal changes in 2nd and 3rd generation.

12.3.6 Teratogenicity Tests In teratogenic testing, usually two species one from rodent (rats) and other from non-rodent (rabbits) are taken for exposure to the test chemical which may be carried out from implantation to parturition. Teratogens are more effective when it is administered during the period of organogenesis, which is considered the most sensitive period for inducing structural malformations. Thus, the animals are usually exposed to one of three

12.6

TOXICOLOGY

dosages during organogenesis and observations may be made immediately prior to birth. The low dose is considered when there is no maternal toxicity. The maternal toxicity is evaluated from the parameters like body weight, food consumption, clinical sign and organ weight. The live foetuses will also be taken for examining the skeletal abnormalities and soft tissue anomalies.

12.4

SUBCHRONIC TESTS

Subchronic tests examine toxicity caused by repeated dosing over a period of time. Such subchronic exposure can last for different periods of time, but 90 days is the most common test duration. The main objective of the subchronic test is to establish a no-observed adverse effect level (NOAEL). The NOAEL is important because it is the first parameter for use in the risk assessment. This value is often defined as the highest dose level at which no deleterious or abnormal effect can be measured. The other aim of subchronic test is to identify and characterize the specific organ or organ affected by the test compound after repeated administration. A subchronic test is usually conducted in two species like rats and dogs through exposure to tested compounds. At least three doses are employed such as high, intermediate and low dose. The highest should produce toxicity but no high mertality whereas low dose should not have any effects and no mortality. The intermediate doses should have the effects between high and low doses. After completing the subchronic tests, the information obtained from the tests are generally used for NOAEL and lowest observed adverse effect level (LOAEL).

12.5

TOXICITY RATINGS

Toxicity rating are used to estimate the toxic effects of various substances to humans. Their ratings or ranks range from 1 (non-toxic) to 6 (supertoxic). Toxicity ranking or ratings may be measured as: The toxic potential = where

1 H ´ LC 50 (or LD 50 )

LC50 ® Lethat concentration H ® Henry’s law constant.

In case of aqueous medium H=

Vapour pressure (Atm) Water solubility (mol/m3 )

From the toxic potential data, it is characterized as the lower the value less is the toxic effect and the greater the toxic potential value, more is the toxic effect. From the above equation, it is found that when there is a substantial difference

EVALUATION OF TOXICITY AND RISK ASSESSMENT

12.7

between LD50 or LC50 value of two different substances, the substance with the lower value is said to be having more toxic potential (Table 12.1). Table 12.1

Toxic rating or ranking.

Approximate LD50/LC50

1 (non-toxic)

4

10

2 (slightly toxic)

103

3 (moderately toxic)

102

4 (very toxic)

10

10 1

12.6

Toxicity ratings

5

5 (extremely toxic) 6 (supertoxic)

RISK ASSESSMENT

Risk assessment is the systemic scientific characterization of potential adverse health effects from exposure to hazardous agents or situations which is essentially a preliminary to setting up proper risk management procedures. Risk is defined as the probability of an adverse effect in an organism, system or population caused under specified circumstances by exposure to an agent. The risk assessment involves three steps such as: • Hazard identification • Characterization of hazards • Characterization of risk.

12.6.1 Hazard Identification Hazard is defined as the biological property of the chemical in its interaction with the affected species. The structure, solubility, stability, pH, sensitivity, electrophilicity, volatility and chemical reactive of a chemical substance are very important for hazard identification. In hazard identification, the ranking of compounds according to their toxicity is important as mentioned earlier. If the toxicity is very low, then the compound is not considered hazardous.

12.6.2 Hazard Characterization Characterization of hazard is the quantitative and qualitative analysis of toxic potential of a chemical. It is used to determine the persistency of chemical in the environment, bioaccumulative power of a chemical, and the degree of toxicity. The hazard information is set against predetermined criteria and is set to determine the safe exposure. In the characterisation of hazardous chemicals, the International Agency for Research on Cancer (IARC) classified the carcinogens as:

12.8 • • • • •

TOXICOLOGY

Group I Group IIA Group IIB Group III Group IV

® ® ® ® ®

Definitely carcinogenic to humans. Probably carcinogenic to humans. Possibly carcinogenic to humans. It is not classifiable as carcinogenic to humans. Probably it is not carcinogenic to humans.

Depending on the circumstances, the hazard characterisation may be used for one of the four different purposes. These are: • It has to be determined that whether a particular chemical is persistent, bioaccumulative and toxic (PBT), or very persistent and very bioaccumulative (VP B). Then the evaluation and management of the environmental risk that the chemical may pose should be an important priority (Table 12.2). Table 12.2 EU criteria for identifying PBT and vPvB chemicals (TGD, 2003). Criterion P

B T

PBT criteria Half life > 60 d in marine water or > 40 d in freshwater or half life >180 d in marine sediment or >120 d in freshwater sediment Biological concentration factor > 2 000 Chronic NOEC < 0.01 mg/L or CMR (carcinogenic category 1 and 2, mutagenic category 1 or 2, toxic to reproduction categories 1, 2 and 3) or endocrine disrupting effects

vPvB criteria Half life > 60 d in marine or freshwater or > 180 d in marine or freshwater sediment Biological concentration factor > 5 000 Not applicable

• Development of exposure standards by setting the information against a predetermined risk evaluation procedure and developing a maximum ‘safe’ exposure. • Setting of the hazard characterization against exposure information to determine a margin of exposure (safety). • The hazard information must be classified and labelled for examining management during transport (UNECE, 2003 a) or through the supply chain (safety data sheets and labels; the globally harmonised system”, UNECE, 2003 b). The quantitative and qualitative description of an agent having the potential to cause adverse effects are well known from the interaction between a chemical and a receptor is the critical interaction for a toxic effect to take place. The chemical has to be released from the source (point or diffuse), pass through one or several media such as air, water, soil and food and reach at the receptor for the interaction to take place.

EVALUATION OF TOXICITY AND RISK ASSESSMENT

12.9

There are simple models which describe the dispersion of toxicants from the source, transport through the medium (air, water, soil and foodstuffs) and transfer between media as well as the models of intake. These models can be classified as (IPCS, 1999): • Simple dilution models: In these models a measured concentration in an effluent is divided by a dilution factor or the chemical release rate is divided by the bulk flow rate of the medium. • Equilibrium models: These models predict the distribution of a chemical in the environment based on partitioning ratios or pugacity (the escaping tendency of a chemical from one environmental phase to another). • Dispersion models: These models predict reductions in concentrations from point sources, based on assumed mathematical functions or dispersion properties of the chemical. • Transport models: These models predict concentration changes over distances that can represent dispersion, biochemical degradation and absorption. The human exposure routes through the environmental medium and the risk assessment due to exposure to toxicants are shown in Figs. 12.2 and 12.3. Air Crops Meat Soil

Animals Milk

Humans

Source Surface water

Fish Drinking water

Groundwater

Fig. 12.2 Schematic representation of human exposure routes via the environment. Environmental routes ; transfer between environmental ; intake through food chain compartments Major accident hazard Accidental Small scale loss of control Deliberate (drug, cosmetic,food/additives) Anticipatable

Direct incidental (occupational, consumer product) Indirect incidental (via the environment or diet)

Fig. 12.3

Potential exposure scenarios for consideration in human risk assessment

12.10

TOXICOLOGY

12.6.3

Risk Characterization

Risk characterization is the combination of evaluation and integration of the major scientific evidence, reasoning and conclusions of risk assessment. The quantitative characterization of risk includes dose-response assessment, exposure assessment and variation in susceptibility. This is the point when the hazard characterization and exposure assessment are combined. Dose-response assessment The characteristics of exposure and the spectrum of effects are correlated to each other biochemically, the relationship is referred to as the dose-response relationship. The dose-response assessment includes the identification of no-observed adverse effect level (NOAEL) or lowest observed adverse effect levels (LOAEL). NOAELs are generally used for risk assessment calculations such as Acceptable Daily Intake (ADI), References doses (RfDs) or References concentration (RfCs). The ADI is defined as an estimate of the amount of substance, expressed in terms of body weight, that can be ingested over a lifetime without appreciable health risk. ADI =

NOAEL mg ´ kg/person/day Safety factor

NOAEL values have also been utilized for risk assessment evaluating a margin of exposure (MOE). Low value of MOE indicates that the human levels exposure are close to levels for the NOAEL in animals. Exposure assessment The exposure assessment involves a screening step and a quantitative exposure assessment. The major objectives of exposure assessment are as follows: • To identify the source of contact with the toxicants. • To classify the types of contact with the toxicants. • To measure the magnitude of contact with the toxicants. • To estimate the duration of contact with the toxicants. Variation in susceptibility Generally, the genetic traits, sex and age, preexisting diseases and coexisting exposures influence the susceptibility of the organisms to the environmental exposure. The ecogenetic surveys identifying inherited variation in susceptibility to specific exposures such as pesticides, food, additives, sensitizing effects and infectious agents.

12.7

RISK MANAGEMENT

The important objective of risk management is to ensure that risks associated with the hazard are minimized and it involves three elements as per OECD, 2003. • risk evaluation • emission and exposure control • risk monitoring

EVALUATION OF TOXICITY AND RISK ASSESSMENT

12.7.1

12.11

Risk Evaluation

The risk evaluation may be defined as the qualitative and quantitative relationship between risks and benefits of exposure to an agent is established through determining the significance of the identified hazards and the risk of adverse effects of the hazards to the system concerned. At the time of evaluation of risk, the primary objective is to achieve low levels of risk. The upper limit of intake hazards should not exceed for any individual. The clear guidelines may be given for intake and uptake so that tolerable region may be achieved. The tolerable region refers to the area where the individual or group of individuals are prepared to tolerate the risk in order to secure benefits from the environment. Reference doses (RfD) or concentrations (RfC) are estimated of the daily exposure to an agent that is likely to be without deleterious effect even if continued exposure occurs over a lifetime. Reference dose (RfD) =

NOAEL (or) LOAEL Uncertainty and modifying factors

The uncertainty and modifying factors may be determined from the data or information collected on: • • • •

Nature of toxicity. Inter-individual variation in humans. Duration of study. Quality of data collected.

The risk evaluation criteria is based on the risk characterization ratio (RCR), which depends on the predicted exposure concentration (PEC) and the predicted no effect concentration (PNEC) Risk characterization Ratio (RCR) = If

PEC PNEC

PEC < 1 then there is little concern for the particular end point. PNEC PEC > 1 then it is likely that further information may be required. PNEC

A schematic representation of the environmental risk evaluation process is given in Fig. 12.4.

12.12

TOXICOLOGY Hazard identification Determination of PEC

Determination of PNEC

PEC/PNEC >1

Can further information/testing lower PEC/PNEC ratio

At present no need for further testing or risk reduction measures

Initiate monitoring programmes to evaluate environmental concentrations

Yes

Perform long term tests. bioaccumulation tests or tests with species from other trophic levels

Obtain additional information on exposures emissions. fate parameters or measured concentrations

Initiate monitoring programmes to evaluate environmental concentrations

PEC/PNEC > 1

At present no need for further testing or risk reduction measures

Fig. 12.4 Schematic representation of the environmental risk evaluation process (from TGD, 2003 with minor modification)

12.7.2 Risk Monitoring In risk monitoring, all measures must be taken to ensure that the risks are kept as low as possible and make it zero tolerance. Safety standards, safety precautions and recommendations strictly followed so that the aim of the risk management is achieved. Risk monitoring procedures are intended to cover the best requirements so that there is a benefit associated with it. The best available technique and the best practicable environmental option are the important requirements for risk monitoring. The risk monitoring can lead to find multiple standards which in turn will be helpful for achieving an equity-based “broadly acceptable risk”. Risk monitoring helps at eliminating use of or exposure to that chemical and/or remediation of the damage caused by that chemical.

12.7.3 Emission and Exposure Control The approach to controlling risks associated with the emission and exposure of chemicals or toxicants to the humans may be achieved efficiently through the following ways:

EVALUATION OF TOXICITY AND RISK ASSESSMENT

12.13

• Substitution: Substitution is a process in which less risky process or chemical is used. Ensure the low toxicity of chemicals before using them. • Engineering control: In this process, the less efficient techniques may be changed to prevent/reduce exposure and/or minimise emissions. • Personal protective equipment: It includes the personal usable things like clothings, gloves, masks and footwares to prevent exposure to various chemicals. In general, principle substitution is preferred to engineering control, which is preferred to protective equipment.

-:-4+151. What are main objectives of toxicity evaluations? 2. What are the chemical and physical properties essential for the toxicity evaluation? 3. Write short notes on: (a) Selective ratio. (b) Toxicity rating. (c) Dose-response assessment. (d) Risk characterization ratio (RCR). (e) Risk monitoring. 4. Differentiate between (a) Acute and chronic tests. (b) Carcinogenicity and teratogenicity tests. (c) Sensitivity and specificity. 5. Discuss about the mutagenicity test. 6. What is reproductive toxicity test? Explain about some of the important tests. 7. Explain about the sub-chronic tests. 8. What are the different steps involved in risk assessment? Explain them. 9. Explain about the hazard characterization. What are the important significances of it? 10. What is risk characterization and its importance? 11. Write notes on risk management. 12. Explain about the emission and exposure control of toxicants.

CHAPTER

!

Air Pollution 13.1

INTRODUCTION

Air pollution refers to the occurrence of an unwanted change in physical, chemical or biological conditions of atmospheric air that adversely affects the health, survival or activities of living organisms or that alters the environment in undesirable ways. The unwanted changes occur due to the action or presence of pollutant. Atmosphere is the fastest moving gaseous medium in the environment, therefore, atmosphere is considered the most convenient place to dispose of unwanted gaseous or particulate wastes. Atmosphere is the greatest sink for air pollutants. The problems due to pollutants are observed when the amount of air pollutants (gaseous and or particulates) of the ambient air (the air immediately arround us) exceeds the ability of the atmosphere to disperse or degrade the pollutants. The air-contaminant emissions and ambient air contaminate concentrations can be measured in a number of ways. The Environmental Protection Agency has recommended the following units for particulates and gaseous pollutants. Gaseous pollutants are to be given in a mass per unit volume as mg/m3. The volume concentration is usually measured in terms of parts per million (ppm) or parts per billion (ppb.) Parts per million (ppm) can be converted to mass per unit volume mg/m3 by using the following equation. ppm ´ g mole ´ 10 3 mg/m = L / mol. Particulate fallout may be expressed as milligrams per square centimeter per unit time interval (mg/cm2 sec). In particulate counting, it is expressed as million particles per cubic meter of gas (106/m3). Excessive pollutant concentrations cause adverse effects. except for global air quality issues, the regional air quality issues are relatively short. The major 3

13.2

TOXICOLOGY

concern of the air pollution is its effect on the living organisms. Air pollution includes both inorganic and organic pollutants of various kinds but they have a strong relationship in the atmosphere. Usually, much attention with respect to air pollution is given to the troposphere as the living organisms are found in this sphere. The factors, such as temperature, wind movement, humidity, pressure, influencing atmospheric composition and their effects on the concentration and on the air pollutants have already been discussed in the chapter 6.

13.2

SOURCES OF AIR POLLUTION

The sources of air pollution may be natural and/or anthropogenic (man-made). Natural sources of air pollution include pollen, fungi spores, salt spray, smoke, dust particles from natural activities like volcanoes, earthquakes, landslides, forest fire, cyclone, tsunami, etc. The chemical gases like carbon monoxide (CO), carbon dioxide, (CO2), methane (CH4), hydrogen sulphide (H2S), chlorine, etc., emitted from volcanic and forest fire activities are also reponsible for air pollution. The anaerobic decomposition of organic matter also releases gases like methane (CH4) and hydrogen sulphide (H2S) into the atmosphere. Generally, the concentration of pollutants released from the natural sources are quite high in comparison to the concentrations of pollutants released from anthropogenic sources. The anthropogenic sources of air pollution are industries, road and railways construction sites, transportation, domestic and commercial activities. Both the natural and anthropogenic air pollution sources may be grouped into two major sources known as stationary sources and mobile sources (Fig. 13.1). The stationary sources refer to those sources which have a relatively fixed location. The stationary sources can be further grouped into three categories such as: • Point sources • Fugitive sources, and • Area sources. Point sources emit the air pollutants into the atmosphere from a fixed point like smoke-stacks and chimneys of power plants, steel plants and other industrial set-ups. Fugitive sources refer to those stationary sources where the location is fixed but it is open to the other environmental forces like wind, water, etc. For example, construction of roads, buildings, commercial and residential complexes, surface mines, open garbage dumping grounds and other exposed areas from which particulates may be removed by wind. Area sources are the well defined areas like industrial sites, mining areas, agricultural lands, urban set-up from which air pollutants are emitted into the atmosphere. Mobile sources refer to the sources that emit air pollutants while in the moving state. For example, the automobiles, train engines, aeroplanes, ships, buses, trucks and other vehicles exhaust air pollutants into the atmosphere while

A IR POLLUTION

13.3

moving. The total anthropogenic emissions of air pollutants have been increased tremendously may be due to the high population growth and its sustenance, the human activities like rapid industrialization, urbanization, deforestation, modern agricultural practices, luxurious lifestyle have also increased simultaneously. These activities lead to the exploitation of natural resources. Thus, there is a degradation in environmental qualities. These human activities also give birth to new sources of air pollution. SOURCES OF AIR POLLUTION

Natural Sources Volcanoes Earthquakes Cyclones Forest fires Land slides

Anthropogenic Sources

Stationary Sources

Mobile Source Roadways Aircraft Railways Ships

Point Source Fugitive Area Sources Chimneys Construction sites Industrial sites Smoke stacks Storage sites Urban set ups Surface mines Mining areas Agricultural areas

Fig. 13.1 Different sources of air pollution.

13.3

TYPES OF AIR POLLUTANT

Air pollutants, in general terms, can be defined as any factor that has a harmful effect on living organisms or their environment, due to inhalation or in contact with atmospheric air. All the air pollutants may be classified based on their origin, chemical composition, state of matter, and concentration and toxicity of the pollutants in the atmosphere. Based on Origin

Based on the origin, these air pollutants are divided into two main groups known as primary and secondary pollutants. Primary pollutants are those emitted directly into the air from the source itself. Primary pollutants such as particulates, sulfur dioxide, (SO2), nitrogen oxides (NOx), carbon monoxide (CO) and hydrocarbons (HC) are directly emitted to the atmosphere and remain in the same state in which they were emitted from the sources. Secondary pollutants are produced through the reactions between primary pollutants and normal atmospheric compounds like moisture, and oxygen. For example, ozone (O3) and peroxy-acetyl Nitrate (PAN) are formed in the atmosphere by photochemical or hydrolysis or by redox reactions.

13.4

TOXICOLOGY

Based on Chemical Composition

Both the primary and secondary pollutants may be classified into two major groups based on their chemical composition such as organic or inorganic pollutants. Organic pollutants contain major share of carbon and hydrogen and to some extent other elements like oxygen, nitrogen, sulfur and phosphorus. For example, hydrocarbons (HC), aldehydes, ketones and volatile organic compounds (VOCs) like alcohol, esters, ethers, etc. Inorganic pollutants include carbon monoxide, carbon dioxide, sulfur (oxides) (SOx), nitrogen oxides (NOx), hydrogen sulfides (H2S), hydrogen fluoride (HF) and hydrogen chlorides (HCl). Based on States of Matter

The air pollutants may be classified as gaseous and particulate pollutants based on states of matter. Gaseous pollutants are completely present in the gaseous form in the atmosphere and will have the behaviour of gases. These pollutants are carbon monoxide, carbon dioxide, sulfur oxides, nitrogen oxides and hydrocarbons. The particulate pollutants are present in the form of both solids and liquids. These pollutants include dust, smoke, aerosols, ash, mist, salt spray, liquid droplets. Particulate pollutants have the characteristics of settling out of the atmosphere. Based on Concentration

The air pollutants may be classified into two major groups based on the concentration and effect of pollutants on human health and their environment. These are known as: • Conventional or Criteria Pollutants • Unconventional or Non-criteria Pollutants. Criteria or Conventional Pollutants

Criteria pollutants are designated to major seven pollutants for which maximum ambient air levels are mandated. The areas or localities that meet the maximum ambient air levels are known as attainment areas. these seven conventional or criteria pollutants are sulfur dioxide (SO2), carbon monoxide (CO), hydrocarbons (HC), nitrogen oxides (NOx), photochemical oxidants, lead (Pb), and particulates. These are placed as criteria pollutants because pollutants contribute the largest volume of air-quality degradation and also are considered the most serious threat of all air pollutants to human health and their welfare. These are very common air pollutants and have no adverse effect if their concentration is below the threshold level. Non-criteria Pollutants

The non-criteria or unconventional pollutants are also considered hazardous air pollutants (HAP). Most of these pollutants have anthropogenic source of origin. They are present in low concentration in the atmosphere but their effects are serious. These pollutants include asbestos, benzene, arsenic, beryllium,

A IR POLLUTION

13.5

mercury, polychlorinated biphenyls (PCBs), vinyl chlorides, formaldehydes, dioxins, cadmium and ethylene oxides. The non-criteria pollutants need special attention as most of these are suspected carcinogens or develop birth defects or reproductive problems. The anthropogenic sources or criteria pollutants are shown in Fig. 13.2(a) and (b). 100

N ® Natural A ® Anthropogenic

A

90

N

N

N

N

80 70 e In percantage (%)

N 60 50

A

A

N

40 30

A

20 A 10

A

A SOX

N NOX

CO

HC

Particulates (Lead)

VOC

Fig. 13.2(a) Major natural and anthropogenic sources of criteria pollutants.

Others Industry

Electric utilities

Sulphur dioxide Other Transportation

Solvents

Non road VOC

Paved road

Unpaved road

Agriculture Construction Others Particulate material Fig. Cond.

13.6

TOXICOLOGY

Fig. Cond. Metals

Solvents waste disposal

Others Transportation

Non road engineers

Carbon monoxide

Others

Waste Transportation

Metals Lead

Industry

Non road

Power plants

Others Transportation

Nitrogen oxide

Fig. 13.2(b) Major air pollutants.

13.4

SOME MAJOR AIR POLLUTANTS AND THEIR EFFECTS

Criteria pollutants are the major concern as they have adverse health effects. Based on these criteria pollutants, the primary and secondary standards have been established. Primary standards are set at levels necessary to protect public health whereas secondary standards are designed to protect the public welfare and the environment from known or anticipated adverse effects of pollutants (Fig.13.2c). Ozone Depletion Global warming

CFC

Acid rain

CH4

SO2

CO

NO

SO2

CO2

Smog

Cutting trees

Motor Vehicle

Fig. 13.2(c)

Effects on air.

Fridge

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13.7

Now let us study these pollutants to observe their effects and behaviour. Before discussing individual pollutant, the effects of pollutants in combination may be broadly grouped into three categories. • Additive effects: The combination of two or more chemicals results into the additive effects where the combined toxicity can be predicted simply by adding their toxicities (1 + 1 = 2). • Synergistic effects: The interaction between two chemicals becomes more toxic than can be predicted (1 + 1 = > 2). Therefore, synergism is an important concept in considering pollution problems. • Antagonistic effects: The results when the toxicity of one of the chemicals is reduced by the other making the combination less toxic than can be predicted (1 + 1 = < 2).

13.5

PROPERTIES OF POLLUTANTS

Carbon Monoxide Carbon monoxide is a colourless, odourless and tasteless gas with boiling point (–192°C). It is not irritating but even in very low concentration it is extremely toxic to humans and other animals. It is 96.5% as heavy as air and is not soluble in water. Approximately 90% of carbon monoxide in the atmosphere comes from natural sources and other 10% by the activities of human. This toxic gas is produced by: (a) Incomplete combustion of fuel, i.e., coal, oil, gas, charcoal, etc.: 2C + O2 ® 2CO It is also produced in a similar way by the incineration of biomass or solid waste. (b) In industrial process by the reaction between CO2 and carbon containing materials as: CO2 + C ® 2CO (c) Dissociation of CO2 at high temperature: CO2 CO + O The rate of oxidation of carbon monoxide to carbon dioxide in the atmosphere is very slow (residential time is about six months). Toxic effect: The high toxicity results from a striking physiological effect because of its strong affinity toward the haemoglobin of the blood stream (250 times more rapidly than oxygen) and is a dangerous asphyxiant. CO is hazardous to the human beings with heart disease, anemia, or respiratory problems. To some extent it may cause birth defects, mental retardation, etc. Concentration profile: About 90% of the CO in the air is consumed in photochemical reactions. The soil is the natural sink for atmospheric CO, but it is not uniformly distributed.

13.8

TOXICOLOGY

Carbon Dioxide

Carbon dioxide is not a conventional pollutant as it is usually considered nontoxic and innocuous. The predominate form of carbon in the atmosphere is carbon dioxide (CO2) which is abundant in the air due to human activities. It is produced by burning of fossil fuels and biomass whose contribution is about 4.3% per year. More than 90% of CO2 emitted per year is from respiration system of plant and animal cells. The high rate of carbon dioxide emissions is due to high population growth, deforestation, increase of automobiles, etc. Toxic effect: CO2 gas is considered nontoxic but approximately 50% to 60% of the anthropogenic greenhouse effect is attributed to CO2 gas, i.e, the average global temperature increases considerably which is a serious threat to earth. Greenhouse Effect

Greenhouse effect is the trapping of heat by the atmosphere. The temperature at the earth’s surface is determined by (a) The amount of sunlight the earth receives (b) The amount of sunlight the earth reflects (c) Retention of heat by the atmosphere (d) Evaporation and condensation of water vapour. The ultraviolet (UV) sunlight that reaches the earth warms both the atmosphere and the surface. The greenhouse gases cannot stop these UV rays as they are of very short wavelengths but they can be checked by the ozone which is not sufficient enough. The earth reflects infrared readiatoin of long wavelength, which can be trapped by the greenhouse gases like CO2 along with water vapour, methane gas, nitrous oxides, ozone, and CFCs (chlorofluro carbons). Because of these greenhouse gases the average global temperature at the earth’s surface increases considerably. The warming of earth causes increase in melting of frozen zones at high altitudes and polar regions which ultimately increases water level in defferent water bodies. In addition to that additional release of greenhouse gas particularly methane into the atmosphere as a by-product of decomposition of organic material below the ice caps. Methane: Approximately 14 to 20% of the anthropogenic greenhouse effect is attributed to this gas. It is produced from the sources of agricultural activities (paddy cultivation), cattle, plants in marshy land, burning of biomass (logs), etc. Chlorofluorocarbons (CFCs): The CFCs are highly stable compounds and mainly used in refrigeration units and aerosol propellants. It contributes 15 to 20% to anthropogenic greenhouse effect. its greenhouse effect is due to mainly depletion of ozone layer from the atmosphere, so that more amount of UV sunlight reaches the earth. CFCs undergo decomposition reaction under the influence of UV radiation releasing free chlorine. The released chlorine is responsible for the conversion of ozone to oxygen molecule. Consequently, the

A IR POLLUTION

13.9

depletion of ozone layer occurs. The potential global warming from CFCs is considerable because they absorb several thousand times more infrared radiations emitted from earth than is absorbed by CO2 gas molecules. Moreover, it is a stable compound in the lower atmosphere. Nitrous oxide: About 5% of the anthropogenic greenhouse gases is attributed to this gas which is produced by burring fossil fuels, fertilizers used in agricultural activities, etc. It is also a stable compound having long residential time in the atmosphere. Ozone: Ozone is a nontoxic, nonflammable and stable in the atmosphere. They are used as coolants in refrigerators, air-conditioners and in spray cans as aerosol propellants. Ozone is an important trace gas in the stratosphere (20 km above earth’s surface) acting as a protective UV radiation shield for living organisms on earth. In the stratosphere, ozone is formed by a photochemical reaction, followed by three-body reactions which stabilizes the O3 molecule by absorbing the excess energy released by the photochemical reactions. UV) ¾® O + O O2 + hn ¾(¾

O + O2 + M(N2 or O2) O3 + M where, M is the third body. Ozone strongly absorbs the short wavelength radiation (UV). CFCs were the prime suspect for causing ozone depletion. It is believed that one molecule of CFC is capable of destroying 1,00,000 O3 molecules in the stratosphere. The negative aspect of ozone is that it produces the photochemical smog which is harmful to plants, animals and human beings.

Nitrogen Oxides (NOx ) Nitrogen oxides occur in many forms in the atmosphere but only nitric oxide (NO) and nitrogen dioxide (NO2) are subjected to emission regulations as these two forms of nitrogen oxides are primarily involved in air pollution. Often NO and NO2 are referred to as NOx. Nitric oxide (NO): Nitric oxide is a colourless, odourless gas produced largely by fuel combustion. The formation of NO is favoured at high temperature (1200° to1750°C).The nitric oxide oxidizes further in the atmosphere to nitrogen dioxide as its average residential time is about 4 days. Nitrogen dioxide: Nitrogen dioxide is a reddish brown colour and pungent suffocating odour gas. It is a secondary product as nitric oxide oxidizes to nitrogen dioxide in the atmosphere. The other sources of nitrogen dioxide are automobiles and burning of fossil fuels. The residential time of NO2 is 3 days in the atmosphere.

13.10

TOXICOLOGY

Environmental effect of NOx: NO and NO2 are the major contributors for the smog. NO2 is of major concern as a pollutant which is a major contributor to the acid rain. A possible mechanism for the formation of HNO3 is 4NO2 + 2H2O + O2

4HNO3

The environmental effect of NOx on humans is the irritation of eyes, throats, nose and lungs. It increases the susceptibility to viral infections. Nitrogen oxides suppress plant growth and damage leaf tissue. When nitogen oxides are converted to their nitrate forms, in the atmosphere, it reduces the limits of the visibility on roads.

Sulfur Oxides The most important oxide emitted by pollution sources is sulfur dioxide (SO2). It is a colourless and pungent odour gas. It is moderately soluble in water, forming weakly acidic sulfurous acid (H2SO3). It is normally present on the earth’s surface on the low concentration. It is produced from the combustion of any sulfurbearing material which is always accompanied by a little SO3. The mixture is referred as SOx. SO2 S + O2 2SO2 + O2

2SO3

SO3 + H2O ® H2SO4 Once SO2 is emitted into the atmosphere it may be converted through complex reactions to fine particulate, i.e., sulphate (SO4). The major source of SOx is the natural processes like volcanoes about 67%, burning of fossil fuels, industrial processes (petroleum products), coal fired power plants, etc. Both SO2 and SO3 are relatively quickly washed out of the atmosphere by rain or settle out as aerosols. Environmental effect: Sulphate particles and droplets reduce the visibility on the roads. The adverse effect of sulfur dioxide depends on the dose which may cause death to animals and plants. It corrodes the paint and metals, and in the form of sulphate aerosol, causes severe damage to lungs. It is also one of the main contributors to the acid rains.

Acid rain The contributing factors for the acid rain are pollutants like CO2, CO, SOx, NOx. When these pollutants enter the atmosphere they are converted into their corresponding acids. The detailed photochemical reactions are: (1) 2SO2 + O2 + 2H2O ® 2H2SO4 (2) 4NO2 + O2 + 2H2O ® 4HNO3 (3) HCl (g) + H2O ® HCl (aq) (4) 4CO + 2H2O + 2O2 ® 4HCO3

AIR POLLUTION

13.11

Out of these acids, HNO3 is removed as precipitate or as particulate nitrates after reacting with basses—NH3 or lime. When HNO3 and H2SO4 combine with HCl to generate acidic precipitation it is called acid rain which is a major pollution problem locally. Effects of acid rain: It increases the acidity of rainwater which is very harmful to living organisms as well as to human beings. It causes extensive damage to structural materials like marble, limestone, mortar, slate, etc. For example, Taj Mahal is affected by the acid rain. It reduces the mechanical strength of the structure as the sulphates are leached out by rainwater, CaCO3 + H2SO4 ® CaSO4 + CO2 + H2O Out of these, H2SO4 is the major contributor, HNO3 ranks second and HCl is on third place. The acid rain causes irritation to eyes and mucus membrane, and it accelerates the rate of corrosion in metals.

Hydrocarbons and Photochemical Oxidant The gaseous and volatile liquid hydrocarbons are of great interest as air pollutants. Over 80% of hydrocarbons that enter the atmosphere are emitted from natural sources. CH4 is the major naturally occurring hydrocarbons (40 to 80%) which is produced in large quantity by bacteria in the anaerobic decomposition of organic matter in water, automobiles, domesticated animals. ¾¾ ¾® CO2 + CH4 2(CH2O) ¾Bacteria

The hydrocarbons in air by themselves alone cause no harmful effects. But some of the hydrocarbons (methane, propane, butane, etc.) are more reactive with sunlight producing photochemical smog. The hydrocarbons are thermodynamically unstable and undergo oxidation to produce CO2, acids, aldehydes, solid organic particulate matter, etc. Photochemical oxidants: The hydrocarbons undergo chemical reactions in the presence of sunlight and nitrogen oxides forming photochemical oxidants of which the predominant one is ozone. In addition to ozone, a number of photochemical oxidants known as PANs (Peroxyaetyl nitrates) occur with photochemical smog. When hydrocarbons undergo chemical reduction reactions with high levels of SO2, it is called reducing smog. Environmental effect: The photochemical smog is brown hazy fumes that causes irritation to eyes, nose, throat and lungs. It causes extensive damage to plant life and destroy the rubber vegetation.

Hydrogen Fluoride Hydrogen fluoride (HF) is a gaseous pollutant that is produced primarily from aluminium industry, phosphate fertilizer industry, metallurgical processes, coal

13.12

TOXICOLOGY

fired power plants, etc. It is extremely toxic and even a small concentration may cause irritation, bone, skeleton disorders and respiratory diseases. It causes the disease called fluorosis in plants and animals.

Particulate Matter Particulates refer to all small, solid particles and liquid droplets which are present in a significant amount in the atmosphere and pose a serious air pollution problem. A specific type of particle present in high concentration is a serious danger to human life. The particulate materials range in size from a diameter of 0.1 mm to 100 mm. The residential time for particulate materials depends on the settling range, density and movement of air. The particulates are composed of inert or extremely reactive materials. Sources: The major sources of particulate matter are industrial processes, burning fossil fuels, volcanic eruptions, forest fires, etc. The particulate matter is often referred to as total suspended particulates (TSPs). The classification of various particulates may be discussed as follows: (1) Dust: It contains particles of the size ranging from 1 mm to 200 mm. These are formed by natural disintegration of rock and soil. It is also raised by road, buildings and ploughing of lands. That have large settling velocity and removed from the air by gravity. Effects: The dust deposited on the surface of green plants may interfere with absorption of CO2 and oxygen and release of water. Heavy dust may affect breathing of animals and cause respiratory problems such as asthma. (2) Smoke: It is composed of tiny particles of the size ranging from 0.01 mm to 1 mm which can be liquid or solid. These are formed by either combustion of fuels or other chemical processes. The main composition of smoke is carbon. The major sources of smoke emission are rail engines, roads, industrial power plants, automobile engines, open fire, refuge incinerators, etc. Smoke may have different colours depending on the nature of material burnt. Effects: It causes suffocation and affects the lungs, eyes and throat. Some studies have reported that smoke may cause cancer. (3) Fly Ash: The bulk of the mineral particulate matter in a polluted atmosphere exists as oxides and other compounds resulting from the combustion of high ash fossil fuel. Fly ash emission from a variety of coal combustion units occurs in the absence of collector devices. About 10% of total ash produced may be coming out as fly ash from stack. Effects: Fly ash may cause serious problem to human health, animals and plant life. The thick fly ash cover over the green plants may interfere with absorption of CO2, O2 and release of water. It also causes breathing problems and other serious threats to the respiratory system.

AIR POLLUTION

13.13

(4) Aerosol: An aerosol is a system of solid particles or liquid droplets suspended in a gaseous medium. These are generally smaller than 1 mm in size and has small settling velocities. Smog is an aerosol where the smoke particles are suspended in fog. (5) Asbestos: Asbestos is a particulate of several minerals that have the form of small elongated particles. They have wide range of uses. Asbestos is particularly dangerous as it readily penetrates the lung tissues and the digestive tract and remain there for a longer period of time. This causes cancer, asbestosis, lesions-like diseases. (6) Inorganic particulate matter: Metal oxides comprise a major class of inorganic particles in the atmosphere. They are produced by the burning of fossil fuels containing metals. These are: (i) Lead: Lead is an important particulate matter originating from the combustion of leaded gasoline. Once released, lead can be transported through air as particulate or is carried by streams and rivers. The toxic effects of lead on humans are synergistic. Effects: The lead particulates, are taken up by plants through the soil or deposited directly on plant leaves which in turn enter the terrestrial food chains. Lead is a neurotoxin whose poisoning results in convulsions, delirium, coma and irreversible brain damage. The major biochemical effect of lead is its interference with heme synthesis, which leads to hematological damage. The lead ions inhibit at least two enzymes that catalyze the reactions for biosynthesis of haemoglobin. One such intermediate is delta-amino levulinic acid. HO2C

CH2

CH2

C

C

CO2H

O

NH2 Delta-aminolevulinic acid (ALA)

The important phase of heme synthesis is the conversion of deltaaminolevulinic acid porphobilinogen. CH2 HO2C

CH2

H2 N

C

C

C

C

CH2

N H

Porphobilinogen

H

CH2

CO2H

13.14

TOXICOLOGY

Lead poisoning is usually treating with chelating substances which strongly bind Pb+2. Two most common effective compounds for removing lead ions from blood and tissues are EDTA (ethylenediamine tetraacetate ion) (BAL = 2, 3-dimer captopropanol) (BAL = British Anti Lewisite). The calcium form of chelate in solution is fed to the lead poisoning substance, so that Pb+2 diolaces Ea2+ from the chelates are: O

H2C

C O C

O

CH2

O

CH2 N

S

CH2

S

Pb

Pb

O

N C

O

CHCH2OH

CH2 O

CH2

S

S

CH2

C H2C

O Pb– EDTA chelate

CHCH2OH

Pb– BAL chelate

OH O

C

H

C

NH

H3C

C

S

Pb

CH3 Pb–d Penicillanic chelate

(ii) Mercury: Mercury is a toxic metal and is present in gaseous form in the atmosphere because of its relatively high vapour pressure. The toxicity of mercury depends on its state. In nature, mercury occurs as a trace component of many minerals as ores like cinnabar. Trace of Hg can be found in fossil fuels, coal and lignites. Effects: Mercury vapour is particularly very dangerous as it destroys the lung tissues. Methylmercury can penetrate the membranes separating the bloodstream from the brain causing injury to cerebellum and the cortex. It causes the minamata disease, which is fatal to the human being. Mercury enters the environment mainly through human activities.

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13.15

Elemental Hg is fairly inert and nontoxic. The most toxic species are the organomercurials (CH3 Hg+) which are soluble in fat, the lipid fraction of membranes and brain tissue. It is the methyl mercury which enters the food chain by biomagnification process. (iii) Cadmium: Cadmium is a potential health hazard due to its presence in the atmosphere. Cd occurs in nature in association with zinc minerals. Cd is very much present in cigarette smoke, which is a major source of Cd accumulation in human body. The Cd poisoning disease in the form of “itai itai” or “Ouch Ouch” occurred in Japan. Effects: A high level of Cd causes kidney problems, anemia and bone marrow disorders. Cadmium inhibits the performance of certain enzymes thereby producing hypertension in humans. There is a very strong correlation between zinc and cadmium ions, thereby in excessive amount of cadmium, it replaces Zn2+ at key enzymatic sites, causing metabolic disorders. (7) Organic particulate matter: It occurs in a wide variety of compounds in the atmosphere. Volatile organic compounds (VOCs) are organic chemicals that exist as gases in the air. Plants are the largest source of VOCs. These are in the range of 1 m range. Large number of other synthetic organic chemicals such as benzene and benzene derivatives are released into the air. Polyaromatic hydrocarbons (PAH) are important components of organic particulate matter because of their carcinogenic nature. Some PAHS are given below:

Benzo (a) Pyrene

Chrysene

Benzofluoranthene

The sources and effects of some major air pollutants are summarized in Table 13.1. Table 13.1

Effects and sources of some major air pollutants.

Pollutants

Sources

Effects

Gaseous Pollutants CO2 (Carbon dioxide)

Fossil fuel burning, industrial Global warming and process, land cleaning, indirect effect on lives due to rise in respiration atmospheric temperature CO (Carbon monoxide) Incomplete combustion, Reduction of CH4 oxidation, platn haemoglobin carrying metabolism biomass burning. capacity of blood, respiration failure, drowsiness, headaches Contd.

13.16

TOXICOLOGY

Contd.

SOx (Sulfur oxides)

Fossile fuel burning, volcanoes, industries

NOx (Nitrogen oxides) Fossil fuel burning, lightning, soil microbial activities SPM (Suspended Biomass burning, dust, Particulate Materials) seasalt, biogenic aerosols fly ash, smoke from industries Metals Automobile emissions, Pb (Lead) lead smelters, combustion of coal, paints. Cd (Cadmium) Metal industries, mining activities, pesticides, industrial activities like refininng, electroplating and welding. Ni (Nickel) Combustion of coal, metallurgical plants using nickel additives, nickel plating facilities. Hg (Mercury) Mining and refining of mercury metal smelter, perticides, paints, pharmaceuticals. As (Arsenic) Herbicides, metal smelters, pesticides. Zn (Zinc) Zinc refineries, zinc galvanizing processes. Non-metals Autoexhaust, photochemical CHO (Aldehydes) reactions, waste incinerations Cl2 (Chlorine) Chemical industries, leakage from storages. H2S (Hydrogen sulphide) VOC (Volatile organic compounds)

Industrial wastes disposal site, sewage treatment plant, refineries Transportation, waste disposal sites, solvents, industrial processes

Breathing problems like bronchial spasms and asthma, eye irritation, digestive problem Chronic respiratory problem, loss of appetite, corrosion of teeth Chronic branchitis problem, lung diseases, reduction of visibility Neurotoxin, gastrointestinal and respiratory problems, behavioural disorder Cardiovasclar diseases, causes damage to kidney, emphysema, bronchitis, intestinal disorder, damage to brain and liver Respiratory problem, cancer, dermatitis

Protoplasmic poisoning, damage of kidney, brain, and nerve system Corcinogenic, mild bronchitis, cause dermatitis Coarrosive to skin, damage of mucous membrane. Respiratory problems, irritation to eyes and skin. . Irritates eyes, nose and throates. Causes problem in lungs, bronchitis. Conjunctivitis, sleeplessness, headaches, damages nerve tissues. Irritates eyes, skin, causes hypertension, headaches and are carcinogenic.

AIR POLLUTION

13.17

Contd.

HF (Hydrogen floride)

Ethylene (CH2 = CH2)

O3 (Ozone)

13.6

Chemical industries, incinerators, paints, refineries Autoexhausts, chemical industries, incineration of agricultural wastes, paints combustion of gasolines Photochemical reactions

Fluorosis, necrosis of leaf tips. Eye irritation, epinasty, leaf abscission, flower dropping.

Irritation, necrosis.

CONTROL OF AIR POLLUTION

The most effective means of controlling air pollution is to prevent the formation of pollutants or reduce their emission from both the stationary and moblie sources. In case of industrial pollutants, the most reasonable strategies for control have been to reduce, collect, capture or retain the pollutants before they enter the atmosphere. Pollution problems vary from region to region. When the source of correction is not so effective then attention should be given to emission control technology.

13.7

FATE AND TRANSPORTATION OF AIR POLLUTANTS

The atmosphere has always been the greatest sink for gaseous or particulate wastes where these pollutants are transported and/or diluted before undergoing physical, chemical and photochemical transformations. The topography, climate, humidity, temperature and other physical processes in the atmosphere play an important role in transport, dispersal, concentration, dilution and/or chemical transformation of many air pollutants. The health effects to humans, animals and plants depend on the concentration and residence time of the pollutant in the atmosphere. Even if a very low concentration toxin remains for a longer period, it causes serious health hazards to living organisms. Dilution is the best method to the problems of pollution. Thus, dilution of air pollutants in the atmosphere is an important process in preventing undesirable levels and effects of pollutants in the ambient air. The atmospheric dispersion of air pollutants is the result of wind action, atmospheric turbulence and molecular diffusion.

Lapse Rates and Dispersion of Air Pollutants The change of temperature with altitude of the troposphere is called lapse rate. As the altitude increases, temperature and pressure decrease. Then the gaseous molecules tend to move from the region of high pressure to the region of low pressure. Thus, gas expands and if there is no interchange of heat with the surroundings, the gas will become cooler. This is called adiabatic cooling.

13.18

TOXICOLOGY

The degree of stability of the atmosphere depends on the rate of change of ambient (air around us) temperature with altitude. The adiabatic lapse rate is calculated for dry air. But if the air contains moisture, the water present may undergo phase change from vapour to liquid in the higher altitude. Thus, the adiabatic decrease in temperature with altitude is especially important in the vertical movement of air. As the water vapour condenses, it releases latent heat. Thus, the actual moist adiabatic lapse rate is less than the dry lapse rate. This process depends on the humidity of the ambient atmosphere. It is in the range of –6 to –7° C/km with higher values occurring at greater heights where the water content is less.

–5

p eg era at tu iv re e la Inv ps er e ra sion te

Te

te

– 10

N

ra

tic

e

ps

– 15

aba

lap se r a c lapse rate te

diabati

– 20

la

adi

m

e

tiv

si

Altitude

Po

Dry

Super-a

– 25

Isothermal

In the hot days, the air near the surface of earth is heated so rapidly that the lapse rate is super adiabatic, i.e., greater than adiabatic. It is said to be positive adiabatic lapse rate when the temperature decreases with increase of altitude. The increase of temperature with increase of attitude is called negative lapse rate. The negative lapse rate is also known as temperature inversion. The inversion of temperature is most unfavourable for the dispersion of air pollutants. Because at this condition the atmosphere is said to be stable. The dense cold air lie at the bottom and has no natural tendency to rise (Fig. 13.3).

0 5 Temperature

10

15

20

25

Fig. 13.3 Adiabatic lapse rate and inversion of temperature.

The unstable atmosphere favours the dispersion of pollutants due to the air from different altitudes mixes thoroughly. The environmental (ambient) lapse rate may be compared with adiabatic lapse rate to predict the dispersion of the pollutants released from the stack, chimney, or from an elevated source. The relationship between the lapse rate and dispersion may be explained as plume behaviour by comparing the ambient lapse rate and adiabatic lapse rate. Case 1. When the environmental lapse rate is greater than the adiabatic lapse rate, i.e., super adiabatic condition, there is a turbulence of the air which favours the dispersion of air pollutants effectively (Fig. 13.4a) The resultant plume is known as looping plume which is very common.

13.19

Altitude

AIR POLLUTION

Temp

Looping

Fig. 13.4a

Strong unstable atmosphere.

Altitude

Case 2. When the environmental lapse rate is equal to the adiabatic lapse rate, the plume coming from elevated source tends to rise directly into the atmosphere. This type of emission is called neutral plume. This neutral plume tends to be cone type plume when the wind velocity is greater than 20 m/h (W. L. Faith and A.A. Arthur, 1972) (Fig. 13.4b and 13.4c).

Temp

(b) Neutral plume

Fig. 13.4b and c

(c) Coning

Plume behaviour (near neutral stability of the atmosphere).

Altitude

Case 3. When the environmental lapse rate is less than the dry adiabatic lapse rate (sub-adiabatic) then the atmosphere is slightly stable. This is not a suitable condition for pollutant dispersion because in this condition there is limited vertical mixing due to low atmospheric turbulence. Thus, the pollution problem in that area is increased as the pollutants are not dispersed well. This condition produces coning plume (Fig 13.4c). Case 4. When there is a negative lapse rate, i.e., temperature increases with the increase in altitude, the dispersion of pollutant gets minimum. Under this condition the atmosphere is most stable. Thus plume moves horizontally even for a longer distance. This type of plume is called fanning plume (Fig. 13.4d)

Temperature

(d) Fanning

Fig. 13.4d Plume behaviour (fanning).

13.20

TOXICOLOGY

Altitude

All the above 4 cases of plume behaviour are observed under the conditions of uniform lapse rate. When there is a break in lapse rate due to the changes from stable to unstable lapse rate, a situation obtained is known as fumigation. Case 5. When an inversion layer occurs a short distance above the plume source (stack) and superadiabatic condition prevails below the plume source, then the plume is said to be fumigating (Fig. 13.4e).

Temperature

(e) Fumigation

Fig. 13.4e Plume behaviour (fumigation).

This situation is usually occurring in the early morning when sun breaks up a radiation inversion and the superadiabatic conditions. This type of plume usually last for a short period of time. It is very common in summer days with clean sky and mild winds. This is very dangerous but it lasts for a short while.

Altitude

Case 6. When the reverse condition of the fumigation occurs the plume is said to be lofting (Fig. 13.4f ). Under this condition the lapse rate above the plume is unstable while below the plume is stable. When the pollutants are emitted from elevated source, they move above the inversion layer and are dispersed well vertically. This is also very suitable condition for dispersion of pollutants. Under these conditions the pollution ground level gets minimum.

Temperature

Fig. 13.4f

(f) Lofting

Plume behaviour (lofting).

Case 7. When the inversion layer occurs both above and below the plume or the source then the plume is said to be trapping plume (Fig. 13.4g). The diffusion of effluents is severely restricted to the unstable layer between the two stable regions. This is very unfavourable condition for dispersion of pollutants.

13.21

Altitude

AIR POLLUTION

(g) Trapping

Temperature

Fig. 13.4g

Plume behaviour (Trapping).

Wind and Dispersion Air in the horizontal motion is called wind. Its movement in the atmosphere is always turbulent. The air in motion is due to the differential solar heating of the earth’s surface which produces temperature and pressure gradients. When the air exerts high pressure atmosphere becomes stable which is quite related to clear skies and mild winds. Thus, the dispersion of air pollutant is less and causes air pollution problems. But at low pressure, the atmosphere is unstable and dispersion is maximum. Thus, there is a reduction of air pollutant concentration and air pollution problem is less. Wind is one of the important means of transportation, dispersion, distribution and dilution of air pollutants in the atmosphere. The wind velocity determines the dispersion rate of air pollutants and also the residential time of pollutants in the atmosphere. This wind velocity also determines the travelling distance of the pollutants. The relationship between the wind velocity and concentration of air pollutants in a plume is expressed as: m´

1 Cp

m ® velocity of wind, Cp ® concentration of pollutants. Both vary inversely with each other, for example, assuming wind speed of 1 m/s and source emitting 15g of air pollutants per second. Thus, the concentration of air pollutants in the plume is 15 g/m3. If the wind velocity increases to 5 m/s then pollutant concentration from the same source will become 3 g/m3. The process of dilution and transportation depends on the turbulence of atmospheric air. This turbulence is produced during the day time. During the daytime, solar heating causes thermal turbulence and produces convective currents so that turbulent mixing is increased. If the size of thermal turbulence is greater than the size of plume, then the plume will be transported down wind with little dilution. Under this condition molecular diffusion will ultimately dissipate the plume (Fig. 13.5). If the size of thermal turbulence is smaller then the size of plume, the plume will disperse uniformly as it entertains fresh at its boundaries (Fig. 13.6).

13.22

TOXICOLOGY

Top view Turbulence > Plume size

Fig. 13.5 Plume transported without dilution.

Turbulence < Plume size

Fig. 13.6

Dispersion occurs.

Topographic conditions have strong influence on the wind velocity and air quality. Because of particular geographic structure, e.g., surface topography, ocean and land mass, mountains, plains, etc., can influence the velocity and direction of the wind. The differing heat conductive capacity of land mass and water mass gives rise to the altering flow of sea breeze and land breezes (Fig. 13.7a, b). In the day time the land mass is heated quickly and the adjacent air mass is also heated. Thus, it creates a low pressure air mass which moves up. Now, the winds from the high pressure oceans blow toward the land mass. This is called sea breeze which is very turbulent over the land mass. In the evening this pressure gradient becomes reverse and the wind moves from land mass region towards oceans which is known as land breeze. Due to this alternative directional flow of winds, the air pollutants released within the inflow layer move towards land areas in the day time and towards the ocean in the evening. Thus, it creates a problem in coastal cities.

Land Oceans Daytime

Fig. 13.7a Sea breeze.

AIR POLLUTION

13.23

Land Oceans Night-time

Fig. 13.7b

Land breeze.

Similar type of topographic effect is observed in mountain and valley wind movement relationship. In the daytime mountain slopes are heated up quickly thus wind blows from valleys toward the mountain tops. In the night-time this pressure gradient is reversed and the wind blows from mountain top to valley areas. Therefore, the plume discharged in a valley may be confined within the valley because of the regularly changing wind patterns (Fig. 13.8) and pollutant concentration may be increased to a maximum level.

Daytime

Night-time Valley

Fig. 13.8

Mountain-valley wind movement pattern.

Design of Elevated Sources of Air Pollutants Meteorological information about the wind velocity, temperature, pressure, humidity, etc., are very essential for the effective designer of an elevated source of air pollutants like stack or chimneys. The stacks or chimneys are designed in such a way to disperse the pollutants into the upper atmosphere and away from the immediate area may result in fallout or washout far downwind (S. Miller, 1975). Locations of nearby structures, mountains or any other high-rise building may cause major influence on the distribution of pollutants from a stack on or close to the structure, especially when the stack is downwind of the building and wind speed is high (Fig. 13.9).

13.24

TOXICOLOGY

Wind

Stack

Building

Fig. 13.9 Behaviour of plume.

To avoid this problem, the height of the stack should be at least two-and-ahalf times the height of the surrounding high-rise buildings. If the stack height is much below this value, the plume is trapped in the wake zone (Fig. 13.9) while designing the stack the topographical structures like flat, level terrain, irregular terrain must be taken into consideration. The effective stack height (H) is usually calculated as the actual physical height of the stack (h) and the height upto which the plume rises (Dh) (Fig. 13.10). Generally, Holland’s equation is used to calculate the height upto which plume rise from a stack as: Dh = where

LM F MN GH

Vs @ DT@ . + 2.68 ´ 10-3 P 15 u Ts

Dh = height of plume above stack (m) VI = gas velocity of the stack (m/s) Dh

H = h + Dh H h

Fig. 13.10 Effective height of a stock.

IJ OP K PQ

AIR POLLUTION

13.25

@ = diameter of the stack (m) u = velocity of the wind (m/s) P = Atmospheric pressure (millibar) DT = Difference of temperature between the atmosphere and stack gas (°K) Ts = stack gas temperature (°K)

13.8

GLOBAL AND REGIONAL AIR POLLUTION PROBLEMS

The air pollution problems may be observed regionally or globally. The regional air pollution problems are more localized and the effects are immediate and dense. These problems are mainly due to the human activities particularly overexploitation of natural sources. They may be as; acid rain, photochemical smog, drought and desertification. These effects are localized. The global air pollution problems are bigger issues and these are equally contributed by natural and anthropogenic activities. These problems include global warming, greenhouse effect, and ozone depletion.

Acid Rain Acid rain is a regional problem because it occurs near and down wind areas where major emissions of sulfur dioxide (SO2) and oxides of nitrogen (NOx) result from the burning of fossil fuels. The rain is said to be acidic only when there is a presence of acids stronger than CO2 (aq). Acid rain includes both acid precipitation and dry deposition (Fig. 10). Deposition in solution or wet form like rain, snow and fog is acid precipitation and deposition of dry gases, particulates and compounds are called dry deposition. Besides the primary contributors (SO2 and NOx) other acids like hydrochloric acids emitted from coal fired power plant also contribute to acid rain significantly. Sulfur dioxide contributes more to the acid rain (Fig. 13.11).

Cloud

Dry deposition

Power plants

Fig. 13.11 Acid rain.

Acid rain

13.26

TOXICOLOGY

The pure rainfall has a pH value of about 5.6, thus the acid rain must have the pH value less than 5.6. the burning of sulfur containing gasoline exhaust SO2 into the atmosphere where it is oxidized to sulphuic acid (H2SO4). Similarly, through chemical reactions oxides of nitrogen is converted into nitric acid (HNO3) either in the gaseous phase or within water droplets (e.g., clouds) as following: Sulphur containing gesoline Fossil fuel nitrogen

Combustion

Combustion

•

SO2 + OH

NO

Oxidation

Photooxidation

H2SO4

•

NO2

OH

Photooxidation

O3 NO3

HNO3 H2O

Night NO2

N2 O 5

Generally, sulfur dioxides are emitted from the stationary source like coal fired power plants and nitrogen oxides from both stationary and mobile sources. After acid formation, the acid rain may be transported 100 km away from its sources. Tall stack may be reduced the local concentrations but it increases regional effects by spreading pollution more widely.

Effects of Acid Rain Some of the major effects of acid rain are listed below: (a) Acid rain has very serious impact on soil as well as aquatic ecosystems. It is more dangerous to the sensitive areas and sensitive lives. Sensitive areas are those in which bedrock or soil composition cannot be able to buffer acid input, for example, the soil containing calcium carbonate (CaCO3), limestone and mineral calcite can neutralize the effect of acid rain. Thus, these areas do not suffer much due to acid rain. (b) Similarly, excessive acid rains are phototropic (toxic to plants). There have been widespread death of trees in forests due to acid rain. Because of acid deposition, the abilities of vegetation cover to tolerate harsh climatic conditions like too hot or too cold and become more susceptible to many diseases. (c) Because of the acid rain many micro- and macro-nutrients soluble in water leach away. Thus, these elements are not available to plant lives. (d) Generally, reproduction is the most sensitive stage in fish life cycles. Eggs and fry of many species are killed where there is a decrease in pH value of water below 5.0. (e) Acid deposition affects aquatic ecosystem by disturbing food chain. The essential nutrients for aquatic life may be dissolved in water due to low pH

AIR POLLUTION

13.27

value and washed out on the down stream. Algae cannot grow without nutrients, thus the animals which feed on algae cannot grow in the unavailabilty of food and so on. Thus, the aquatic food chain is completely disturbed. The above case is applicable for the freshwater ecosystem. But the ocean waters have good buffering capacity to acid rain. (f ) Exposed surfaces of buildings and statues get corroded, limestone (CaCO3) structures are specially damaged. The chemical reaction of the corrosion is as follows: CaCO3 + H2SO4 ® CaSO4 + CO2 + H2O (g) Acidic sulphate when present in the atmosphere causes laziness. Acids falling on the ground reduce visibility. It affects the respiratory system of humans and animals.

Photochemical Smog Photochemical smog is a major regional air pollution problem which is highly detrimental to health and to the quality of life. It is a regional problem because development of smog is directly related to types of industrial set-up and the automobile use. Thus, smog may be of two major types such as (i) Photochemical smog or brown air and (ii) Sulphurous smog or gray air or industrial smog (Fig. 13.12). Sun Organic compounds SO2

NOx from exhaust

Smog

Fig. 13.12

Formation of photochemical smog.

Solar radiation is particularly important in the formation of photochemical smog. The other conditions for the development of photochemical smog are air stagnation, high concentration of oxides of nitrogen, hydrocarbons and oxidants (mostly ozone) in the atmosphere. Thus, smog is a combination of fog, smoke and fumes released by industries and automobiles into the atmosphere. Smog arises from photochemical reactions in the lower atmosphere early morning, when traffic begins to build up, the concentration of nitrogen oxides (NOx) and hydrocarbons begins to increase (Fig. 13.13). Thus, smog is considered a secondary pollutant. The interaction of solar radiation, oxide of nitrogen and hydrocarbon involve a series of complex reactions which produce secondary pollutants like ozone, aldehydes, ketones and peroxyacetyl nitrate (PAN). Ozone

13.28

TOXICOLOGY

and PAN are particularly very strong chemical oxidants whereas aldehydes and ketones irritate mucous membranes. The primary photolytic reactions are as follows: NO2 + hn ® NO + O

...(1)

Nitrogen dioxide decomposes photochemically to produce nitric oxide and highly reactive oxygen atom. This reactive oxygen atom quickly combines with oxygen molecule to form ozone which is an oxidant. O + O2 + M ® O3 + M

...(2)

(where M is third body usually N2 or O2) NO + O3 ® NO2 + O2

...(3)

This equation (3) is a very important mechanism for the removal of ozone from troposphere. 0.35

0.30 Hydrocarbon

Concentration (ppm)

0.25

0.20

0.15

0.10

Oxidant

NO2

0.05 NO

0000

0600

1200

1800

2400

Local time

Fig. 13.13 Dynamic behaviour of photochemical smog (P. A. Leighton, 1961).

The hydrocarbons react with free oxygen atom that release due to decomposition of nitrogen dioxide to form oxygen bearing free radicals. Aldehydes undergo photolytic reactions to produce hydroproxyl, alkyl peroxyl radicals as per the following reactions.

AIR POLLUTION

13.29

HR + O ® RCO• (acyl radical) HCHO + hn ® H• + HCO• HCO• + O2 ® HO2• + HCO• H• + O2 ® HO2• HCHO + hn + 2O2 ® 2HO2• + CO Hydroperoxyl and alkyl peroxyl radicals can react to oxidize nitric oxide (NO) to NO2 and also generate alkyloxyl radicals. HO2• + NO ® •OH + NO2 (hydroxyl radical) RO2• + NO ® RO• + NO2 The most important reactive intermediate species in atmosphere to form smog is hydroxyl radical which can be reconverted to hydroperoxy radical by several reactions as: CO + •OH ® CO2 + H• H• + O2 ® HO2• Peroxyacyl nitrates (PAN) are highly significant air pollutants and corresponding to the different possible ‘R’ groups. There are three most common members of PAN family as follows: O HCOONO2 O

Peroxyformyl nitrate (PFN)

CH3COONO2

Peroxyacetyl nitrate (PAN)

O C6H5COONO2

Peroxybenzoyl nitrate (PBzN)

PAN is formed generally by additional reaction of nitrogen dioxide and peroxyl radicals as: O

O

R — C — OO O· + NO2 ® R — C — COONO2 (PAN) This is the termination reaction of the radical. Thus, the end product of all these above photochemical reactions is photochemical smog. Sulphurous smog: The sulphurous smog is produced primarily by burning of sulfur containing fossil fuel (coal and oil). Sulfur dioxide is responsible for the sulphurous smog by combining with particulates or water droplets. The sulfur dioxide (SO2) reacts with hydroperoxyl radicals to produce H2SO4 droplets resulting in sulphurous smog.

13.30

TOXICOLOGY

HO2• + SO2 ® •OH + SO3 SO3 + H2O ® H2SO4 SO2 + Particulates ® Sulphurous smog

Effects of photochemical smog • Smog formation is accompanied by temperature inversion or thermal inversion. Temperature inversion causes smog to settle and remain near the ground till wind sweeps it away. It causes several deaths of humans and animals. • It reduces the visibility due to thick concentration of aerosol in the lower atmosphere. Some aerosol particles are in colloidal size and these are particularly dangerous as they scatter the light more effectively. • The three major oxidants present in smog particularly ozone, PAN and nitrogen oxides are very highly toxic to plant life. It attacks the younger leaves causing bronzing and glazing of their surfaces so that photosynthesis activities are stopped. • Exposure to smog causes respiratory problems, bronchitis, sore throat, cold, headache and irritation to eyes (red shot eyes).

Desertification and Droughts Desertification is the deterioration of land in arid, semi-arid and dry sub-humid areas due to climate changes and human activities (U.N. Food and Agricultural Organization, 1998). Most of the deserts are found primarily between latitudes 15° and 30° north and south of the equator. Deserts occur naturally where there is too little water for sustainable plant growth. The principal climatic conditions that lead to the formation of a desert is low precipitation and the factors that destroy the ability of a soil to store water can create a desert (Fig. 13.14).

Fig. 13.14

Desert.

The main cause of desertification is the removal of vegetation cover so that the water holding capacity of the soil reduces. The other leading causes of desertification are bad farming processes, overgrazing, conversion of rangelands

13.31

AIR POLLUTION

into croplands, and deforestation. The greenhouse effect and acid rains are the other causes to the desertification. The loss of vegetation cover leads to the soil erosion and loss of its water holding capacity thus eventually the marginal land is converted into deserts. Drought: Drought is a condition of water shortage, resulting from regional variations in stream flow and long-term deficiency of rainfall. This process ruins vast areas of fertile and very productive lands. Generally, droughts are naturally occurring events which can be minimized with proper planning like plantation of trees and good farming practices.

Greenhouse Effect (Global Warming) Global warming is defined as the increase of atmospheric temperature near the earth’s surface. The literal meaning and function of greenhouse is to trap heat. The solar radiation that reaches the earth warms both the surface and atmospheric air near the surface. The incoming solar radiations are of short wavelength. The earth’s atmosphere reradiates heat as longwave radiation (infrared). The elements such as water vapour (H2O), methane (CH4), carbon dioxide (CO2), Chlorofluoro carbons (CFCs) present in the atmosphere are able to absorb the longwave radiations. Therefore, the temperature of the atmospheric air increases. The gases or elements which can absorb the infrared radiations are called greenhouse gases. Now, the greenhouse effect may be defined as the trapping of heat (long wave radiations) by the atmosphere (Fig. 13.15). Sources of greenhouse gases: The greenhouse gases such as CO2, CH4, H2O CFCs, O3 (ozone) and nitrous oxides (N2O) are released into the atmosphere through both natural and anthropogenic sources. The natural sources of greenhouse gases are volcanoes, marshy lands, and natural trees like pines. The anthropogenic sources are combustion of fossil fuels, deforestation, industries, urban lifestyle (using refrigerators, air-conditioners that release CFCs), intensive rice cultivation, and modern agricultural practices.

Atmospheric Window Sun

io iat ad

f heat ption o

Industry

n

Absor

Earth

Fig. 13.15 Greenhouse effect.

av -tw or

n

Lo

er

er

av

w g-

Sh

Vehicle

n

io

at

i ad

13.32

TOXICOLOGY

Although the atmospheric greenhouse gases trap the infrared radiations but the cooling processes are also carried out by air circulation. Thus, greenhouse effect is a very complex situation which gets both positive and negative feedbacks (Fig. 13.16). Negative feedback refers to the feedback that occurs when the system’s response is in the opposite direction of the output. Thus, it is self-regulating and result in global cooling in response to a warming circumstances. The positive feedbacks are self-enhancing that cause increase in global temperature.

Sun Sun

w ds

in

enh gas ouse es

By

Gre

(a)

sss

(b)

Fig. 13.16 (a) Positive feedback, (b) Negative feedback.

Greenhouse gases: The carbon dioxide is the major greenhouse gas as it contributes about 50 to 60% of the anthropogenic greenhouse effect. The other greenhouse gas, methane (CH4) which has the 10 to 20 times greater absorbing capacity of heat than CO2. But its concentration in the atmosphere is only 1% of the greenhouse gases. The major contributor of methane gases are termites which produce methane as they process wood. Decomposition of biomass, burning of fossil fuels, anaerobic microbial activities and expels of cattles release methane into the atmosphere. CFCs in the atmosphere absorb hundred times more infrared radiations emitted from earth than is absorbed by carbon dioxide. CFCs are released from refrigeration, air-conditioners and spray coolants. Next to carbon dioxide, nitrous oxide (N2O) is the main contributor about 30 to 45% of the anthropogenic greenhouse effect and they accumulate in the atmosphere at much faster rates than carbon dioxide.

Effects of Global Warming Greenhouse effect leading to global warming shall have severe effects on rainfall, rise in sea level, plant growth and animals. Some important effects of global warming are:

AIR POLLUTION

13.33

1. Rise in sea level: It is estimated that by turn of the century a rise of 5°C in global temperature will happen due to the effect of greenhouse gases if it is not checked now. Polar ice caps would melt because of rise in temperature and more water will be added to sea, it leads to rise in sea level. It will flood the low-lying coastal areas and many cities will get submerged in water ecosystems such as marshes and swamps. 2. Drought: A 3°C rise in temperature will result in 10% decrease in precipitation (rainfall) which will create drought condition. 3. Effects on plant growth: Drought will reduce down the rate of photosynthesis in plants and thus reduces the growth. Because of the increase in atmospheric temperature, the fruits ripe about two to three weaks earlier than the normal time. It is also observed that the food production has been reduced 2/3rd of the normal production. 4. Effects on animals: Warmer conditions will encourage growth of pests so that animals are susceptible to many diseases. 5. Water shortage: Increase in temperature will lead to the increased evaporation resulting into the shortage of water in soil for plant growth, industrial use and municipal use. 6. Climatic change: It has great effect on climatic changes. it disturbs the hydrologic cycle so that the rainfall and humidity of the atmosphere. It has been reported that spring now occurs about a weak earlier than the normal time. Increase in CO2 and warmer conditions accelerate microbial degradation of organic matter and add more CO2 to the atmosphere. 7. Variation in day and night temperatures: Night temperature has increased more than the day temperature as greenhouse gases prevent heat from escaping at night.

Depletion of Ozone Layer Ozone (O3) is a triatomic form of oxygen, in which three atoms of oxygen are bonded. It is a very strong oxidant and reacts with many materials in the atmosphere. The ozone is produced in the stratosphere as per the following photochemical reactions. O2 + hn ® O + O O + O2 + M ® O3 + M M is the third body usually N2 or O2 which absorbs the heat of reaction. Thus O3 is very stable one. Ozone effectively absorbs the short wavelength ultraviolet (UV) radiations in stratosphere thus it is also called ozone shield. Ultraviolet radiation consists of wavelength 0.1 to 0.4 mm and subdivided into three parts such as: (i) Ultraviolet (C) – UVC which has shortest wavelength and most energetic radiation. This radiation is completely absorbed by ozone in the stratosphere.

13.34

TOXICOLOGY

(ii) Ultraviolet (B) – UVB which is the major concern relative to ozone problem. Ozone is the only known gas which can absorb UVB. It is fairly energetic and strongly absorbed by ozone. Depletion of ozone layer in stratosphere will allow the UVB to reach the earth and create many biological problems. (iii) Ultraviolet (A) – UVA has the longest wavelength of all UV radiations and can cause damage to living cells. It is not affected by stratospheric ozone and reaches the earth’s surface. Ozone absorbs the ultraviolet radiation and breaks down to diatomic oxygen (O2 ) and monoatomic oxygen (O) with the release of heat. Thus, atmosphere is dynamic as ozone is formed and destroyed naturally as per the following equation. O3 + hn ® O2 + O The concentration of ozone is measured in units of Dobson. One Dobson unit is equivalent to a concentration of 1 ppb O3.

Ozone Hole Ozone hole refers to the depletion of stratospheric ozone layer over a particular area. in 1997, ozone hole over Antarctica was the largest ever recorded, covering 22 million km2 in which all the ozone between 14 to 20 km altitude was destroyed (Fig. 13.17). Various chlorine containing molecules are the major culprits of ozone layer depletion. The dominant sources of the chlorine atoms are CH3Cl (methyl chloride) chlorofluoro carbons (CFCs) – CFC-11 and CFC-12 and carbon tetrachloride (CCl4). The CFC compounds are commonly known as freons. Which are used in refrigeration mechanisms.

Fig. 13.17 Ozone hole.

AIR POLLUTION

13.35

Bromine containing compounds such as Halons are used as fire extinguishers. The most common Halons are Halon-1211 (CBrClF2), Halon1301 (CBrF3) and Halon-2402 (C2Br2F4). CFCs and halons are major compounds which destroy the ozone layer very seriously (Table 13.2). CFCs are molecules that contain chlorine, fluorine and carbon and are extremely stable in the lower atmosphere. CFCs have a long residence time in the lower atmosphere. CFC-11 and CFC-12 are believed to have lifetime of 60 and 110 years, respectively, hence they do not disappear from the atmosphere. Once they have reached the stratosphere, they may be destroyed by solar ultraviolet radiations and release chlorine. Chlorine atom is very reactive and it destroys the ozone as per the chemical equation: CFC – 12 ® C Cl2F2 + hn ® Cl + CClF2 Cl + O3 ® ClO + O2 ClO + O ® Cl + O2 These three equations define the chemical cycle of ozone depletion. These reactions are known as catalytic chain reactions in which chlorine reappears and the process may be repeated over and over again. It has been estimated that each chlorine atom may destroy approximately 1 lakh molecules of ozone. The chemical formula of CFC may be calculated as: 1st step – Add 90 to its suffix number. For example, CFC–12 then 90 + 12 = 102. 2nd step – The leftmost digit stands for the number of carbon atoms, middle one are represents the number of hydrogen atoms, and the rightmost represents the number of fluorine atoms. Thus, Herein 102, 1 represents the number of carbon atoms (C = 1); 0 represents that it does not have any hydrogen atoms (H = 0), and 2 is the number of fluorine atoms (F = 2). To calculate the no. of chlorine atoms: In the above example C = 1 H = 0 and F = 2. Since there is only one carbon atom, there is no carbon to carbon bonds. The total possible number of single bonds attach to carbon is four. F+H®2+0=2 carbon no. of no. of Total no. of No. of chlorine = single bonds — hydrogen + fluorine + to carbon atom is single bond atoms atoms of carbon

= 4 – (0 + 2 + 0) = 2 Thus, CFC – 12 contains CCl2F2 Similarly, CFC – 113 then 90 + 113 = 203 No. of carbon atoms = 2, No. of hydrogen atoms = 0

13.36

TOXICOLOGY

No. of fluorine atoms = 3 Carbon-to-carbon single bond = 1 No. of chlorine atoms = 7 – (0 + 3 + 1) = 3 Thus, C2Cl3F3 Table 13.2

Some important chemicals responsible for ozone depletion.

Chemical

Formula

Application

CFC – 12 CFC – 113 CFC – 11 Carbon tetrachloride Methyl chloride Halon – 1301 Halon – 2402 Halon – 1211

CCI2F2 C2Cl3F3 CCI3F CCl4 CH3Cl CBrF2 C2Br2F4 CBrdF2

Refreigeration, air-conditioning, aerosols, foams. Solvents Refrigeration, aerosols, foams Solvents Solvents Fire extinguisher Fire extinguisher Refrigiration, foams

The Antarctic Ozone Hole Antarctic ozone hole occurred during the month of October (spring) in 1997. Under natural conditions, the highest concentration of ozone is found in the polar region and lowest in the equator region. Much of the world’s ozone is produced near the equator and in stratosphere it moves towards polar region. Polar stratospheric clouds form during the exceptionally cold temperatures (– 85 to – 90°C) called polar winter or polar night because of the lack of sunlight due to the tilt of earth’s axis. During the polar winter period, the Antarctic air mass is isolated from the rest of the atmosphere and circulates only about the pole known as polar vortex. Depending on the earth’s rotation, the vortex rotates anticlockwise by which cooling occurs due to the loss of heat during rotation. The air masses cool and descend to from clouds. These clouds are known as polar stratospheric clouds. At these low temperatures small sulfuric acid particles are frozen and serve as seed particles for nitric acid. Thus, all the nitrogen oxides in the air mass are tied up in the clouds as nitric acid. The nitric acid particles grow large enough to fall out by gravitational settling from the stratosphere as ice crystals as per the equation. HCl + ClONO2 ® Cl2 + HNO3 During the spring season, when the sunlight returns, it breaks the chlorine molecule. Nitrogen oxides are absent from Antarctic stratosphere as it is tied up with ice crystals in the form of HNO3. Then chlorine is free to destroy ozone. When the ice melts, nitrogen oxides back to the atmosphere and reacts with chlorine to form chlorine nitrate and stop chlorine from the ozone depletion activities.

AIR POLLUTION

ClONO2 + HCl

Cloud

(Cl2) + (HNO3)

hn

Cl + O3

13.37

ClO + O2

Ice crystals

Effects of Ozone Depletion Ozone layer destruction will allow more UV rays to enter the troposphere and cause a series of harmful effects such as: 1. It produces ecological imbalances by disturbing terrestrial and aquatic food chain. Since more UV rays enter into the troposphere, the humans suffer from skin cancers and cataracts and suppression of immune systems. 2. 1% decrease in ozone results in a 2% increase in UV reaching the earth’s surface and could result in about a million extra human skin cancers per year. 3. UV radiation will fasten the formation of smog which may cause death of humans and animals. 4. It causes chlorosis problems, i.e., loss of chlorophyll and start yellowing. Thus, photosynthesis process will be reduced and there will a reduction of plant growth. 5. It will also increase the atmospheric temperature thus it may affect the climatic conditions, animals and humans health, productivity and natural disasters like flooding and rise in sea level. 6. Ozone depletion reduces substantially the primary production. 7. Due to reduction of immune system, people may suffer from AIDS and any other deadly diseases.

13.9 INDOOR AIR POLLUTION Indoor pollutants of toxic air pollutants are often higher than outdoors. More to that people generally spend more time inside than out and, therefore, are exposed to higher doses of these pollutants. The indoor pollution is caused due to both human activities and natural processes. Some of the sources of indoor air pollutants are listed below: 1. Smoke is an important indoor pollutant particularly in rural areas where firewood, coal and other items like cowdung cakes are used for cooking purposes. 2. Luxurious lifestyle using air-conditioners, refrigerators and other coolant agents are the main sources of indoor air pollutants. Most commonly air-

13.38

TOXICOLOGY

conditioning equipment harbor the disease causing bacteria in air ducts and filters. These bacteria are responsible for Legionnaires’ disease. 3. Asbestos are used as building materials in houses, schools, and offices. The particulate of asbestos causes lung cancer. 4. Formaldehyde is used in foam insulation materials, wood paneling and particle board. It causes irritation to eyes, noses and skins. 5. Radon gas seeps up naturally from soils and rocks below buildings. Radon causes lung cancer. Sick building syndrome is a condition associated with a particular indoor environment with symptoms like headache, dizziness, nausea and hypertension. Some of the important indoor air pollutants, their sources and health effects are given in Table 13.3. Table 13.3

Air pollutants, sources and their health effects.

Pollutant Asbestos

Source

Fireproofing insulation, vinyl floor, cement products Silicon – Carbon dioxide Smoking, motor vehicles Cadmium Smoking fungicides Fluorides Paints coatings Mercury Fossil fuel combustion Cotton fibres Cotton processing Ozone Photocopying machines, air cleaners Radon Construction materials Tobacco Smoke, ciggarrette smoking

Health effect Asbestosis, lung cancer, skin irritant Silicosis Dizziness, headaches, nausea Itali-itali (Ouch-Ouch) Fluorosis Minamata insomnia Byssinosis Fatigue, respiratory irritant Lung cancer Tobacosis

EXERCISE 1. Define air pollution. What are the different sources of air pollution? 2. Differentiate the followings: (a) Mobile source and stationary source (b) Point source and area source 3. What are the different types of air pollutant? Explain them in detail. 4. What are the criteria pollutants? What is the significance of criteria pollutants and how they differ from non-criteria pollutants? 5. Classify the effects of air pollutants. Discuss sulfur dioxide and oxides of nitrogen pollutants and their effects on human health. 6. How do the air pollutants released in the atmosphere?

AIR POLLUTION

13.39

7. What is the lapse rate and how is it related to the dispersion of air pollutants? 8. Discuss the wind movement and the dispersion of air pollutants. 9. What are the parameters taken into consideration for designing the elevated sources of air pollutant? 10. What are the different global and regional air pollution problems? 11. What is acid rain? Discuss its effects. 12. How does photochemical smog form? Discuss its effects. 13. Explain the greenhouse effect. What are the sources of greenhouse gases? Discuss the effects of greenhouse. 14. Discuss the ozone layer depletion. 15. What is indoor air pollution? Discuss.

CHAPTER

"

Water Pollution 14.1

INTRODUCTION

Water, representing the medium of life on earth and one of our four ancient “elements” is a summarizing and general term, for which no exact scientific definition can be given. There is only one common characteristic, namely, that the major constituent of water in any case is H2O and it forms about 75% of the matter of the earth’s crust. Although biological and physiochemical properties of pure chemical water are fascinating, its use or consumption determines its importance. Thus, for the agronomist, water is necessary for food crops. For the industrial engineers, the major use of water is as a cooling agent or as steam. For biologists, water is the medium of life, and for the meteorologist, water (rain) is a dominating factor of climate and an energy stock to equalize fluctuations in temperatures. Water is a resource which cannot be produced or added as and when required by any technological means. The total fresh and seawater content of earth is essentially fixed. The circulations of freshwater over the earth can be represented by a continuous process under the influence of solar energy, whereby water follows a cycle of evaporation from the earth’s surface condensation, precipitation, flow over the land surface and below it and returning back to the oceans. The impurity or contamination of natural water which results in the alteration of its physical, chemical or biological properties is called water pollution. The impurities present in natural water may be classified as follows. 1. Dissolved solids, liquids and gases, for example, chlorides, sulphates, nitrates, bicarbonates and phosphates of sodium, potassium, calcium, magnesium, iron and manganese and some of the fluorides are soluble in water. The gases like oxygen, nitrogen, carbon dioxide and oxides of nitrogen.

14.2

TOXICOLOGY

2. Suspended matter: Insoluble matter in suspension which may be inorganic or organic or both in nature. These are like clay, sand, vegetable and animal matter, etc. 3. Colloidal impurities: These are like emulsified oil, amino acids, dyes, finely divided silica, fats, ether, etc. 4. Biological pollutants: Biological pollutants may be classified into two groups, namely (i) Primary pollutants like bacteria or viruses and (ii) Corollary pollutants like weeds, algae, etc.

14.2

TYPES OF WATER

Water is classified into two types based on its action with soap solution. These are hard water and soft water. Hard water 1. Hard water does not produce lather with soap solution readily. 2. Hard water may be pezrmanent or temporary. Both types of hardness are due ot presence of impurities like Ca+2, Mg+2, Mn+2, Fe2+, Al+3 ions. 3. Water is said to be hard when hardness is above 100 mg/L.

Soft water Soft water produces lather readily with soap solution Soft water contains negligible or little amount of such ions like Ca+2, Mg+2, Al+3, Mn+2, Fe2+, etc. In soft water hardness is below 100 mg/L.

Fresh water is classified into five types based on the water quality criteria and its use. According to Central Pollution Control Board, India, water is classified as: Class A. Drinking water source without conventional treatment but after disinfection. The water quality should have dissolved oxygen (DO) minimum 6 mg/L, BOD maximum 2 mg/L, MPN of coliform per 100 ml is maximum 50, and the pH range 6.5 to 8.5. Class B. Outdoor bathing water. The water quality should have DO minimum 5 mg/L, BOD maximum 3 mg/L, MPN of coliform per 100 ml is maximum 500 and the pH range 6.5 to 8.5. Class C. Drinking water source with conventional treatment followed by disinfection. The water quality should have DO minimum 4 mg/L BOD maximum 3 mg/L, MPN of coliform per 100 ml is maximum 5000 and the pH range 6.0 to 9.0. Class D. Propagation of wildlife, fisheries, etc. the water quality should have DO minimum 4 mg/L, free ammonia as N maximum 1.2 mg/L and pH range 6.5 to 8.5.

WATER POLLUTION

14.3

Class E. Irrigation, industrial cooling and controlled waste disposal. Water quality is—electrical conductivity maximum 2250 mmho sodium absorption ratio (SAR) maximum 26, boron maximum 2 mg/L and pH range 6.0 to 8.5.

14.3

TYPES OF WATER POLLUTANT AND THEIR SOURCES

Water has always been vital for the existence of living organisms. Its use for drinking, cooking, agriculture, transport, industry, and recreation show immediately the extent to which it is an integral part of our life. No matter the purpose for which water is required, it has long been recognised that its suitability for that purpose can be affected by other substances dissolved and/or suspended in the water. The number of impurities of concern has been continually increasing and smaller and smaller concentrations of many substances are attracting attention. Water pollution may be defined as any physical, chemical and biological change in water quality by other substances (dissolved and/or suspended) that adversely affect the living organisms. It is a fundamental principle that the quality of water determines its potential use. The physico-chemical characteristics of the aqueous phase have direct influence on the type and distribution of aquatic biota. These characteristics are also influenced by the activity of the aquatic biota. For determination of water quality, characterization of water is essential which involves: (a) The dynamic distribution of chemicals in the aqueous phase. (b) Accumulation and release of chemicals by aquatic biota. (c) Sorption behaviour of bottom sediments. (d) Inputs and outputs from land and atmosphere. The water pollutants enter into the water body from point and/or non-point sources. Point sources are distinct and specific, for example, sewage from specific industry, domestic sewage, etc. Since, these sources are identifiable, they can easily be monitored whereas the non-point sources are scattered and depend on certain natural and artificial factors, for example, surface runoff like rivers, runoff from roads, streets, etc. As the classification of pollutants and their effects are strongly correlated, it is convenient to classify the large number of water pollutants into five major categories. These are: 1. Organic pollutants 2. Inorganic pollutants 3. Sediments 4. Radioactive substances 5. Thermal pollutants We will discuss each of the above-mentioned pollutants in details.

14.4

TOXICOLOGY

14.4

ORGANIC POLLUTANTS

Organic pollutants are derived from any living organisms. Thus, organic pollutants include oxygen-demanding wastes, disease-causing agents, plant nutrients, synthetic organic compounds and oil.

I. Oxygen-Demanding Wastes Dissolved oxygen: The greater the amount of dissolved oxygen (DO) in water, the better is the quality of water, and thus, it will give better support to the aquatic life. The dissolved oxygen in the range of 4 to 6 ppm will support plant and animal population in any water body. Water with less than 2 ppm DO will support mainly worms, bacteria, fungi and other detritus feeders and decomposers. Thus, decrease in this DO value is an index of pollution mainly due to organic matter (raw sewage, agricultural waste, urban garbage, human and animal excrement and urine, etc.). There are four processes which actually affect the DO content in water— reaeration, photosynthesis, respiration and chemical processes that consume oxygen (oxidation). Reaeration is the addition of oxygen to water by the process of diffusion from air. The solubility rate of oxygen in water is high when there is a turbulence and these rates are low at high temperature i.e., with increase in temperature, solubility of oxygen decreases. Green plants and algae require carbon dioxide and inorganic nutrients present in water to synthesize organic materials and liberate oxygen. This process of photosynthesis occurs in the presence of solar radiation. Thereby, DO increases in water during day time and this process undergoes reverse process in the night. Oxygen is removed from water by respiration due to bacteria and algae. DO increases in water as the organic matters undergo degradation by bacterial activity in the presence of DO. C + O2 ® CO2 ­

Biochemical Oxygen Demand (BOD) Biochemical oxygen demand is the amount of oxygen required by microorganisms to carry out the oxidation process of organic materials. BOD and DO are indirectly related to each other. When the BOD is too high, the DO becomes too low to support the living organisms. BOD is commonly used to carry out the water quality measurement. When there is enough bacterial activity, there is the depletion of oxygen in water downstream. This is called the oxygen sag (Fig. 14.1). The oxygen sag is generally represented by three zones. These are: 1. Pollution zone: This is the zone where the initial decomposition of waste begins. In this zone BOD content is high and DO content is low. 2. Active decomposition zone: In this zone DO content is minimum due to biochemical decomposition of organic matter.

WATER POLLUTION

14.5

3. Recovery zone: In this zone BOD is reduced and DO content will increase considerably. It is because all of the oxygen-demanding wastes have been decomposed.

DO or BOD

DO

Pollution Zone

Active Decomposition Zone

Recovery Zone

BOD Oxygen Sag Distance Downstream

Fig. 14.1

Oxygen sag curve.

Chemical Oxygen Demand

Chemical oxygen demand (COD) is the amount of oxygen required to carry out the oxidation process of organic matter chemically. It is a rapid test for determination of the total oxygen demand by organic material present in the sample. Since, many organic materials are chemically oxidizable but not by biochemical means, then COD values do not indicate whether the organic matter present in sample is biodegradable and at what rate biological oxidation would proceed. Apart from the organic matter, COD is required for oxidation process in certain inorganic compounds like sulfites, thiosulfates, ferrous ions and other metals in the reduced state.

II. Disease-Causing Agents The most serious and concerned water pollutants in terms of human health are disease-causing agents. The disease-causing agents may be divided into two groups, such as: (1) Pathogenic organisms (pathogens): They cause disease by direct ingestion into the human body through water or food. The pathogens are bacteria, viruses, worms, protozoa, etc. (2) Water-borne insect vectors: They cause disease in human body indirectly by ingestion of protozoans or parasites through the insects. For example, mosquitoes cause malaria. Malaria is a vector disease. Water-borne diseases are typhoid, cholera, bacterial and amoebic dysentery, entritis, polio, infections, hepatitis, etc. Similarly, the vector diseases like malaria, yellow fever, filariasis, encephalitis and dengue fever are transmitted by insects. The major sources of pathogens are from waste waters containing

14.6

TOXICOLOGY

untreated human wastes, animal wastes, wastes from agricultural farms and various food processing industries. The pathogenic organisms are transmitted to the human body through direct contact or by consumption of contaminated water and food. It is very difficult to monitor disease-carrying organisms directly. Therefore, the count of fecal coliform bacteria is a standard measure and indicator of disease potential. The coliform bacteria grow in the colon or intestines of humans and animals. If large number of these organisms are found in a water sample, then the water is unsafe for consumption and may cause many diseases. It is assumed that if coliform bacteria are present in a water sample, infectious pathogens are also present. The presence of fecal coliform is the real threat to human health and it is tested as 100 ml water is passed through a filter that removes bacterial cells. The filter is placed in a container having liquid nutrient medium that supports the bacterial growth. it is cultured on suitable temperature for 24 hours. Each living cell will have produced a small colony of cells on the filter. For drinking water quality, the number of coliform bacteria is nil and for swimming water it is 200 colonies per 100 ml. Some important pathogens causing disease are discussed as follows: Bacteria: Bacteria is a microorganism which causes many water-borne diseases in human beings when they are ingested directly. Some bacteria also cause disease in animals. Some of the important microorganisms (bacteria) and the diseases caused by them are listed in Table 14.1. Table 14.1

Microorganisms and the diseases caused by them.

Microorganisms 1. Salmonella typhi 2. Salmonello paratyphi 3. Common Salmonella and Shigello spp., Proteus spp. 4. Vibrio cholerae and its biotype “EL Tor” 5. Shigella sonnei, Shigella flexneri and Shigella shigae 6. Pasteurella tularensis 7. 8. 9. 10.

Compylobacter spp. Mycobacterium Escherichia coli Leptospira spp.

Diseases Typhoid Paratyphoid Gartroenteritis and food poisoning Cholera Bacillary dysentery Tularaemia (causes fever and weakness) Intestinal infection Tuberculosis Infantile diarrhoea Leptospirosis

Viruses: Sewage and polluted water contain various types of virus, many of which are transmitted into humans and animals directly through water. These

WATER POLLUTION

14.7

viruses can be grouped into four major categories (Chang, 1968) as: (i) Enteroviruses (polio viruses, ECHO viruses, coxsackie viruses) (ii) Adenoviruses (iii) Reoviruses (iv) Hepatitis viruses Enteroviruses and hepatitis viruses cause enteritis in human body due to contamination of water by untreated sewage. Infectious hepatitis (jaundice) is the most concerned disease caused by hepatitis viruses which infect the liver to induce excess production of bile. The secretion of bile causes the yellowness of the body. Parasites: The parasites generally are transmitted into the human body through contaminated or untreated water. The parasites infect the large intestine causing ulceration which results in the release of necrotic mucous membrane and blood. Some of the parasites and the diseases caused by them are listed in Table 14.2. Table 14.2

Some parasites and the diseases caused by them.

Parasites 1. 2. 3. 4.

Diseases

Entamoleba histolytica Fasciola (or) Dicrocoelium Dracunculus medinensis (Guinea worm) Nematoda (roundworms) and Platyhelminther (tapeworms)

Amoebic dysentery Distomatosis Dracontiasis Loss of appetite and weakness, infection of intestine.

Water-Borne Insect Vectors

The diseases caused by bacteria, viruses or protozoans which are transmitted into the human body through intermediates called vectors, for example, mosquitoes. The diseases caused by the indirect ingestion of diseases-causing agents by vectors are called vector diseases. Some of the important microorganisms, their vectors and the diseases caused by them are listed in Table 14.3. Table 14.3

Water-borne insect vectors and the diseases caused by them.

Vectors 1. Anopheles mosquito 2. Aedes mosquitoes of subgenus Stegomyia and Haemagogus 3. Aedes aegypti and Aedes albopictus 4. Black flies of genus Simulium 5. Culex pipiens fatigans

Microorganisms

Diseases

Plasmodium Arboviruses Gp. B.

Malaria Yellow fever

Arboviruses

Dengue

Helminth, Onchocerca volvulus Wuchereria bancrofti and Brugia malayi

Onchocerciasis or River blindness Filariasis

14.8 III.

TOXICOLOGY

Nutrients

There are five essential elements required by the aquatic biota for their survival. These elements are sunlight, oxygen, carbon dioxide, temperature and nutrients. Excess nutrients released by human activity particularly related to land use. The two important nutrients that cause pollution problems are phosphorus and nitrogen. When these two nutrients reach the excess in rivers or lakes, there is a huge growth or population explosion of photosynthetic blue-green bacteria and algae. Generally, algae require about 20 elements for their growth and absence of any of one them can restrict their growth. Table 14.4 shows the relative requirements of these elements by plants. The chemical element, phosphorus is very essential for all plants and which is very short in supply followed by nitrogen. With the excess supply of these nutrients through human activities (modern agricultural practices—fertilizer), there is an increase in biological productivity particularly rapid growth of blue-green bacteria and algae. The increase in concentration of essential nutrients required for living things (plants) is called eutrophication (eu + trophic = truly nourished) of the ecosystem. Because of eutrophication, there is a very high biological productivity, i.e., population explosion of blue-green bacteria and algae. The mats of the algae and bacteria become so thick that the penetration of sunlight to deep water is impossible. Thus, the organisms at the bottom died and these dead organisms become food for other bacteria. Thus, there is a further increase in bacterial population which uses more and more oxygen for respiration. This process depletes the concentration of total dissolved oxygen and the living organisms begin to die. Fish is the worst affected of eutrophication as it requires more oxygen than other organisms. Table 14.4 Relative quantities of essential elements required by plants and their natural supply in river water (after Vallentyne, 1973). Element Oxygen Hydrogen Carbon Silicon Nitrogen Calcium Potassium Phosphorus Magnesium Sulfur Chlorine Sodium

Plant Requirement (%) 80.5 9.7 6.5 1.3 0.7 0.4 0.3 0.08 0.07 0.06 0.06 0.04

Present in Water (%) Demand/Supply ratio 89.0 11.0 0.0012 0.00065 0.000023 0.0015 0.00023 0.000001 0.0004 0.0004 0.0008 0.0006

1 1 5000 2000 30000 < 1000 1300 80000 < 1000 < 1000 < 1000 < 1000 Cond.

WATER POLLUTION

14.9

Cond.

Iron Manganese Boron Zinc Copper Molybdenum Cabalt

0.02 0.0007 0.001 0.0003 0.0001 0.00005 0.000002

0.00007 0.0000015 0.00001 0.000001 0.000001 0.0000003 0.000000005

< 1000 < 1000 < 1000 < 1000 < 1000 < 1000 < 1000

Oligofication (Oligo = little + trophic = nutrition) is the reverse process of eutrophication in which there is short supply of nutrients, therefore, low biological production occurs. These aquatic ecosystems have clear waters. Organic Chemicals

Organic chemicals include both natural and synthetic organic chemicals used or manufactured in the chemical industries. Many of these chemicals are highly toxic and even exposure to a very low concentration can cause birth defects, genetic disorders and death. Most of the natural organic chemicals are biodegradable whereas the synthetic organic chemicals which include pesticides, soaps, detergents, pharmaceuticals, plastics and pigments. Some of these chemicals can persist in the environment because they are resistant to degradation and toxic to organisms that ingest them. Some important and most used synthetic organic chemicals are discussed below. Pesticides

Pesticides are biologically active chemicals that are used for killing pests. Pesticides may be classified as insecticides (killing insects), herbicides (killing herbs) and fungicides (killing fungus). The two most important sources of toxic organic chemicals in water are improper disposal of pesticides runoff from farm fields or agricultural activities. These pesticide residues in water may reach humans through drinking water and food chains in the ecosystem because of their non-biodegradability and long persistent in environment. Prominent pesticides are chlorinated hydrocarbons, organic phosphates, carbamates, DDT, dieldrin and aldrin. Pesticides, once entered into the aquatic ecosystem, concentrate in all the components of the system. These chemicals in water can remain in dissolved or suspended form and to some extent it is absorbed on the colloidal surface and ultimately settled down in the sediments. Pesticide residues enter the living organisms directly through water system or food chain. All pesticides are highly toxic to humans and animals. Human toxic responses to the major groups of pesticides are listed in Table 14.5. Some pesticides and their chemical structural formula are given below:

14.10

TOXICOLOGY

Pesticides

Chemical structure S

—

CH2 —COOC2H5

(i) Malathion

—

—

H3C — O —P — S —CH CH3— O

C — O — C2H5 O

—

CCl3

(ii) DDT

C

Cl

—

Cl

H

Cl

(iii) Hexachloro Benzene

Cl

Cl

Cl Cl

(iv) 2, 3, 7, 8-tetrachlorodibenzo

Cl

p-dioxin (TCDD) Cl

O

Cl

Cl

O

Cl

Cl

(v) Hexachlorophene

OH

Cl

Cl

Cl

CH2 Cl

Table 14.5 1966).

HO

Human toxic responses to the major groups of pesticides (After Brown,

Groups 1. Naturally occurring organics (Rotenoides, Pyrethroides, Nicotine, Alkaloides)

2. Chlorinated hydrocarbons

Effects Rotenoides and pyrethroides have usually low toxicity, but kidney and respiratory effects in severe cases. Nicotine compounds highly toxic with convulsions, cardiac irregularity and coma in severe cases. Low to moderate acute toxicity, affect mostly central nervous system (CNS), tremors and incoordination in severe cases, lipid build-up. Heptachlor, aldrin and dieldrin show CNS disturbance and parasympathetic faliures. Other effects include liver damage and gonadal and endocrine effects. Contd.

WATER POLLUTION

14.11

Cond.

3. Organophosphates

4. Carbamates

5. Mercurials

6. Herbicides

7. Rodenticides

Extremely toxic, absorbed through all routes of entry, symptoms include parasympathetic failures, diarrhoea and vomiting, tremors and muscle seizures, mental aberrations in chronic exposure due to suppression of cholinesterase. Unusually hazardous on direct exposure. Parathion converts in filds to paraoxon (more toxic). Guthion and malathion least toxic of all. Normal dimethyl carbamates are strong inhibitors of cholinesterase. Other action and symptoms like organophosphates. Organic mercury, particularly alkyl-Hg is more toxic than inorg Hg. Stored in living tissues as methyl-Hg. CNS symptoms appear first (incoordination, parathesias, tremors) followed by muscular atrophy and mental instability. Acute toxicity to man is low. Chlorophenoxy compounds (2, 4-D; 2, 4, 5-T) produce a mild irritation on exposed areas. Gastrointestinal effects when taken internally. 2, 4, 5-T teratogenic on chronic exposure. Common rodenticides are not chemically related therefore, have no common symptoms. Sodium fluoroacetate is extremely toxic and disturbs citric acid metabolism with resulting cardiac depression, fibrillation and peripheral nervous system effects. Cyanide (as NaCN in “coyotegetters”) is extremely toxic producting respiratory system failure. Strychnine affects all parts of CNS resulting in asphyxia and dyspnea. There are no antidotes for mammal poisons.

The selective absorption and concentrations of environmental chemicals by living cells is known as bioaccumulation. The increase in concentration of certain stable chemicals (pesticides and other synthetic chemicals) in successively higher trophic levels of a food chain or web is known as biomagnification. Detergents and Soaps

Detergents and soaps are the chemical agents used for cleaning materials. Synthetic detergents have good cleaning properties and do not form insoluble salts with calcium or magnesium ions which are responsible for hardness. The detergents composed of 20 to 30% of surface active chemicals are called surfactants and 70 to 80% of other called detergent builder chemicals. The surfactants or soaps have two ends such as hydrophilic nature (water loving) and other end hydrophobic nature (water repelling). All surfactants based on their ionic charges may be divided as cationic, anionic and non-ionic. Hydrophilic

14.12

TOXICOLOGY

ionic soaps or detergents consist of an ionic carboxyl ‘head’ and a long hydrocarbon ‘tail’. The surfactants arrange themselves with their hydrophilic heads in water and hydrophobic tails projecting out of water. Similarly, in the presence of oils or fats, the tail of the anion tends to dissolve in the organic group whereas head out of it. O +

C — O– Na (Head)

(Tail)

The detergents show differential rate of biodegradation depending on the length and branching of carbon chain. It is said to be hard detergent if it is not easily biodegraded. when it is easily biodegradable it is called a soft detergent. As the length and branching of carbon chain increase, the biodegradability decreases, for example, alkyl benzene sulphonate (ABS) is very slowly biodegradable because of its branched chain structure. H

—

H

—

—

H H

—

—

—

—

—

H H

CH3 H CH3 H CH3 H CH3 H

—

—

—

—

—

—

—

O

—

C — C — C — C —C — C— C — C — C — CH3

—S

—

Na+O

H H

—

H

O –

CH3

(ABS)

Detergents are directly toxic to several species of animals and plants in water. Polychlorinated Biphenyls (PCBs)

The PCBs are manufactured by chlorination of biphenyl molecule which have very high chemical, thermal and biological stability. They have also very high dielectric constants so they are used as coolant insulation fluids in transformers and capacitors for the impregnation of cotton and asbestos, as plasticizers and as additives to some epoxy paints. The chlorination of biphenyl molecule can lead to the replacement of 1 to 10 hydrogen atoms by chlorine as shown in Fig. 14.2. Cl

Cl Cl

+ (Cl)X = 1 to 10 Cl Cl (PCBs) Fig. 14.2

Polychlorinated biphenyls. (PCBs)

WATER POLLUTION

14.13

The products do not have single configuration. The PCBs are not easily degradable and they have low volatility and low solubility in water. They are easily soluble in lipids and fats. Thus, PCBs in water remain adsorbed onto the particulate matter which slowly settles down to the bottom sediments. PCBs are bioaccumulated and biomagnified in the living organisms through food chain. Oil

Oil discharged into surface causes major pollution problem. The sources of oil pollution are oil spills from cargo oil tankers, production of oil, oil used in industries, etc. Oil pollution reduces light transmission and hence, photosynthesis by marine plants is hindered, so there is a decrease in DO in water and causes damage to aquatic biota. Oil pollution in oceans or marine ecosystems may occur in large quantity from oil leakage, spills and deliberate discharge. The oils in ocean waters remain in the following forms: (i) Floating material (ii) Emulsion dispersed in seawater (iii) Dissolved in seawater (iv) Adsorbed or sediments (v) Locked in marine organisms The residual oil spreads over the water surface forming a thin layer and it is stirred with water to form a water-in-oil emulsion. The uptake rates are usually governed by the ambient concentration of these oil fractions. Oils affect the organisms in a number of ways depending upon the characteristics of the oil fractions and their concentration in water. The responses of marine organisms to various concentrations of soluble aromatic hydrocarbons are listed in Table 14.6. Table 14.6 The responses of marine organisms to various concentrations of soluble aromatic hydrocarbons (After Miller, 1982). Concentration (ppb) 0-10 10-100 100-1000 1000-10000 > 10000

14.5

Response Bioaccumulation Effect on behaviour Effect on growth and reproduction Lethal to larval and juvenile forms Lethal to adults

INORGANIC POLLUTANTS

This group of pollutants includes inorganic salts, mineral acids, trace elements finely divided metals or metal compounds, organometallic compounds, etc. These pollutants enter the water bodies generally from point sources.

14.14

TOXICOLOGY

Acid Mine Drainage Mine drainage is an important source of increased acidity in normal waters. Acid mine drainage can originate from the mining of sulfur bearing ores and coal mines discharge substantial quantities of H2SO4 and Fe(OH)3 into local streams. This results from the reactions between air, water and pyrite (FeS2) 2FeS2 + 2H2O + 7O2 ® 2Fe+2 + 4HSO4– 4Fe+2 + O2 + 4H+ ® 4Fe+3 + 2H2O The acidic water is toxic to the plants and animals of an aquatic ecosystem. It also damages biological productivity. Alkalies discharged by industries such as textiles, tanneries and coke-oven operations can also destroy aquatic life. Mineral salts cause the hardness of water which have already been discussed in water treatment. Heavy Metals

The existence of heavy metals in aquatic environment has led to much concern over their influcence on the living organisms in these environments and indeed on man’s need for wholesome water. Most of these substances produce physiological poisioning by becoming attached to the tissues of aquatic organisms and accumulate. Many metals such as mercury, lead, cadmium and nickel are highly toxic as they accumulate in food chains and have a cumulative effect in humans. Cadmium solubility in water is influenced by the nature of the source of cadmium and the acidity of the water. The levels of cadmium could be higher in areas supplied with soft water of low pH. Acute effects have been seen where food has been contaminated by cadmium. Severe gastrointestinal upsets, bronchitis, emphysema, anaemia have been reported. Concentration of lead in natural water increases mainly through anthropogenic activities. Lead pipes are a serious source of drinking water pollution. Lead is present in industrial effluents from battery manufacture, printing, painting and dyeing, ceramics pesticides, plastics, etc. The insoluble galena (PbS) mineral is slowly oxidized into soluble lead sulphate after exposure to air. PbS + 2O2 ® PbSO4 In aquatic systems, lead has been found to be quite toxic to many organisms even in small concentrations. Lead is a cumulative poison and concentrates primarily in the bones. Mercury is discharged into natural waters from industrial effluents. It is extensively used in caustic soda, chlorine industries, manufacturing industries like batteries, vapour lamp fertilizers, pesticides, etc. Mercury has a great tendency to bioaccumulate in the form of methyl mercury and shows a greater capability of biomagnification through food chains. It causes irreversible brain damage. Heavy metal pollutants and their effects are listed in Table 14.7.

WATER POLLUTION

14.6

14.15

SEDIMENTS

The natural process of soil erosion gives rise to sediments and suspended solids in water. It consists of silt, sand, soil, clay and gravels which can produce the largest volume of water pollution as it represents the most extensive pollutants of surface water. Bottom sediments are important sources of inorganic and organic matter which can be subjected to anaerobic action. The sediments produce turbidity in water and consequently reduce the amount of sunlight available to aquatic biota. The sediments have the ability to exchange cation with surrounding aquatic medium.

14.7

RADIOACTIVE MATERIALS

The radioactive materials enter the aquatic environment through two broad sources: (1) Natural sources, (2) Man-made sources. The man-made sources can be further subdivided into four ways: (i) Mining and processing of ores. (ii) Use of radioactive materials in nuclear weapons. (iii) Use of radioactive materials in nuclear power plants. (iv) Use of radioactive isotopes in medical, research applications. Table 14.7 Interaction of various industrial pollutants among themselves and with the conditions prevailing in water (Based on McCaull and Crossland, 1974) Substances Arsenic Ammonia, ammonium ammonium hydroxide Cadmium Calcium Chlorine

Fluorides

Chromium

Interactions It is very poisonous, can cause cramps, paralysis and even death. Toxicity increases with increases in pH; toxicity to fish increased 200% when pH was raised from 7.4 to 8.0. Synergistic with copper; the toxicity of zinc and cadmium is additive. Antagonistic to lead, zinc, aluminium and toxic solutions of sodium, magnesium and potassium chloride salts. Toxicity increases with decrease in pH; combines with thiocyanate to form, paraoxan: combines with phenols and ammonia to form chlorophenols and chloramines, both toxic substances. Toxicity increases with decrease in pH. Above 1 mg/L cause fluorosis, mottling of teeth-enamel, nervous and skeleton disorders. With the decrease in oxygen toxicity of sodium, chromate increases.

Contd.

14.16

TOXICOLOGY

Cobalt sulphate Copper

Cyanide, hydrogen cyanide

Hydrochloric acid Manganese Mercuric chloride

Nitriloacetic acid Organochlorin insecticides

Phenol Lead

Sodium Sodium terrocyanide Sodium sulphide Sulfuric acid Zinc

Iron and manganese

Increase the toxicity of nickel. A high pH above 7 may reduce the toxicity by forming a precipitate of copper hydroxide; copper precipitates are also formed in water with high hardness; low oxygen increases the toxicity of copper; synergistic with chlorine, zinc, cadmium and mercury; antagonistic towards sodium nitrite and sodium nitrate, and decreases the toxicity of cyanide. Below pH 8, HCN is in undissociated form and is toxic; toxicity increases 2-3 times with 10°C rise in temperature; toxicity increases with fall in oxygen, highly toxic with zinc or cadmum. Toxic only when pH is below 5. Nickel and manganese are antagonistic. Synergistic with small amounts of sodium chloride; however, the effect is antagonistic with high concentration of sodium chloride. Synergistic with cadmium. Experiments with mammals show interaction with each other in biological tissues; for example, when aldrin, dieldrin, heptachlor or chlordane are fed to animals with DDT, the amount of these insecticides that is stored in body is greatly reduced a number of drugs such as barbiturates are also more quickly metabolized with DDT. At high temperature and lower hardness it becomes more toxic; toxicity is also higher at decreasing oxyge. Synergistic with calcium and a cumulative poison, causing loss of appetite, constipation, abdominal pain, nervous disorder, and brain damages. Antagonistic towards the toxicities of potassium, ammonium and calcium salts. Decomposes under sunlight to produce cyanide and hydrogen cyanide which are more toxic. Toxicity increases with decrease in pH from 9 to 6. Toxic when pH is below 5. Toxicity increases with increasing temperature and decreasing oxygen, toxicity decreases with increasing hardness; synergistic with nickel cyanide and copper toxicity of zinc and cadmium is additive. Stain fabrics cause off tastes and odour, modify colour in dyeing. Manganzese causes paralysis of lower limbs.

The natural sources of radioactivity consist mainly of the cosmic radiation received from the space, the presence of radionuclides in the lithosphere, hydrosphere and atmosphere. For example, 3H, 14C, 40K 82Pb, etc. Naturally occurring radionuclides on the earth’s crust are uranium, thorium, potassium-40, etc.

WATER POLLUTION

14.17

In man-made sources like in nuclear power plant, the most common fuels used for fission are uranium, thorium and plutonium. They produce low level radioactive liquid wastes. Radioactive substances can enter the humans with food and water and get accumulated in blood, thyroid gland, liver, bones and muscular tissues. These radioactive materials cause mutations leading to skin cancer or leukaemia and they damage the reproductive cells. They also reduce the effectiveness of certain enzymes. The average artificial radioactivity in the waters is much less than the natural radioactivity. But the much higher levels of radioactive elements exist for a short time in the water body. The waste disposal operations also maintain locally high concentrations of radioactivity. Based on the concentration of radioactive elements in water body, the waste waters may be classified into three categories, such as: 1. Low level wastes: These wastes may be liquid, solid or gaseous wastes having a very low radioactivity and are produced in large volume. 2. High level wastes: These are usually liquid or solid wastes having very high level of radioactivity and released in low volume. These wastes directly cannot be released into the environment without treatment. 3. Intermediate level wastes: These wastes are also in liquid or solid state with high enough radioactivity. These are also released in low volume with proper treatment. The movement of radioactive materials in the environment and their ultimate accumulation in human body or in other animals through the food chain by bioaccumulation and biomagnification processes. The radioactivity can be measured in terms of radiation emitted or in terms of radiation absorbed by an organism. Radioactivity is generally expressed in terms of Curie (Ci), Rad and Rem. Curie (Ci) is a unit of decay of an isotope and is equal to the radiation emitted by 1 gm of radium that corresponds to 3.7 ´ 1010 disintegrations per second. Rad: Rad refers to radiation absorbed dose and one rad equals to 100 ergs of energy absorbed by 1 gm of irradiated material (1 J/kg). Rem: Rem refers to ‘roentgen equivalent man’. Since different forms of radiations produce different biological effects which can be measured by a factor called relative biological effectiveness (RBE) is used in biology. Similarly, a factor called quality factor is used in human health to measure the relative effectiveness of different radiations to produce some biological effects. The dose in Rem can be calculated as: Dose in rem = Dose in rad ´ RBE For gamma and beta radiation 1 rem dose will be equal to 1 rad.

14.18

TOXICOLOGY

For alpha radiation, 1 rem dose will be equal to 20 rad. Similarly, for others are given in Table 14.8. Table 14.8

14.8

Radiations

Rad

Alpha (a) Gamma (g ) Beta (b) Neutron (n) X-rays

20 1 1 5 1

THERMAL POLLUTION

If there is any change in water temperature from normal levels it can adversely affect water quality and aquatic life. Aquatic temperature is more stable than the atmospheric temperature. Most of the thermal pollutions are caused by the human activities. The most important anthropogenic sources of thermal pollution are the coal fired power plant and industries which reject vast quantities of heat directly into water bodies. This could result in the increase in temperature of water bodies with deleterious consequences for aquatic inhabitants. The increase in heat contributes to the physical, chemical and biological changes in receiving waters. The temperature influences the viscosity, density, solubility, surface tension of water. As the temperature increases, there is a decrease in DO level in water which affects adversely to the aquatic life and simultaneously BOD level increases. Behaviour reproduction cycles, respiration rates, digestive rates and many other physiological processes are normally changed because of rise in temperature in water bodies. The Central Pollution Control Board (CPCB) of India has set up standards for thermal discharges from thermal power plants stipulates that the condenser cooling water should not have temperature more than 5°C higher than the intake water temperature. The maximum temperature of a thermal discharge (tww) in a water basin can be evaluated by using the formula: where

tww = (aQ/q + 1) tp + tmax tmax = maximum temperature water body at summer. tp = permissible temperature rise. Q = flow rate of water above the discharge in the water body. q = flow rate of thermal discharge.

a = mixing coefficient. If there is any change (raising or lowering) in water temperature from normal levels it can adversely affect water quality and aquatic life. Aquatic temperature

WATER POLLUTION

14.19

is more stable than the atmospheric temperature. Therefore, the aquatic organisms are not well adopted to the rapid change of aquatic temperature. Thermal pollution is considered as a local water pollution which refers to an accumulation of unusable heat from human activities that disrupts the aquatic environment. Most of the thermal pollutions are caused due to human activities. The most important anthropogenic sources of thermal pollution are the coal fired power plant and industries which reject vast quantities of heat direct into water bodies. This could result in increase in temperature of water bodies with deleterious consequences for aquatic inhabitants. The increase in heat contributes to the physical, chemical and biological changes in receiving waters. In general, the rates of chemical reactions decrease with decreasing temperature. The relative concentrations of reactants and products in chemical equilibria can also change with temperature. Temperature can, therefore, affect every aspect of the treatment and delivery of potable water. Increasing the temperature will also increase the vapour pressure of trace volatile compounds in drinking water and may lead to increased odour. Turbidity and colour are indirectly related to temperature as the efficiency of coagulation is strongly temperature dependent. The optimum pH for coagulation decreases as temperature increases Maudling and Harrish (1968). As temperature decreases, the viscosity of water increases and the rates of sedimentation and filtration decrease (Butterfield, 1943). The effect of temperature on corrosion in water treatment systems demonstrated that corrosion increased as a function of temperature. Sodium hydroxide adjustment of the pH halved this increase over the same temperature range. At temperatures below 10°C, however, water containing sodium hydroxide showed a higher corrosion rate than the untreated water. The corrosion rate is also a function of the dissolved oxygen concentration in the water. Dissolved oxygen variation with temperature is small compared to the much larger (and opposite) change in corrosion rates Mullen and Ritter (1974). The solubility product of calcium carbonate decreases with temperature. At low alkalinities however (50 mg/1 as calcium carbonate) the decrease in pH with increased temperature actually increases the solubility of CaCO3 (A WWA, 1971). Power plants along rivers which discharge waste water at significantly high temperatures into the rivers and cause thermal stress in the river system, should modify their cooling systems and discharge their wastewaters after spraying them into air before release into rivers. Many industrial processes involve evaporation or drying in which cooling water is needed. In the process only a fraction of the heat is converted to useful work and the rest is wasted.

14.20

TOXICOLOGY

The efficiency of an engine, i.e., to use maximum amount of heat to get maximum work which is given by second law of thermodynamics as: Wmax T – T1 = 2 =h Q T2

Now the heat goes waste = Q – Wmax = Q ´

T1 T2

where

T2 = Higher temperature of body T1 = Lower temperature of body. W = Work output Q = Heat input. It has been well established that efficiencies cannot be a unity, i.e., complete conversion of heat into work is just impossible. Even in most modern power plants and steel plants the efficiency does not exceed 40%. Hence, large amount of heat goes waste. The wastage heat is transferred to the coolant during condensation and the warmed water may become a thermal pollution in terms of the receiving water body.

14.8.1 Effects of Thermal Pollution The changes of aquatic temperature can contribute to the physical, chemical and biological changes in the receiving waters. Physical properties: The change in temperature generally influences the physical properties such as viscosity, density, solubility and surface tension of water. The influences of temperature on these physical properties are shown in Table 14.9. Table 14.9 Physical properties of water at various temperatures (Parker and Krenkel, 1969). Temperature °C

Vapour pressure (mm Hg)

Viscosity (centipoise)

Density (g /ml )

Surface tension dynes /cm

Oxygen solubility (mg /L )

Oxygen diffusivity (cm2/sec ´ 10 –6 )

0 5 10 15 20 25 30 35

4.579 6.543 9.209 12.788 17.535 23.756 31.824 42.175

1.787 1.519 1.307 1.139 1.002 0.890 0.798 0.719

0.99984 0.99997 0.99970 0.99910 0.99820 0.99704 0.99565 0.99406

75.6 74.9 74.2 73.5 72.8 72.0 71.2 -----

14.6 12.8 11.3 10.2 9.2 8.4 7.6 7.1

------15.7 18.3 20.9 23.7 27.4 ----

40

55.324

0.653

0.99224

99.6

6.6

---

WATER POLLUTION

14.21

As the temperature increases there is a decrease in DO level in water which affects the aquatic life adversely and simultaneously BOD level increases. Chemical effects: The kinetics of any chemical reaction increases with increase in temperature. According to the Arrhenius theory, with every 10°C rise in temperature the rate of the chemical reaction increases by two to three times. The significant effect is that BOD increases with temperature. The toxicity of some chemical pollutants increases with temperature; thus summer water carries more toxic elements. Biological effects: Behaviour, reproduction cycles, respiration rates, digestive rates and much other physiological process are normally changed because of rise in temperature in water bodies.

14.9

GROUNDWATER POLLUTION

Approximately more than one half of the population in India depends on groundwater as a source of drinking water. Groundwater pollution commonly from both anthropogenic and natural sources, susceptible to percolation or leaching process and osmosis process. The percolation or leaching efficiency depends on the texture, structure and porosity of the soil through which it occurs. This leaching or percolation water is a primary factor in carrying pollutants down through the soil profile. The dispersion of the pollutants in groundwater is greatly influenced by the rate of water movement and soil porosity. Anthropogenic sources include industrial waste water, modern agricultural practices like use of fertilisers, pesticides, etc., mining and dumping of radioactivity inside the soil. The natural sources include geological activities like volcanoes, weathering of rocks, etc. In this section about the leachates like what leachates are, and how and where they come from will be discussed. Table 14.10

Variations in leachate composition (Jenkins, 1974).

Analysis

Composition

pH Total hardness (mg/I as CaCO3) Total alkalinity (mg/I as CaCO3) Total Iron (mg/I) Sodium (mg /I) Potassoim (mg /I) Sulphate (mg/I) Nitrate (mg/I as N) Ammonia Nitrogen (mg/I as N) COD (mg/I) BOD(mg/I) Total volatile acids (mg/I CH3 COOH)

4.9–8.4 30—13, 100 100–20, 805 2–1000 85–1805 28–3770 24–1220 5–196 0.2–1106 246–750, 000 5.9–720, 000 < 100–10, 000

Total dissolved solids (mg/I)

1740–11, 254

14.22

TOXICOLOGY

Leachates: Leachates are stored in the bottom of landfills and from there it moves through the underlying strata–both lateral and vertical–depending upon the soil porosity and the characteristics of surrounding materials. But in most cases the rate of flow of groundwater is low and dilution of leachates is limited. When water entering a landfill exceeds the field capacity of the deposited refuse, leachate is produced. The quantity and quality of leachate escaping to the environment may vary considerably, depending on the nature of the refuse, the state and extent of its decomposition and reaction, and the chemical and physical characteristics of the percolating waters and the adjacent soil or cover. Attempts have been made to characterise leachate but due to the uncertainties associated with its origin and conditions influencing its nature, such information is usually only of value to display the frequent variances between individual samples, collection procedures and /or analytical techniques. A typical record of variations in leachate composition is not unlike that indicated in the table below (Jenkins, 1974). Although an explicit definition of the condition of the site and/or its pollutional potential is difficult from such data, it is possible to render some judgement concerning a possible degree or stage of stabilization which causes variations in leachate composition (Jenkins, 1974). Osmosis: This is another process by which the pollutants can enter into the groundwater. As the landfills are saturated with toxic pollutants and these can migrate through the unsaturated soil zone to groundwater, the movement of water body including pollutants from saturated zone (landfill) to the unsaturated zone (groundwater) is known as osmosis.

14.9.1 Fate of Pollutants in Groundwater Very often groundwater lacks oxygen which helps the microorganisms of anaerobic varieties to grow in that water. But the bacterial breakdown of pollutants is generally confined to the soil profile which dose not occur readily in groundwater. The bacterial decomposition of organic matter in soil or byproducts of reduction of sulphur from mineral deposits may produce carbon dioxide (CO2) and hydrogen sulphide (H2S) which are more soluble in groundwater than the surface water due to high pressure and temperature. Hence, the groundwater may contain considerably higher concentrations of these gases. Similarly, in anaerobic conditions, iron and manganese in +2 form are found in appreciable amounts in groundwater as they are more soluble. These +2 forms are more toxic than the +3 state. The effects of the groundwater pollutants will be the same as those of surface water pollutants.

14.10

MARINE POLLUTION

Ocean is an important component of the earth which regulate the global climate. Oceans are important in cycling of carbon dioxide, nitrogen, phosphorous and provide necessities such as foods and minerals to the aquatic biota as well as to other living organisms in the environment.

WATER POLLUTION

14.23

Ocean dumping contributes to the larger ocean pollution problem which affects the marine environment adversely and cause serious health hazards. The types of wastes dumped in the oceans include high levels of toxic chemicals, heavy metals, degrades and spoils industrial wastes, mine trailings, sewage sludge, disease-causing organisms, oils, radioactive substances, agricultural runoffs, farm and forest runoffs, sediments, plastic refuse and wastes of all kinds including biodegradable as well as non-biodegradable substances. The transport of huge quantities of oil through ocean sometimes creates a dangerous marine pollution due to oil spills. In the marine environment the pollutants are transported throughout a region by wind, currents, waves and tides so that they subject to various natural processes such as evaporation, dissolution, emulsification, sedimentation, oxidation and reduction.

14.10.1 Effects of Marine Pollution Marine pollution has a variety of effects on ocean ecosystems. But marine ecosystems have an enormous ability to recover from pollution problems and to regenerate biological communities. The effects of pollution may be stated as: 1. DO has low value and BOD, high value in oceans due to pollution. 2. The physical properties such as viscosity, density, solubility and specific gravity are affected. 3. The growth and metabolism of marine organisms are reduced. 4. The behaviour and habitat of ocean life are changed. 5. Cause of eutrophication and oligofication in oceans. These two will be discussed in detail.

14.10.2 Eutrophication The eutrophication is a natural phenomenon that occurs in lakes in which waters are rich in organisms and organic materials. Human activities can greatly accelerate eutrophication processes in which there is an increase in nutrient levels and biological productivity. The process of eutrophication is directly related to the aquatic food chain. The tropical or hot climate and increased nutrient flows usually support a higher rate of eutrophication as it supports higher nutrient utilization and algal growth. The various human activities such as industrial wastes, agricultural and domestic sewage runoff which are responsible for higher rate of eutrophication. The high biological productivity of eutrophic system leads to 'algal blooms' or thick growths of aquatic plants which use carbon dioxide, inorganic nitrogen, orthophosphate and trace nutrients for their growth. Increase in photosynthetic rate due to high algal growth leads to the consumption of greater amounts of bicarbonates resulting in the formation of carbonates raising the pH of water. It

14.24

TOXICOLOGY

also increases bacterial growth due to large amount of organic matter. The amount of plant growth and normal balance of the food chain are controlled by the limitation of plant nutrients. Through there is an algal bloom in marine environment it cannot be consumed as food by other organisms. Hence, there is an imbalance of normal succession. This water becomes opaque and has unpleasant tastes and odours. This algal growth will reduce the penetration of sunlight through water and also restrict atmospheric reoxygenation of the water. The dense algal growth eventually dies and the subsequent biodegradation produces as oxygen deficit, i.e., reduction of dissolved oxygen level in water. The decaying algae also settle to the bottom. The deposition of silt and organic sediment caused by eutrophication can accelerate the 'aging' of a water body. When the lake becomes marsh of debris, the stage is called eutrophic.

14.10.3 Oligophication Oligotrophic derives from the words oligo which means little and tropic which means nutrition. Thus, oligotrophic lakes are nutrient poor and biologically unproductive. When the lake is formed, it tends to have clear water with little nutrients, hence greater dissolved oxygen value in water. As it grows, the nutrients through water runoff from various human activities will be deposited and slowly oligotrophic will be transferred to eutrophic. As it is earlier mentioned the hot climate is best suitable for eutrophication, in contrast to that deep cold water will limit the plant growth and reoxidation of water by atmospheric air is more so that the water is transparent having high dissolved oxygen value. Oligophication is just the reverse process of entrophication. Mesotrophic is having the intermediate characteristics of both oligotrophic and eutrophic in which there is some aquatic plant growth, greenish water and moderate population of other organisms. Gradually this mesotrophic leads to eutrophic.

14.11

ENGINEERED SYSTEM FOR WATER POLLUTION CONTROL

An adequate supply of pure water free of deleterious chemicals as well as pathogens is absolutely essential for human consumption. Thus, unsafe natural water and waste should be treated to meet modern drinking water standards. In this section, we will discuss the conventional natural water treatment which is performed by two unit operations: (1) Settling and filtration. (2) Unit process of disinfection. In this conventional water treatment processes (both surface and groundwater) aeration, coagulation, and softening processes are followed to facilitate the degasification, settling and filtration processes. Settling and filtrations are unit operations that are used in similar ways in natural water treatment plants, waste water treatment plants, and other treatment plants. Therefore, a unit

WATER POLLUTION

14.25

process or a unit operation is that which is used in similar ways in different types of plants. For example, the unit operations are: settling, filtration, presedimentation, mixing, flocculation and storage. The unit processes are: aeration, softening and disinfection. The nature and extent of treatment depend on the nature and extent of pollutants. Figs. 14.3 and 14.4 are schematics of typical water treatment plants for surface water and groundwater respectively. Chemicals used Process

Raw water

Waste stream

Presedimentation

Chlorine Ammonia

1

Sludge removed periodically

Mixing flocculation settling

Alum Polymers

2

Sludge removed continuously

Filtration

Chlorine

3

Backwash water decanted

Disinfection

Chlorine

4

Storage

5 To distribution system

Fig. 14.3 Typical plant flowsheet treating turbid surface water. Process

Chemicals used Raw water

Aeration

1

Softening

Lime Soda ash

2

Filtration

Chlorine

3

Disinfection

Chlorine

4

Stroage

Waste stream

Gases to atmosphere CaCO3 Mg(OH)

Sludge removed Backwash water decanted

5 To distribution system

Fig. 14.4 Typical plant flowsheet treating hard groundwater.

14.11.1 Aeration Aeration is a process followed for saturating the water with oxygen. It may be used to remove undesirable gases like carbon dioxide and hydrogen sulphide

14.26

TOXICOLOGY

(H2S) into the atmosphere (degasification). Aeration is more often used to treat groundwater, as most surface water have been saturated with oxygen. It may also be used to oxidise undesirable metal ions like Fe+2 and Mn+2 to their higher oxidation states, +3 and +4 state respectively. These higher oxidation states of metals may be removed from water body as they precipitate out. 4Fe+2 + O2 + 10H2O ® 4Fe(OH)3¯ + 8H + 2Mn+2 + O2 + 2H2O ® 2MnO2¯ + 4H + In both the cases, the pH of the solution is lowered by the product of hydrogen ions. Chemical oxidants like KMnO4 sometime used with aeration to speed up the process. But the volatite liquids such as humic acids and phenols can be removed although at lower rate from water body by aeration. The process of aeration can be carried out by either dispersing the water into the air or by dispersing the air into the water. When water is dispersed into the air, the oxygen mass transfer from air to water and is based on the concept of a driving force. In general, the mass will always tend to fill a void space. Since the dissolved oxygen in water body is zero, the water is devoid of oxygen. Thus, oxygen will flow into it. The greater the void, the faster will be the rate. This void is known as here driving force. In other words, the voidness in water is the difference between the saturation value of the dissolved oxygen (C1) and the actual concentration of dissolved oxygen in liquid (Cs). Then, Cs–C1 is a void; it is the driving force for oxygen mass transfer to water at any time. In any case, C1 is greater than Cs, then desorption of oxygen will occur and it is shown in Fig. 14.5 (a and b). Absorption Cl > Cs

Gas film

Gas film Bulk gas

Desorption

Bulk liquid

Desorption

Liquid film

Cl < Cs Bulk liquid

Absorption

Absorption

Desorption

Liquid film

(a) Desorption

(b) Absorption

Fig. 14.5 Water dispersed in air.

The same principle of driving force is also applied to the dispersion of air into the water. In general, this approach works better for absorption (unsaturated water) than for desorption. It is shown in Fig. 14.6 a and b).

WATER POLLUTION

14.27

Absorption

Desorption

Gas film Gas film

Absorption

Bulk liquid

Cs > Cl Desorption

Bulk liquid

Bulk gas Absorption

C s < Cl

Desorption Liquid film Liquid film (a) Desorption

(b) Absorption

Fig. 14.6

Air dispersed in water.

In water purification plants, water in air systems consist of fountains, cascade towers or tray towers. Fountains consist of a piping grid with nozzles suspended over a catch basin to direct the waterflow upward as finer sprays depending on the size of nozzles. As the waterflow is directed upward, the finer sprays are in direct contact with atmospheric air. The water-air contact time depends on the height of the spray (Fig. 14.7). Finer sprays Catch basin

Inlet

Nozzles

Outlet (Acralted)

Fig. 14.7 Fountains water treatment plant.

Cascade towers consist of a series of waterfalls that fall into small pools where it is exposed to the atmospheric air. The greater the number of pools and thinner the height of water layer, the greater is the aeration. Thus, the number of steps determines the contact time between the water and the air (Fig. 14.8) Catch basin

Water pools

Fig. 14.8

Cascade towers of water treatment plant.

14.28

TOXICOLOGY

14.11.2 Settling or Sedimentation Settling or sedimentation in general, are classified into four important types depending upon the characteristics and concentrations of suspended materials in water body. Type 1 settling involves the removal of discrete particles whose size, shape, and specific gravity do not change with time. Type 2 settling involves the removal of flocculent particles whose surface properties are such that they aggregate with other particles upon contact, thus changing size, shape, and specific gravity with each contact. Type-3 settling involves removal of particles that settle in a centiguous zone, and type-4 settling involves settling where compression or compaction of the particle mass occurs at the same time. Dilute suspensions are those in which the concentration of particles is not sufficient to cause significant displacement of water as they settle. Concentrated suspensions are those in which the particles is too great to meet these conditions. In this chapter, only Type 1 and 2 will be discussed where Type 3 and 4 will be discussed in the chapter on purification of waste water. • Type-1 settling: Discrete particles in dilute suspension tend to act independently as the particles behave discrete with respect to each other. Thus, type-1 settling is also called discrete settling. If a particle is suspended in water, it has three forces; body force ( fg ), buoyant force ( fb ), and drag force ( fd ) acting upon it. According to the Newton's second law; fg – fb – fd = ma ...(1) where, m is the mass of the particle and a is its acceleration. Let, fp = mass density of particle fw = mass density of water Vp = volume of the particle g = the acceleration due to gravity. Then; fg = fP g Vp fb = fw g Vp Substituting these values in equation 1 ( fF ` fw) g Vp – fd = ma ...(2) Since particles alternately settle at its terminal velocity where the acceleration a is zero. ...(3) Then, (fP – fw) g Vp – fd = 0 Once motion has been initiated, the drag force (fd) is created due to viscous friction. This drag force is quantified by fd = CD Ap Fw

V

...(4)

The drag force is directly proportional to the dynamic pressure fw V / MDAHA V is the terminal settling velocity of the particle. CD is the coefficient of drag: Ap is the cross-sectional area of the particle perpendicular to the direction of movement.

WATER POLLUTION

AP =

pd 2 4

14.29

...(5)

4 p (d/2)3 ...(6) 3 where d is the diameter of spherical particle. Substituting the equation (4) into equation (3); (FP – Fw) Vp = CD AP Fw V2/2 ...(7)

Vp =

Vp Ap

4 p ( d / 2) 3 2 3 = = d pd 2 3 4

...(8)

Substituting equation (8) in equation (7) 4 ( f p – f w )d g 3 CD f w

V=

...(9)

The value of CD changes with characteristics of different flow regissmes is such that it arrives at the sampling part at a time t = t. Covering the distance Z0. Then the settling velocity is V0 =

Z0 Z or t = 0 t V0

Let another particle be initially suspended at a distance Zp above the sampling part and its terminal velocity be less than that of the particle at surface such that both the particles reach the sampling port at the same time, i.e., t = t. Then VP = t=

Zp t

or

Zp Vp

=t

Zp Vp Zp Z0 = or = V V0 V0 Z0 p

Based on the above equation, the salient features of type-1 settling are: 1. If dP ³ d0 and VP £ V0; then all the particles will arrive at the sampling part in time t. 2. If dP < d0 and VP < V0; then all the particles will arrive at the sampling port in time t, provided its original position was at or below point Zp. 3. If the suspension is mixed uniformly, then the settling efficiency of any size particle is the ratio of the settling velocity of that particle to the settling velocity V0 defined by Z0 /t0.

14.30

TOXICOLOGY

The settling efficiency h = VP/V0. Thus, the particles of velocities equal to or greater than V0 will all be settled. If x0 is the fraction of all particles having velocities less than V0; 1 – x0 is the fraction of all particles having velocities equal or greater than V0, then the fraction of particles that are settled with certainty is 1 – x0. Since the settling is proportional to the velocity of particle, then the portion in x0 that can be settled is (Vi /V0) x0 where Vi is the particles average velocity. Let dx be a differential of the remaining X0 with average velocity of the removable portion equals Vp. The partial removal in the fraction dx is therefore (VP/V0) dx. Then the total removal will be R = 1 – x0 +

z

X0 Vp

0

V0

sss dx

...(10)

where R = total removal of particles. In concentration terms, if the original concentration in the column is C0 and after a time interval (t) the concentration reached at sampling port is Ct. Then the fraction of particles remaining in the water column adjacent to part is (mass fraction) x =

Ct C0

...(11)

Mass fraction remaining (X)

From equation 10, we can plot the mass fraction remaining versus settling velocity in Fig. 14.9 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 .16 .48 .70 .85 1 1.25 1.5 2

3

4

–2

Settling velocity m/min ´ 10

Fig 14.9 Plot of mass fraction remaining vs. settling velocity.

• Type-2 settling: Type-2 settling involves flocculation particles in dilute suspension. Since the flocculation particles are continually changing in shape, size and have affinity toward each other, the Stokes' equation cannot be used here. These particles coalesce and form into flocs or aggregates. The velocity of the floc will therefore not be terminal but change as the size changes. In this case, the velocity becomes greater at

WATER POLLUTION

14.31

greater depth. It indicates that the increase in particle size and subsequent increase in settling velocity because of continued collision and aggregation with other particles. Thus, in type-2 settling, to catch the changing behaviour, multiple sampling ports are provided as in Fig. 14.10. Flow regimes of laminar, transitional, and turbulent flow, the values of CD are CD =

24 (laminar flow) Re

24 3 + 1/ 2 + 0.34 (transitional flow) Re R CD = 0.4 (turbulent flow) where Re is the Reynolds number

CD =

Re =

fvfwd m

For perfect spherical particle f = 1.0 Substituting CD value for Laminar flow V=

g ( Fp – Fw )d 2 18m

This equation is known as Stokes, equation. In an actual treatment plant, there are multitude of particles settling in a column of water. Therefore, an indirect method for measuring settling velocity was devised by Camp, 1943. The suspension in the column and mixing it completely to ensure uniform distribution of particles as shown in Fig.14.10. Water

Zo Zp

Sampling port

Fig. 14.10 Settling column for analysing type-1 settling.

Suppose that a particle is just at the surface at the initial stage of suspension i.e., let t = 0. Its settling velocity

14.32

TOXICOLOGY Water

Sampling port

Fig. 14.11

Settling column with multiple sampling ports.

The samples are drawn off at several time intervals and analysed for suspended solid concentrations. These concentrations are used to compute mass fraction removed at each depth and for each time.

FG H

xij = 1 –

IJ × 100 C K cij

o

where xij is the mass fraction in per cent at the ith depth at the jth time interval. Cij is the concentration removed at the ith depth at jth time interval. By plotting the different depth for each of the time parameters, an isoremoval graph is obtained (Fig. 14.12) 0

100%

Depth (m)

20 75%

40

60%

60 40%

80

20%

100 t1

t2 Time (min)

t3

t4

Fig. 14.12 Setting of flocculent particles.

The slope becomes steeper with greater velocity at greater depth.

14.11.3 Coagulation Coagulation is a process to remove colloidal particles from the water body. Colloidal particles sizes range from 1m to 50 mm approximately. Virtually all

WATER POLLUTION

14.33

surface water sources contain colloidal particles. To remove colloidal particles, special treatment is required, i.e., colloids must be destabilised by coagulation. The degree of stability of a colloidal particle is the result of the interaction of the potential force of repulsion and the van der Waals attractive force. When the van der Waals force of attraction exceeds the potential force of repulsion, coagulation of the colloid particles results and the colloid is destabilised. There are four general ways of coagulation: (1) double layer compression, (2) charge neutralization, (3) entrapment in a precipitate, and (4) intraparticle bridging. • Double layer compression: Structurally a colloidal unit may be viewed as an aggregate of thousands of molecules forming a sort of microcrystal. These microcrystals have an enormous surface area and hence pronounced adsorption characteristics. They absorb ions, either positive or negative from the environmental medium in which they are present. Thus, the colloidal particles are charged and are surrounded by opposite charges (counter ions). Theses opposite charges will, in turn, be surrounded by charges opposite to them, thus forming an electrical double layer. When the concentration of counterions in the dispersion medium is lesser, the thickness of the electrical double layer is larger. Therefore, the collidal particles cannot come closer to each other, thus the colloid units are stable. But when the concentration of counterions is more, then the colloidal charges are neutralised, causing the double layer compression. At this point, the van der Walls force will be predominant across the entire area of influence and will overcome the electrostatic force of repulsion, resulting in coagulation. • Charge neutralisation: The counter ions, i.e., 1st layer at the vicinity of the colloidal particles is known as the fixed part and the opposite charges, i.e., second layer surrounding the counter ions is known as diffusion part of the solution side of the double layer. Thus, the nature of the ions is of prime importance in the theory of adsorption and charge neutralization. The charge of a colloid can also be neutralized directly by the addition of ions of opposite charges that have the ability to absorb directly to the colloid surface. For example, if an indifferent electrolyte, aluminium sulphate of ferric chloride, is added AI+3 or Fe+3 ions will be preferentially absorbed on the fixed part of the solution side of the double layer. The colloidal particle with the fixed part of the solution side will now have a resultant surface density considerably less than before. The consequence will be the release of a number of H+ ions from the diffuse part of the double layer to the bulk solution affecting a contraction of the value of the zeta potential (the potential changes across the diffuse portion of the double layer. These ions have a great affinity for surface and are absorbed onto the surface of colloid where they are neutralised, hence the ionic cloud dissipates and cause coagulation.

14.34

TOXICOLOGY

Al+3 + H2O ® AlOH+ + H+ • Entrapment in a precipitate: When the electrolyte live Al2 (SO4)3 or FeCl3 is added, it undergoes hydrolysis to produce Al(OH)3. Al+3 + 3H2O ® Al(OH)3 + 3H+ The Al(OH)3 forms an amorphous, gelatinous flocs that are heavier than water and settle by gravity. Colloids may become entrapped in a floc and are close to each other, resulting in coagulation. • Intraparticle bridging: A bridging particle (synthetic polymer) is highly surface reactive and may attach one colloid particle to one of its active sites and another colloid particle to another site. Thus, several colloid may become attached to one polymer and several of the polymer colloid groups may become enmeshed, resulting in coagulation. With regard to coagulation, surface waters can be grouped into the four categories as below (O' melia, 1973). Group-1 High turbidity—low alkalinity: Relatively low dosages of coagulant is required for coagulation. Here adsorption and charge neutralization mechanism operates. Group-2 High turbidity—high alkalinity: Higher coagulant dosage is required and entrapment in a precipitate mechanism operates. Group-3 Low turbidity—high alkalinity: It is difficult to coagulate and entrap in a precipitate mechanism operation. Addition of turbidity is required to make it Group-2 and then coagulate it. Group-4 Low turbidity—low alkalinity: It is also difficult to coagulate. Addition of turbidity is required to make it group-1 then coagulate it.

14.11.4 Filtration Normally, filtration follows settling which involves passing the water through a stationary bed of granular medium. There are various modes of filtration (Fig. 14.13 a, b, c, d). These include (1) upflow filtration in which influent water is introduced at the bottom and subsequently pass through the sand bed in the upward direction and thus filtered, (2) biflow filtration in which the influent is split into two flows, (3) dual media filtration, and (4) mix media filter. While these filtrations may be used at specialised conditions, the most common use of filtration is gravity filtration in which the influent is introduced at the top and in allowed to flow downward, with the weight of the water column above the filter providing the driving force. Gravity filtrations are of two types based on their rate of filtration. (1) slow-sand filtration, and (2) rapid sand filtration. • Filter media: The filter media must be of the appropriate size and must be uniform. Therefore, silica sand is most commonly used in granular medium filters because of their uniform size and density. The smaller the size of granular media, greater is the filtration efficiency but have higher lead losses.

WATER POLLUTION

14.35 Influent

Effluent Fine Fine

Sand Effluent

Sand Coarse Coarse

Influent (a)

(b) Influent

Influent Inter mixing zone

Anthracite coal

Silica sand

Finer

Inter mixing zone

Coarse:anthracite coal

Silica sand

Finest

Effluent (c)

Fig. 14.13

Effluent (d)

Different modes of filtration (a) upflow, (b) biflow, (c) dual media, and (d) mix media filters.

• Dual media filters: Dual media filters are usually constructed of silica sand and anthracite coal at the depth range of 0.15 to 0.4 m and 0.3 to 0.6 m respectively. Size and uniformity coefficients of the two should be selected in such a way that they can produce a distinct mining zone which is the filter. Because of larger pore size of anthracite coal, bigger particle and flocs are removed. Similarly, smaller materials are filtered out by small pore size of silica sand. • Mixed media filters: Mixed media filters consist of a column having larger pore size media at the top, finer at the middle and finest at the bottom. It is also known as triple media filter. Here also the size and uniformity coefficients of these media should be selected to provide a distinct mixing zone.

14.36

TOXICOLOGY

• Slow sand filter: These filters were constructed of fine sand with an effective size ranges from 0.25 to 0.35 mm with uniformity coefficient ranging from 2 to 3. Slow-sand filters normally operate at a rate of 1 to 10 mgad (million gallons per acre per day). Because of the small size, all of the suspended material are removed at the filter surface. • Rapid sand filter: In rapid-sand filters, the effective size ranges from 0.45 mm and higher with uniformity coefficient ranging from 1.5 and lower. Silica sand is generally used in rapid-sand filter. Rapid-sand filters normally operate at a rate of 100 to 200 mgad.

14.11.5 Disinfection Disinfection refers to operations aimed at rendering of pathogenic organisms harmless. Sterilisation refers to complete vetting of all living organisms, therefore, generally not practiced in water treatment. The effect of disinfection on the reduction of water-borne disease and the effluent must meet the water standard and the coliform rule. A good disinfectant and must be toxic to microorganisms at concentrations well below the toxic thresholds to humans and higher animals. The disinfectant must be persistent enough to prevent regrowth of microorganisms in the distribution system. Normally, in the disinfection, the rate of kill of microorganisms follows first order reaction. dN = – kN dt

or

z

dN = – kdt on integrating. N

z

t dN = –k dt N0 N 0

In where

Nt

Nt = – kt or Nt = No e–kt N0

No = Intial present of microorganisms. Nt = Number of microorganisms at time t. k = Rate constant

• Disinfectant: Disinfectants include chemical agents such as the chlorine ozone, chlorine dioxide, and other disinfectants like irradiation with ultraviolet light (UV). • Chlorination: Chlorine may be applied as a gas (Cl2 ) or as the salts of hypochlorite [Ca(OCl2)2 and NaOCl ]. The reactions in water are as follows: Cl2 + H2O ® HOCl + H + + Cl –

WATER POLLUTION

14.37

Ca(OCl)2 ® Ca+2 + 2OCl– NaOCl ® Na + OCl– H +, OCl –, and HOCl depend primarily on the pH of the solution and they have very strong co-relationship as: HOCl ® H+ + OCl– HOCl is a stronger disinfectant that OCl–. According to Le Chatelier’s Principle, the higher the concentration of H+ ion, i.e., at low pH value, reaction shifts to left, so that more HOCl exists. Thus, to be more effective, the pH of the solution should be lowered. At pH 5.5 and below at temperatures of 0 to 20ºC, the concentration of HOCl is practically 100%. The sum of HOCl and OCl– is called the free chlorine residual. Being a strong oxidant, chlorine will react with reducing species such as Fe+2, Mn+2, H2S and nitrites. Thus, these oxidisable materials will consume chlorine before the formation of free chlorine residual (disinfectants). The amount of chlorine required for oxidation of reducing species must be determined and proper dosages of chlorine can be calculated as shown in titration curve. Destruction of chlorine residual by reducing materials Formation of chloroorganic compounds and chloramines 0.7

Free residual

B L) / g (m al

Free + combined residual

ed re sid

u

0.5

Formation of free chlorine and presence of chloro-organic compounds not destroyed

mb in

0.4 0.3

Break point

Co

Chlorine residual (mg/L)

0.6

Destruction of chloramines and chloro-organic compounds

s

0.2 0.1

Combined residual

A 0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Chlorine added (mg/L)

Fig. 14.14 Chlorine residual versus chlorine applied.

Reactions of chlorine with natural organics such as fulvic and humic acids produce undesirable chlorinated-hydrocarbon compounds and these by-products are suspected carcinogens. Minute quantities of phenolic compounds react with chlorine to form servers taste and odour problems. Therefore, the original organics must be removed before chlorination or undesirable compound formation must be prevented. The organic compounds can be removed by

14.38

TOXICOLOGY

adsorption onto activated carbon or their formation can be prevented by the substitution of chloramine. Chloramines do not react with organics, phenols or phenolic compounds, hence avoiding the formation undesirable by-products. Chloramines can be formed by first adding a small quantity of ammonia to the water, then adding chlorine. The reactions are as follows: NH3 + HOCl ® NH2Cl (monochloramine) +H2O NH2Cl + HOCl ® NHCl2 (dichloramine) +H2O NHCl + HOCl ® NCl3(nitrogen trichloride) + H2O The amount of each species of chloramines produced in these reactions depends on the pH, temperature, and concentration of HOCl used. The sum of the concentration of monochloramine and dichloramine is called combined available chlorine. The sum of free chlorine residual and combined available chlorine is called total residual chlorine (TRC). Chlorine may be added at several points within the water treatment process. Chlorine may be added just prior to filtration to keep algae formation at the medium surface and to prevent large populations of bacteria from developing within the filter medium. • Ozone: Ozone is a powerful oxidant produced in a high strength electrical field from pure oxygen or dry, clean air, which reacts readily with reducing species as organic materials without forming residual disinfectant. O2

High voltage

O+O

O + O2 O3 Ozone has been found to be more effective disinfectant than chlorine on inactivating resistant strains of bacteria and viruses. • Chlorine dioxide (ClO2): ClO2 is similar to ozone as a powerful oxidant. It does not form chloramines but is more effective in destroying phenolic compounds. It does not react chemically with water and its contact with light causes it to photooxidize, therefore, it is generated on-site, in aqueous form. Its principal application has been in waste water disinfection and often used in potable water treatment for oxidizing iron and manganese and for the removal of taste and odour. Its possible reduction to chlorate, which is toxic to humans, thus it is objectionable for the use in potable water. UV irradiation: Irradiation with ultraviolet light is a more effective disinfectant in inactivating bacteria and viruses and it does not produce any residual disinfectants. The most effective band for disinfection is from 2000 to 3000 Å. A power input of 30 mw/cm2 applied to thin sheets of turbidity-free water should be sufficient. The other disinfectants halogens bromine and iodine, the metals copper and silver, sonification KMnO4 electric current, heating or other physical means have been used.

WATER POLLUTION

14.39

EXERCISE 1. Define water pollution. How many types of water impurities are present in water body? 2. What are the different types of freshwater defined by CPCB? 3. What are the different types of water pollutants? State their sources of generation. 4. What is BOD? How it is related with water pollution? 5. Explain the terms DO and COD and what are the significances of these terms? 6. What are the disease-causing agents? Explain the activities of bacteria and viruses. 7. What is eutrophication? How does it form? How is it related to water pollution? 8. Discuss briefly the pesticidal pollution in water. 9. How does oil enter the living organisms and explain its effect? 10. What is acid mine drainage? 11. How the heavy metals pollute the water? Discuss the effects of heavy metals in water. 12. What are the different units of radioactivity? What are the different types of waste water based on presence of radioactive elements? 13. How does the detergent or soap pollute the water body and explain their effects on living organisms? 14. What is thermal pollution of water? State the thermal standards set for thermal power station. 15. Why sediments are considered as water pollutants?

CHAPTER

#

Toxicity Related to Soil 15.1

INTRODUCTION

Soil toxicity or pollution refers to degradation of physical, biological or chemical conditions in soil quality that becomes unsuitable for plant growth and microorganisms in the soil. Generally, soil serves as a reservoir of many toxicants and is also a major primary recipient of solid wastes, industrial waste products and chemicals. Since the soil toxicity adversely affects the flora and fauna, the amount and degree of soil degradation can alter the number of individuals as well as the number of species. It can also be defined in relation to its effects on plants and soil organisms in the soil environment. It is a great concern that potentially toxic chemicals added to the soil may be absorbed by plants in sufficient quantities to be harmful to humans and other animals. To understand the pollutants in the soil, the following points are to be observed. (a) Toxicants reactions in soil (b) The available means of managing the soil (c) Inactivation of soil Thus, the soil pollution may also be defined as any substance present in soil capable of changing the physical, chemical or biological characteristics of the soil to make them inactive and interfere with the quality of crop which adversely affects with the humans and other animals.

15.2

SOURCES OF SOIL TOXICITY

The sources of soil pollution are broadly divided into two groups as natural and anthropogenic sources. The natural sources include the natural activities like soil erosion, land degradation, landsliding, earthquakes and volcanoes. The anthropogenic sources include the industrial solid waste products, domestic wastes, municipality wastes, agricultural and farm wastes and deforestation.

15.2

TOXICOLOGY

15.2.1 Soil Erosion Erosion is an important natural process and is a more destructive phenomenon than the other ones when it occurs in wrong place at the wrong time. Soil erosion is serious in all climates. Since, wind as well as water can be the agent of removal of soil. Soil erosion refers to the wearing away of the land surface by running water, wind, ice and other geological agents. There are two types of soil erosion observed. These are (1) natural or geological and (2) anthropogenic or accelerated erosion. There are some major causes of soil erosion like: Deforestation: Deforestation refers to the destruction of forest cover indiscriminately. As the vegetation cover is lost, the soil is not tightly held and exposed to the erosive agents like water run-off, wind and ice. Thus, there is a soil erosion. Overgrazing: Overgrazing of the grassland also exposes the soil to the erosive forces. Agricultural practices: The excessive ploughing of the soil leads to soil erosion as much of the soil surface is exposed to the erosive forces. There are some controlling methods to check the soil erosion, such as: (1) Stop deforestation and overgrazing of grasslands. (2) Afforestation of the openlands. (3) In the slope areas, build small barriers to check the velocity of water runoff. (4) Change in the agricultural practices.

15.2.2 Land Degradation Land degradation is also one type of soil pollution where it refers to degradation of soil quality and made unfit for human habitat. Land degradation is broadly categorized into four types such as: Light degradation: In this process, part of the removed. In this type about 70 to 75% of natural vegetation remains at their places. However, soil loss is greater than the replacement state. Moderate degradation: All topsoils are removed. As a result nutrients are depleted or toxic chemical build-up. Soil no longer absorbs and retains water. Only 30 to 50% of natural vegetation remains. Severe degradation: In this type of soil degradation, deeper and more frequently gullies. Severe nutrient depletion and toxification. Less than 30% vegetation remains. Restoration of this soil is difficult. Extreme degradation: No vegetation remains at all. Restoration is impossible. The causes of land degradation are caused due to the following factors:

TOXICITY RELATED TO SOIL

15.3

(1) Industrialization, (2) overgrazing (3) deforestation, (4) overexploitation of soil and (5) agricultural activities. The other factors are soil erosion, salination, acid rain, desertification, urbanization, mining, and nuclear explosion responsible for land degradation. The land degradation can be controlled by installing water and wind barriers, contour terracing, plantation, crop rotation, strip farming and dry land farming. Acid rain effects can be minimized by applying suitable quantity of lime. If the land is managed properly and efficiently, this natural resource has long-term sustainable potential for production.

15.3

TYPES OF SOIL TOXICANT

There are six general kinds of soil pollutant. These are as: (a) Pesticidal toxicants (b) Inorganic toxicants (c) Solid wastes (d) Radionuclides (e) Soil salts (f) Acid rains Once these materials enter the soil, they become part of a cycle that affects all forms of life. The toxic materials may be absorbed by plants in sufficient quantities to be harmful to humans and other animals.

15.3.1 Pesticides in Soil or Pesticidal Toxicity The pests are undesirable competing organisms that reduce the availability of quality or value of resources useful to humans. The major agricultural pests include the insects, nematodes, bacteria, weeds, and vertebrates which feed on different parts of plants. In the modern agricultural practices, the synthetic pesticides commonly known as perfect pesticides have been developed to prevent or kill the particular pest species without harming the other forms of life. The indiscriminate and excessive use of synthetic chemical pesticides has caused serious ecological damage and long-term harm to human health. In addition to negative environmental effects on soil, the pesticides have other major drawbacks such as: 1. Pesticide resistance: Some pest organisms have developed resistance to the chemicals as every population contains some diversity in tolerance to adverse environmental effects. Therefore, higher dosages or new chemicals should be developed to control them. The pesticide resistant genes are being transferred from one species to another through vectors like viruses and plasmids.

15.4

TOXICOLOGY

2. Effect on non-target species: About 5 to 10% of the pesticides applied may contact the target organisms and the rest (90%) moving into the soil where many beneficial organisms (flora and fauna) are adversely affected. The chemicals in the soil can build up in organisms as movement up the food chain occurs. 3. Secondary pest outbreak: By the excessive use of pesticides, there is a reduction in one target species which reduces the competition with a second species. In consequence the second species increases and becomes a pest. 4. Persistence and mobility in the soil environment: Some pesticides are not readily biodegradable and tend to persist for years in the environment. The stability, high solubility and high toxicity of some pesticides cause a serious threat to the soil quality and other lives in the soil. For example, organo-chlorine pesticides persist in the soil environment and are not easily biodegradable. The different kinds of pesticides have already been discussed in the chapter on water pollution.

15.3.2 Behaviour of Pesticides in Soil Pesticides are commonly applied to plant foliage or on the soil surface which eventually enters into the soil and affects the soil environment due to their various chemical reactions and behaviour in soil. The fate and movement of pesticides in the soil are as follows: (i) They undergo chemical reactions with the different soil components. (ii) They may be absorbed by the soils. (iii) They may be leached or percolated downward through the soil profile. (iv) They may be decomposed by the soil microorganisms. Chemical reactions: Many pesticides undergo hydrolysis and subsequent degradation depending on soil temperature, pH value, soil water and air, and other minerals. For example, degradation of Malathion (organophosphate insecticide) (CH3O)2

P S

S

CH

COOC2H5

CH2

COOC2H5

H2O OC2H5

S

HO

CH

CO

H2C

CO

OC2H5 + (CH3O)2 P

H

The organophosphate insecticide undergoes hydrolysis and subsequent absorption in the soils.

TOXICITY RELATED TO SOIL

15.5

Absorption: Depending on the molecular structure of the pesticides, i.e., the presence of functional groups such as —OH, —NH2, —NHR, —CONH2,— +

COOR and — N R3 in the molecular structure are more favourable for absorption in soils, particularly in the soil humus. This adsorption is further encouraged due to hydrogen bonding present in it. The larger the size of the pesticide molecule, greater is the adsorption. The adsorption of pesticides are greatly influenced by the presence of organic matter, clay minerals particularly silicate and the pH value of the soil. Percolation or leaching: Some pesticides are readily soluble in soil water and their downward movement through the soil depends on the downward movement of the soil water. The leaching process is more favourable in porous soils, i.e., permeable sandy soils. This percolation or leaching process is reduced in nonporous soils like in clay and soils having high amount of organic matter. In general herbicides are more mobile than insecticides or fungicides. For example, DDT has a very high mobility in soil. Decomposition by soil microorganism: The presence of certain polar groups like —OH –, —COO –, —NH –2 and NO2– help in biochemical degradation of pesticides by soil organisms. Most of the organic fungicides are subjected to microbial decomposition. Those pesticides do not degrade, have potential for environmental damage. It is evident that the risks or environmental pollution are the highest with those pesticides with greatest persistence.

15.3.3 Effects of Pesticides on Soil Organisms Different pesticides have different effects on different organisms. The extensive use of pesticides adversely affects specific groups of organisms, some of which carry out important processes in the soil. Particularly fumigants have a more drastic effect on both the soil fauna and flora, i.e., the number of species of both flora and fauna reduces to a large extent. On the other hand, the total number of bacteria increases after fumigation due to absence of competitors and predators. Some beneficial organisms like organisms responsible for nitrification and nitrogen fixation are often adversely affected by the extensive use of pesticides. But the negative effects are temporary and can be recovered very shortly.

15.4

INORGANIC TOXICANTS IN SOILS

The soil has been contaminated by a large number of inorganic compounds including some heavy metals which are toxic to humans and animals. The toxic effect of these inorganic contaminants are multifolded, i.e., they can also adversely affect the aquatic environment. The toxic substances adversely affect the soil flora and fauna that will be discussed later in this chapter.

15.6

TOXICOLOGY

Sources: Atmospheric air and to some extent water are the main transporters of inorganic contaminants to the soil. The inorganic contaminants are generated from the burning of fossil fuels, smelting, mining and other industrial processes and they enter into the atmosphere. These aerosol dust particles may be carried for miles and later deposited (wet or dry deposition) on the vegetation and soil. Some contaminants are carried away by the soil water and deposited elsewhere. The deposition depends on the soil water movement. After reaching the soil, these toxic elements become part of the life cycle of soil ® plant ® animal ® human and they accumulate in animal and human body tissues to toxic levels. Humans are most affected as it holds the top position in the food chain. The inorganic contaminants are compounds containing mercury, calcium, nickel, zinc, lead, arsenic, manganese, molybdenum, boron and flourine.

15.4.1 Behaviour of Inorganic Toxicants in Soils In soil chemistry, the heavy metals like zinc, cadmium, copper, nickel and manganese are very closely correlated to each other and undergo almost similar type of chemical reactions in the soil. For example, at pH value of 6.5 and above all these metals tend to be slowly available to plants in higher oxidized forms. Consequently, most soils will tie up relatively large quantities of these elements if the soil pH is high. At this point Cu, Cd, Zn are sorbed in the soil more rapidly than Fe, Mn and Ni. The adsorption of Cu and Zn in the soil mainly depends on the pH, inorganic and organic ligands available in the soil, Fe/Mn oxide concentration, etc. Iron and manganese are strongly adsorbed in the soil. Thus Fe and Mn are not readily released to the bulk of soils for plants at the higher pH range. At higher pH range the solubility of heavy metals Cu, Cd and Zn in soil water is more than that of Fe and Mn. The metals, Fe and Mn, have a stronger affinity to the ligands than Cu, Cd and Zn as Fe > Cu > Ni > Zn. Therefore, Fe and Mn are strongly absorbed in the soil and strongly bond with the ligands available in the soil with high binding energy. Since, Fe and Mn oxides are sinks for Cu, Cd and Zn, these metals are not readily available for the ligands. Thus, at lower pH these heavy metals are readily available to the plants (Pani, 1993). It is evident that the concentration of heavy metals is more at the lower depths. The leachability is mainly dependent on the pH of water and soils. In the acid the metal species can be leached out to the lower depth which can contaminate the groundwater. The inorganic mercury compounds react quickly with the organic matter and clay minerals to form insoluble compounds and thus unavailable to the growing plants. Similarly, lead is unavailable to plants. Arsenic is adsorbed by hydrous iron and aluminium oxides, so they are unavailable to plants. At the lower pH value of the soil boron is available for plant growth but at high pH they are adsorbed by organic matter and clay minerals. The boron and fluorine toxicity are generally localized. Fluorides are insoluble, so they are unavailable to plants.

TOXICITY RELATED TO SOIL

15.5

15.7

SOLID WASTE IN SOILS

Solid waste commonly known as “third pollution” arises from human and animal activities. These are normally solid substances discarded as useless or unwanted. It consists of the highly heterogenous mass of diversified residential and commercial activities as well as the more homogeneous accumulations of a single industrial activity like agricultural, industrial and mining wastes. Generally, the wastes derived from urban, rural and agricultural activities are known as organic wastes.

15.5.1 Types of Solid Waste Solid wastes may be classified based on their sources, composition and physical and chemical properties. The solid wastes are classified into four general categories: (a) Municipal wastes (b) Industrial wastes (c) Hazardous wastes (d) Agricultural wastes (a) Municipal wastes: Municipal wastes are generally organic wastes derived from the rural and urban human activities. The municipal solid wastes are further classified as: (i) Garbage: It refers to fruit or vegetable residues resulting from the handling, preparation, cooking and eating of food. These wastes have a moisture content of about 70% thus they get decomposed quickly, particularly in hot weather. (ii) Rubbish: It refers to combustible and non-combustible solid wastes excluding non-putrescible solid wastes. Combustible wastes include paper, plastic, wood, leather, rubber and textiles. Non-combustible rubbish consists of metals, glass, ceramics, tin cans, aluminium cans and construction wastes. These wastes contain a moisture content of about 25% thus are less decomposable in comparison to garbage. (iii) Pathological wastes: Dead animals, human wastes, etc., fall under pathological wastes which are highly decomposable since they contain about 85% moisture. (b) Industrial wastes: These wastes are generated from the industries. The wastes include chemicals, paints, metal ores, sewage treatment sludge and are classified as: (i) Fly ash and residue: These are generated from the industries by the process of burning of fossil fuels and other combustible wastes. Fly ash and residues are composed of fine powdery materials, partially burnt materials, etc.

15.8

TOXICOLOGY

(ii) Treatment plant wastes: The solid and semi-solid wastes as sewage treatment sludge and other industrial wastes. (iii) Construction wastes: A lot of wastes are generated from the sites of buildings construction, roads, industries, bridges, dams, etc. These wastes include stones, bricks, plaster, plumbing, heating and electrical parts. (c) Hazardous wastes: A waste is said to be hazardous when it has the following characteristics. (i) they are highly reactive. (ii) they are highly toxic to all forms of lives. (iii) they are highly corrosive. (iv) They have high ignitability. The hazardous wastes generate from both domestic and industrial sewage sludges. They include the radioactive substances, chemicals, flammable wastes, explosives and biological wastes. (d) Agricultural wastes: The agricultural wastes include farm animal manures, crop residues, etc.

15.6

RADIONUCLIDES IN SOILS

The earth’s crust contains some radioactive nuclides which continually emit radiation U-238, Th-234, Ra- 226 are present in rocks, soil and natural building materials. The refining of uranium ore is an important source of radioactive waste producing redionuclides of radium, bismuth, etc. The naturally occurring radionuclides K-40, C-14, Rb-87 and Rn-222 undergo a number of fission products. However, only two of these Strontium-90 and Cesium-137 are sufficiently long-lived to be of significance in soils. These radionuclides enter the human body through food chain. Radioactive fallout resulting from nuclear weapons testing from the atmosphere directly on the vegetation is the primary man-made source. Soil is also used as a dumping ground of low level radioactive waste materials. The other sources are from the increasing use of radio isotopes in industry, research, medicine and nuclear reactors which contribute to a significant amount of radionuclei to the soil environment. Even the solid radioactive materials when placed in shallow-land burial pits, some dissolution and subsequent movement in the soil are possible. Radionuclides in wastes vary greatly in water solubility, for example, uranium compounds are quite soluble, followed by cesium compounds. The compounds of plutonium and americium are generally less soluble. The solubility nature is due to the charges carried out by the nuclides. Cesium is positively charged, so it is absorbed by soil colloids, particularly by humus. But uranium is present as a negatively charged complex, so it is adsorbed by clay minerals of the soils. Since, the charge on the plutonium and americium depends on the nature of the complexes, these elements are less soluble.

TOXICITY RELATED TO SOIL

15.9

The radioactive substances can enter humans with food chain which is generally monitored from the actual uptake by plants of these nuclides from soils. The uptake value of plants from soils depends on the presence of organic matter and pH value of the soil. The uptake value of plants for different nuclides are different. The uptake value of plants for some nuclides are: Uptake value of plants for nuclides neptunium > americium > curium > plutonium The uptake value of plants for plutonium is the lowest and for neptunium the highest. Generally, it is found that leaves carry more nuclides than the fruits and seeds. Therefore, fruits and seeds have less nuclides contamination. The effects of radionuclides on humans and animals have already been discussed in the chapter on water pollution.

15.7

SOIL SALINITY

Contamination of soils with salts also interfere seriously with the growth of most plants thus it is considered soil pollution. The build-up of salts on the soil surface is due to salt laden irrigation or due to the movement of salts to the plant rooting zone. This salt concentration further increases due to irrigation in poorly drained soils, so that the salts are accumulated at a particular region and the salts move upward from the lower horizon and concentrate in the surface soil layers. Based on the types of salt and their accumulative capacity on the surface soil layers, the soils may be classified into three groups viz. saline, saline-sodic and sodic. Saline soils sometimes called white alkali soils where generally neutral soluble salts are accumulated in sufficient quantity to cause a serious threat to the plant growth in which the pH value is less than 8.5. About 10 to 15% of the cation exchange capacity of these soils is occupied by sodium ions. But this is more than 15% in case of saline-sodic soils. In these soils the salts are mostly chlorides and sulphates of sodium, calcium and magnesium which can readily be leached out of these soils with no rise in soils pH value. Sodic soils are more toxic to plants than saline or saline-sodic soils because of large quantity of sodium and hydroxyl ions. The pH is also (about 9.5) for which hydrolysis of sodium carbonate occurs. Na2CO3 + 2H2O ® 2NaOH + H2CO3 Na Micelle + H2O ® H Micelle + Na+ + OH – In this soil more than 15% of the cation exchange capacity is occupied by sodium and this soil may be called black alkali soil. The sodium hazard is expressed as exchangeable sodium percentage (ESP) as: ESP =

Exchangeable sodium ´ 100 Cation exchange capacity

15.10

TOXICOLOGY

The salt laden irrigated water in which the measure of potential hazards from high sodium levels is calculated on sodium adsorption ratios (SAR). SAR =

[Na + ] [Ca +2 ] + [ Mg +2 ]

where, [Na+], [Ca+2], [Mg+2] are the concentrations of these ions in a soil extract or irrigation water in millimoles per litre. The water having 0 to 10 SAR value is suitable for all types of crops and all types of soil except for those crops which are highly sensitive to sodium. Water having an SAR of more than 18, is harmful to almost all type of soil.

15.8

EFFECT OF ACID RAIN ON SOILS

The acid rain and its causes have already been discussed in detail in chapter on air pollution. Here, we will study the effects of acid rain on soils. Generally, acid rain increases the acidity of the soil to less extent than water. Because soils generally are sufficiently buffered with the buffering agents like CaCO3 to accommodate acid rain with a little increase in soil acidity. But if it continues for several years, then the soil acidity increases significantly having a pH value of even 4 to 4.5. Particularly in a weakly buffered region, this effect is more vagarious and causes a serious threat to soil environment. The immediate effect is that the fertility of the soil decreases sharply.

-:-4+151. 2. 3. 4. 5.

6. 7. 8. 9. 10. 11. 12.

What are the different sources of soil toxicity? What is soil erosion? How does it occur? What do you mean by land degradation? What are the causes of land degradation? What are the different types of soil toxicants? Explain them. Write short notes on: (a) Pesticide resistance: (b) Secondary pest outbreak. (c) Persistence and mobility of pesticides in soil environment. What is the fate of pesticides in soil environment? Explain the effects of pesticides on the soil organism. What are the different types of solid wastes? Explain them. Give the significance of exchangeable sodium percentage (ESP) and sodium adsorption ratio (SAR). Discuss the effects of acid rain on soils. Explain about the radionuclides in soils. What is soil salinity? Explain the effects of soil salinity.

CHAPTER

16

Ecotoxicology 16.1

INTRODUCTION

The word “ecotoxicology” is a combination of two words “ecology” and “toxicology”. Ecotoxicology is concerned with the study of potentially harmful chemicals (toxins) and their effects upon the ecosystem. Ecotoxicology needs proper understanding of ecological principles and theory which will help to assess that how chemicals can affect individuals, populations, communities and ecosystems (Hoffman et al., 1995). Ecology forms the basis for ecotoxicology which can provide a framework for the formulation of ecotoxicological theory. Ecotoxicology is a discipline within the wider field of environmental toxicology. Ecotoxicology mainly concern with the cause and effects of toxic substances on the ecosystem particularly at higher levels of organization. The natural environmental factors regulate or influence the life cycles of organisms, genetic variability as well as the effects of toxic substances. Thus, the ecological approach to toxicology yields more accurate values of toxic substances (chemical concentrations) in the environment. This accurate ecotoxicological knowledge may be used to determine the seriousness of pollution and with reasonable accuracy the maximum amounts of allowable concentration of a substance emissions into the environment. Ecotoxicology deals with very complex systems and it is not possible to know all the details of all ecological components and processes involved in ecotoxicological problem. But it is possible to apply a number of theories from modern ecology to the analysis of environmental problems by considering at least the most important components and proceses. Hoffman et al. (1995) have offered the descriptions of ecotoxicologic methods and procedures. The ecotoxicologic method is based on the interaction between an individual organism and environmental factors, biological factors like uptake and excretion rates, biological concentration factors and ecological magnification factors.

16.2

TOXICOLOGY

The aquatic and terrestrial ecosystems have different parameters to regulate the life cycle of organisms and toxic effects. Therefore, the ecotoxicology for both aquatic and terrestrial ecosystem should be studied separately. This chapter addresses ecology, aquatic and terrestrial ecotoxicology.

16.2

ECOSYSTEM

The biotic community along with its habitat is known as an ecosystem (Tansley, 1935). A community is an aggregate of organisms which form a distinct ecological unit. Thus, the ecosystem may be defined as a specific biological community and its physical and chemical environment interacting with each other. In simple terms, an ecosystem includes and sustains life. Generally, an ecosystem includes the life—at least an autotrophs, a consumer, a decomposer and life sustaining elements like air, water, soil, energy and other essential elements. Habitat is a specific set of physical and chemical conditions (for example, space, substratum, climate) that surrounds a single species, a group of species or a large community (Clements and Shelford, 1939). The ultimate division of biosphere is the microhabitat and greater than microhabitat is called macrohabitat. Microhabitats are mostly intimately local and immediate set of conditions surrounding an organism, for example, the borrow of a rodent. Thus, an ecological community is a set of interrelated species that occur at the same place. Since plants, animals, bacteria, fungi, etc. all occur together in the same habitat and they are interrelated, they cannot survive independently. The composition and character of the biotic community is the strong indicator of the type of environment that is present. The biotic community may be grouped into two parts based on their sustaining ability as: (1) Major community. (2) Minor community. Major communities are those which along with their habitats form more or less complete and self-sustaining ecosystems (sunlight is excluded). The minor communities are the secondary aggregations within a major community and are not completely independent ecosystem. The biological ecosystems have three important characteristics, such as ecosystem has (1) structure, (2) processes, and (3) succession.

16.3

ECOSYSTEM STRUCTURE AND COMMUNITY DYNAMICS

The ecosystem may be natural or man-made ecosystems. The natural ecosystems may be further categorised as (i) Terrestrial, and (ii) Aquatic ecosystems. These ecosystems are further subdivided as shown in the flow chart (Fig. 16.1).

ECOTOXICOLOGY

16.3

Ecosystem

Natural

Aquatic ecosystem

Terrestrial ecosystem

Desert

Forest

Man- made

Land

Grasslands

Tundra

Gardens

Parks

Lotic (Running) springs, rivers

Fresh lakes, ponds

Fig. 16.1

Farm lands

Lentic (Static)

Saline lakes, oceans, estuaries, etc.

The flow diagram of ecosystem.

Each ecosystem has two important components, namely, (i) biotic component (living organisms) and (ii) abiotic component (non-living things). The biotic component is further subdivided into three important units such as producers, consumers and decomposers. Similarly, abiotic component is further subdivided into physical and chemical components shown in Fig. 16.2. Components of ecosystem

Biotic

Abiotic

Producers

Consumers

Decomposers

Herbivores

Carnivores

Top carnivores

Physical • Light • Temperature • Climate • Rain, humidity • Air, water, soil, etc.

Chemical • Oxygen • Carbon • Nitrogen • Minerals • Organic matters ,etc.

Fig. 16.2 Flow diagram of components of the ecosystem.

Terrestrial Ecosystem Terrestrial ecosystem refers to the ecosystem other than ecosystem of water body, i.e., the terrestrial ecosystem consists of three important biotic provinces or ecosystems, namely: (a) Grassland ecosystem (b) Forest ecosystem, and (c) Desert ecosystem. A biotic province is a region inhabited by a characteristic set of species or

16.4

TOXICOLOGY

families bound by barriers that prevent the spread of the distinctive kinds of life to other regions and the immigration of foreign species (Lentine J.W., 1973).

Grassland Ecosystem Grasslands occur in temperate regions which is moderately a dry climate. The grassland vegetation is completely renewed each year. Grasses may be divided into three categories based on their height as tall grasses (1.5 to 3 m), mid grasses (0.5 to 1.5 m) and short grasses (< 0.5 m). The grassland community typically contains subterraneans, surface and herb strata of vegetation. In temperate grasslands, the dominant species are grasses and other flowering plants, many of which are perennial with extensively developed roots. The grasslands are named differently at different regions such as: Region Grassland North America Prairies Eurasia Steppes South America Pampas South Africa Veldt Because of the dry habitat of grasslands, insects are abundant. The vast majority of populations are restricted to soil, litters and shrubs as grasslands have few trees because of inadequate rainfall. These insects are, such as spiders, ants, leaf hoppers, millipedes, earth worms, etc. Birds are not numerous in grassland. Sparrows, marsh hawk, owls, etc. are generally found in grassland ecosystem. The secondary consumers like fox, wolf, jackals, snakes, hawks are also found in the grassland ecosystem. Grazing animals (primary consumers) are also found in abundance such as cows, buffaloes, deer, sheep, goats, horse, zebra, kangaroos, etc.

Forest Ecosystem The climatic conditions mainly, temperature and precipitation determine distribution of biome in the forest ecosystem. Forests are composed of trees growing sufficiently close together to dominate the entire area of ground surface. The forest vegetations are mainly of two types, namely, closed canopy and open woodland forests. In a closed canopy forest the leaves and twigs of adjacent trees touch each other. In open woodland only some leaves and twigs of adjacent trees overlap (Fig. 16.3).

ECOTOXICOLOGY

16.5

Closed Canopy Forests

Open Woodland

Fig. 16.3 Closed canopy and open woodland.

According to the climatic conditions, the composition of forest may vary. Approximately one-third of the land is covered by forest. forest in terms of ecology includes a complex organism comprising distinct biological units (plants and animals) called forest communities. In warm and moist climates, the forests are mostly broad leaved deciduous, in cold climates they are mostly needle leaved evergreen, and in continuously warm and moist climates the forests are broad leaved evergreen. Based on the climatic conditions, the forest ecosystem may be broadly grouped into the following forest ecosystems: (a) Deciduous forest (b) Coniferous forest (c) Woodland (d) Tundra

16.6

TOXICOLOGY

Deciduous Forest The temperate deciduous forests grow in regions with hot and wet summers. The deciduous trees shed their foliage in the autumn, are bare over winter, and develop new foliage in the spring. The climax of the deciduous forest biome is a community dominated by broad leaved trees. The basic difference of deciduous trees from other trees is the decomposition of broad leaves is rapid and relatively complete to form a rich humus that mixes gradually with the mineral soil. The deciduous forests are best developed in eastern North America, Western Europe and Eastern Asia. The trees usually form relatively dense forests with a closed canopy. The deciduous trees shed their leaves during autumn which consequently affects the seasonal change in forest microclimates, to which animal life must respond. In these forests large mammals are less but birds and insects are abundant. The dominant animals are small mammals including those living in trees such as monkies, squirrels, mice, etc.

Coniferous Forests Coniferous forests are largely confined to the northern hemisphere. This forest is a continuous, often dense, forest of needle or scale leaved evergreen trees. The needle-like evergreen leaves with a thick waxy coating prevent excessive evaporation of water during summer and dry periods, and are adopted to withstand harsh winters. These forests are found on the climatic conditions of low precipitation, low moisture content and short summer growing season. Fire has been an important regular factor in coniferous forests, because the waxy dead, dry needles which cling to the trees feed devastating crown fires. The dominant conifers are pine, hemlock, spruce, cedar, larches, poplars, firs and birches. The dominant animals are shrews, flying squirrels, wolf, fox, bear, lynx, deer, etc. The basic difference of coniferous from deciduous forest is the needle waxy leaves of conifers decompose slowly and form a somewhat acid humus sharply defined from the underlying mineral soil.

Woodland Woodland is an open stand of trees where the leaves and twigs of some trees only overlap. In woodlands, trees are short in height. They may form closed canopy but they are scattered so the forest floor is continuously covered with grasses. The trees vary widely in leaf structure, but nearly all species are adopted to the harsh summer. These vegetation covers are evergreen and they are capable to do photosynthesis in poor conditions also (in dry summer). The dominated vegetations are pinyon pines and evergreen oaks. The trees are scattered, allowing considerable sunlight to reach the ground. Fire is the common disturbance in woodlands.

ECOTOXICOLOGY

16.7

The animals like mule deer, mountain lion, rock squirrel, desert rats, foxes, wolves are generally found in woodlands. Certain bird species like woodpecker, band tailed pigeon, fly catcher, bluebird are found in woodland areas.

Tundra Tundras are found at far northern or southern latitude. Tundra comprises the communities to the zone of perpetual snow and ice. The climatic conditions of tundra are too harsh for trees. Thus, tundras are treeless plains that occur under the harsh climates of low rainfall, high snowfall and low average temperature. Tundra has the appearance of short grass, sedges, rushes, lichens, mosses, ericaceous and some flowering plants. Germination of seeds is extremely difficult. Thus, most of tundra plants are perennial. There are two kinds of tundra such as arctic which occurs at high latitudes and alpine which occurs at high elevation. The arctic environment is extremely harsh and the dominant species are arctic hare, collared lemming, gray wolf, arctic fox, polar bear, ermine, etc. The bird species are snowy owl, willow and rock ptarmigans. The largest alpine areas of the world lie on the Tibet plateau and in the adjacent Himalayan mountains of Asia (Schafer, 1938, Mani 1968). The thin mountain air permits intense solar radiation thus many alpine plants have deep pigmentation that shield their inner cells. Mountain goat, mountain sheep, white tailed ptarmigan are the dominant animals of this region.

Desert Ecosystem Deserts, in the ecological sense, include arid wasteland which contain considerable vegetation in the form of bushes, shrubs and trees especially adopted to tolerate hot dry climates. Generally deserts occur where the rainfall is less than 50 cm/year. Deserts occur in belts at similar latitudes, north and south of the equator around the world and they occur about one fifth of its surface. Prominent deserts occur in the south-western United States, in Sahara, Southern Africa, Arabia, Central Asia and Australia. Deserts are classified as: hot deserts and cold deserts. The hot deserts are characterised by low moisture levels and precipitation and high evaporation rate as the day temperature exceeds 40°C or more. The cold deserts are characterised by low evaporation rate, high moisture level and the annual temperature is approximately 10°C or less. The hot deserts are present in low latitudes, for example, Sahara of Africa and Thar of India. The cold deserts are present in high latitude, for example, the deserts of western Asia and Nevadas may be classified as cold deserts. Animals of the desert have both structural and behavioural adaptation to meet hot and dry climates in terms of water deficiency and high heat. Many desert animals escape the day-time and hide themselves in burrows or rocky shelter to avoid high temperature. The dominant animals are ground squirrel, jack rabbit,

16.8

TOXICOLOGY

kangaroo rat, pocket mouse, fox, grasshoppers, etc. Among birds, the dominant are hawk, humming bird, woodpecker, sparrow and flycatcher. Soils often have abundant nutrients but little or no organic matter and need only water to become very productive. Leaves of plants are reduced to scales or spines to reduce transpiration of water. The dominant plant species in hot desert are cacti, creosote bush, yucca and other xerophyte species. In the cold deserts perennial plants grow to survive under very harsh cold conditions. In the desert areas the net primary production is very low. The distribution of biomes of terrestrial ecosystem based on temperature and precipitation is shown in Fig. 16.4.

Average annual precipitation (cm)

400

300

Tropical rainforest

Sub-tropical rainforest

200 Tropical savana 100

Temperate rain desert

Gree

n lan

d an

d shr

Hot desert

ub la

nd

Temperate deciduous forest Tundra

60

50

40

30 20 Average temperature (°C)

10

0

–10

–20

Cold desert

Fig. 16.4

Different terrestrial ecosystem based on temperature and precipitation.

Aquatic Ecosystem Water is essential for the survival of life in every biological community and it serves as an important habitat to many organisms. The aquatic ecosystems may be classified as: (i) Freshwater ecosystems (ii) Saline ecosystems

Freshwater Ecosystems Freshwater ecosystems include the standing waters of ponds, wells, groundwater and lakes as well as the flowing waters of rivers and streams (Fig. 16.5 (a)). The aquatic habitat offers a variety of unique conditions to which organisms must be adopted before they can occur. The habitat conditions for standing water and

ECOTOXICOLOGY

16.9

flowing water are different. The aquatic habitats may be classified as: (a) Lotic habitat (b) Lentic habitat.

Fig. 16.5 (a) Freshwater habitat.

Lotic habitat: Lotic habitat is essentially the habitats of continuous and rapid flow of water body. For example, streams, rivers and springs. Lentic habitat: In lentic habitat, water is essentially a standing quiescent body. For example, ponds, lakes and wells. Aquatic organisms need carbon dioxide, water and sunlight for photosynthesis, oxygen for respiration, food and mineral nutrients for energy, growth and maintenance. The availability of these above necessities depends on: (1) Solubility in water (oxygen, minerals, etc.) (2) Depth of water body (3) Penetration of light and temperature (4) Flow rate of water body (5) Bottom characteristics.

Lotic Ecosystem Rain water falls on an uneven surface, it collects in depressions. As the water overflows then it will become a stream. When the stream is less than 3 meter wide they are called creeks or brooks. Rivers are the streams of 3 meter or more wide. The river has three stages, namely, youth, mature and old age. At the youth age the rivers are narrow and steepsided. The water current is very high. At the mature age it becomes wider, have gentle slopes and current is slower. In old age, the river system has reached base level and the flow of water is sluggish.

16.10

TOXICOLOGY

Habitats: The important habitats in a stream are falls, rapids, riffles, sand bottom pools and mud bottom pools. The bottom habitats mainly depend on the volume and water current of the flow. The stream bottom composed of cobbles and boulders, too heavy to move, are called the rapid habitat and if the stream bottom is very turbulent, it is called riffle habitat. When the water current is moderate, it forms sand bottom pools and when the water current at the bottom is negligible it forms mud bottom pools. The mud bottom pools have generally high primary productivity as it contains high percentage of organic matter. Stream biocies: Generally plants are not abundant in the stream biocies but to some extent they are found at the upper surfaces of rocks with branched filamentous algae and few species of water mosses (fontinalaceae) may occur. The most characteristic and abundant animals in aquatic ecosystem are caddisfly larvae, mayfly naiads, stonefly naiads, crayfish, trout, snails, sponges, clams, etc. Planktons are abundantly found in sluggish water but are very rare in running water. The nature of stream is the most critical condition to determine the types and numbers of species in the lotic aquatic ecosystem. All organisms that occur in streams must adjust to the action of water current by clinging mechanisms, avoidance or vigorous swimming. Segregation of stream animals between riffles, sand and mud bottom pools may be a response to type of bottom. Animals occurring in mud bottom pools are usually helpless in strong current. The animals must have learnt adaptation to lower oxygen concentrations in the water. Oxygen is ample in streams and low at the sluggish water and at the bottom of very deep water. The gills of animals in mud bottom pools are larger than the gills of stream animals to get more oxygen, e.g. catfish, carp, etc. Some species of stonefly and mayfly naiads and caddisfly larvae are absent in cold water. Animals have various adaptations to light, temperature, oxygen and feed on. Density of individuals biomass and productivity are less in sand bottom pools than either in riffles or mud bottom pools. clams, game fish, for example, are the inhabitants of sand bottom pools.

Lentic Ecosystem Lentic ecosystem is essentially the ecosystem of standing water although at times wind action stirs surface layer and margins into great turbulence. For example, lakes, ponds, etc. are included in lentic ecosystems. The standing aquatic habitat offers a variety of unique conditions to which organisms must be adapted before they occur. Therefore, vertical stratification is an important aspect of standing water ecosystem in terms of light, temperature, nutrients and oxygen availability. The aquatic lives tend to form distinctive vertical subcommunities in response to this stratification of physical factors. Light: Light is essential to plant for photosynthesis and to animals for feeding. Many organisms orient to light and some are sensitive to light. The vertical

ECOTOXICOLOGY

16.11

stratification of standing water with regard to light is based on its penetration. The vertical zone upto which the photosynthesis predominates is called trophogenic zone. Below this zone there may be considerable photosynthesis but oxygen absorption is greater than oxygen release. This zone is called tropholytic zone. Below this zone there is no light called dark zone, which is very deep water (Fig. 16.5 (b)).

Light

Water current

Trophogenic zone

Tropholytic zone

Dark zone

Fig. 16.5 (b)

Vertical Stratification based on light penetration.

Wind, current and temperature: Wind and current are two important environmental factors which can make some movement to the surface water. Similarly, temperature is also an important factor to regulate the water temperature. Based on wind, current and temperature penetration the water body horizontally is stratified as: Epilimnion: It is the horizontal zone of upper water body where the water circulates and is fairly turbulent. Hypolimnion: This is the lower horizontal water body which remains undisturbed by winds or currents. Thermocline: It is the zone of most rapid temperature decrease, generally involving a drop of at least 1°C per meter of depth (Birge, 1904). Above this zone temperature is usually uniform (Fig. 16.6). The distribution of oxygen at various depths depends upon the presence or absence of a thermocline, the amount of vegetation and organic nature of the bottom. Lentic biocies: Lakes and ponds have a tendency to undergo succession, which includes changes in the biological community as a response to increase in nutrient levels. Based on physical characteristics, species composition, productivity and distribution niches, there are two major lake communities called Oligotrophic and eutrophic lake biocies.

16.12

TOXICOLOGY Wind

Water current Epilimnion Thermocline Hypolimnion

Fig. 16.6

Horizontal stratification based on wind, current and temperature.

Planktons are free floating motile organisms and they are microscopically small in size. The species which can be caught by the net are called net planktons. The nonoplanktons include bacteria, protozoan and fungi of size less than 0.06 mm in length. The organisms that depend on the surface film for a substratum are called neuston. Nektons are larger animals capable of locomotion independent of water currents. Many animal species are bottom dwellers that they are attached to the bottom for support, these are sessile, creeping and borrowing forms (e.g., snails, burrowing warms, insect larvae and bacteria). These bottom dwellers are called benthos. The benthos can be divided into four subzones as: littoral zone, limnetic zone, profoundal zone and abysaal zone (Fig. 16.7). Water surface

Littoral zone

Eulittoral zone

Limnetic zone

Sublittoral zone

Profundal zone Abyssal zone

Fig. 16.7 Different zones of deep freshwater ecosystem.

ECOTOXICOLOGY

16.13

Littoral Zone

The littoral zone extends from the water’s edge to the limit of rooted aquatic vegetation. This zone has abundant oxygen and good penetration of light. Littoral zone is further subdivided into eulittoral and sublittoral zone. The eulittoral zone is the zone between high and low water wave action, i.e., the zone where the wave action is more active. In this zone rooted vegetations are maximum. The sublittoral zone extends from the lower limit of eulitteral zone to the lower limit of rooted vegetation. Beyond this there is no vegetation. Limnetic Zone

Limnetic zone is the open water zone away from shore. Vertically, it starts from the open surface water to the depth of light penetration, i.e. upto above the dark zone. Planktons are abundant in this zone. Profundal Zone

Profundal zone is the deep water zone below the littoral zone. This is the entire bottom below the rooted vegetation or biological community. It is commonly the bottom of hypoliminion. Abyssal Zone

This zone is found in deep lakes or oceans since it starts from about 2000 meters from the surface. The water in this zone is very cold, there is no light penetration and low nutritional content.

Saline Water Ecosystem The saline water ecosystem is the largest ecosystem which covers about 70% of earth’s surface. Saline water ecosystem includes oceans, seas, estuaries, etc. This ecosystem plays an important role in our global environment. Water has a high heat capacity and can store more energy. Oceans represent a large and stable ecosystem, and is also known as marine ecosystem [Fig 16.8 (a)]. The most important marine ecosystems are as follows:

Fig.16.8 (a)

Marine habitat.

16.14

TOXICOLOGY

• Oceans buffer and modulate the atmospheric climate. • Oceans are major storehouse of carbon and exchange carbon dioxide rapidly with the atmosphere. • It controls global warming. • It is the greatest habitat to aquatic biota. • Marine ecosystems regulate the atmospheric temperature and they play the major role in hydrological cycles. • Marine algae supply much of earth’s oxygen and take up a huge amount of atmospheric carbon dioxide. • Oceans provide and produce food for many terrestrial organisms. Marine ecology is concerned with environmental factors and problems of organismic adjustments quite different from those on land and also different in many respects from those in freshwater. Habitat

The marine ecosystem [Fig. 16.8 (b)] is considered to have the following divisions: Pelagic zone Littoral zone

Neritic

Oceanic Epipelagic

Sublittoral zone

Photic

Mesopelagic Aphotic

Benthic zone Abyssal Hadal zone

Fig.16.8 (b) Subdivision of ocean floor.

Intertidal Zone (Littoral Zone)

The intertidal or littoral zone extends between the limits of high and low tides. This biome is made up of areas exposed alternately to air during low tide and saline waters during high tide. Constant movement of water transports nutrients into and out of these areas. Large algae are found in these areas. Intertidal zones are major economic resources as shellfish and variety of birds are present in this zone abundantly. The sublittoral zone covers the continental shelf to a depth of about 200 m. Pelagic Zone (or Open Water)

The open waters of the oceans are called pelagic zone which is away from the land. It is generally cold and there is thermal stratification with a constant mixing

ECOTOXICOLOGY

16.15

of warm and cold ocean currents. The pelagic zone is low in nutrients like nitrogen and phosphorus, thus, this is the zone with low productivity and low diversity of algae and other species. Benthic Zone (or Bottom Ocean)

It starts below the pelagic zone but includes very deepest part of the ocean. The bottom of the zone consists of sand, salt, organic decays, etc. Temperature in this zone remains about 3 to 5°C and it further decreases as we go further down in the ocean. The water is too dark for photosynthesis, thus no plants grow in this zone. Low density of fungi, bacteria, sponges, etc. are found in this zone. Abyssal Zone

The deepest part of the ocean is known as abyssal zone. The water in this zone is very cold, there is no sunlight penetration, low nutritional content. Anaerobic bacteria can live in this low oxygen bottom sediments. Below this abyssal zone there are ocean trenches called hadal zone which extends much deeper. Based on light penetration the vertical stratification of ocean (Fig. 16.8) includes photic and aphotic zone. Photic zone is the vertical depth of the ocean upto which sunlight can penetrate and photosynthesis activities are carried out. Aphotic zone is the zone upto which there is no sunlight penetration and there is no photosynthesis activities. The neritic biochore is above the continental shelf and the oceanic biochere is further subdivided vertically as epipelagic and mesopelagic zones depending upon the penetration of light.

Marine Biocies The marine biocies tend to form distinctive vertical sub-communities in response to the stratification of physical factors like light, oxygen, temperature and nutrients. The marine life is generally distributed between open ocean water ecosystem and deep ocean water ecosystem (bottom). Plankton

The plankton subcommunity consists mainly of microscopic plants, animals, and protists (single celled organisms such as amoebae) that float freely within the water column. The nanoplankton consists of mostly protozoans, algae, bacteria, fungi and viruses. The bacteria are largely periphytic in that they are attached to the surfaces of floating plants, animals and to particles of detritus. The green phytoplankton is composed primarily of several kinds of algae. The algae are very important as they are the producers and represent the first trophic level of the oceanic food web or food chain. The microanimals include zooplanktons which occupy the next trophic level of oceanic food chain. The species composition of zooplankton is not uniform throughout the ocean.

16.16

TOXICOLOGY

Nektons

Nektons are larger animals capable of locomotion independent of water currents. For example, fishes range from sharks to numerous varieties of small species and mammals like seals, dolphins and whales. The distribution of fishes is irregular, but in general they occur more abundantly in neritic waters than in open oceans. Benthos

Many animal species are bottom dwellers such as snails, burrowing worms, bacteria, etc. Benthos is of much greater variety and abundant in the littoral zone and decrease in numbers with depth. Oxygen level is lower in benthic environment. Anaerobic bacteria can live in this low oxygen bottom sediments. Emergent plants such as cattails and rushes are rooted in bottom sediments of the littoral zone (near shore). They create important structural and functional links between strata of ecosystem and often are the greatest producers of net primary productivity in the ecosystem.

16.4

EVOLUTIONARY ECOLOGY

The fascinating varieties of organisms and complex ecological relationships that give the biosphere its unique productive characteristics. This leads to the biodiversity. Understanding of biological diversity is followed by the understanding of biological evolution, interactions between species and the effects of environment on life diversity. Charles Darwin and Alferd Wallace developed the theory of evolution. Biological evolution is a process through which new species are formed and it also refers to the change in inherited characteristics of a population from generation to generation through mutation, natural selection, migration and genetic drifts. The new species formed through biological evolution can no longer reproduce the original species. Thus, biological evolution is a one way process. Once a species is extinct, it is gone forever.

Mutation The gene, complex chemical compound called DNA (Deoxyribo-Nucleic Acid) is the building block of a life which is inherited from one generation to the next. When a cell divides, the DNA is reproduced so that each new cell gets its share. Sometimes there is a failure in the reproduction of the DNA due to the presence of toxic chemicals or other foreign body in it. Thus, it results in a change in the DNA and there is a change in inherited characteristics. The change of DNA characteristics by any means in next generation is called mutation. Mutation can result in a new species giving them natural advantages so that they are relatively more likely to survive and reproduce and are better adapted than its parental species to the environment.

ECOTOXICOLOGY

16.17

Natural Selection Natural selection favours the survival of the fittest. It is a process by which the new species with better adapted to a particular set of environmental conditions (temperature, precipitation, etc.) will survive and produce more successfully than their less fit competitors. These new species through natural selection are also better adapted to the presence or deficiency of nutrients, diseases caused by bacteria or viruses. Natural selection is relatively less effective in small population than in large ones.

Migration The migration of one population of a species into the habitat of other occupied species that can lead to changes in gene frequency is called hybridization. In hybridization, the result of introgression is the gradual intrusion of the characters of each population into the other, so that all distinction between them disappears (Anderson, 1949). The hybrids show better adaptation than their parents. These hybrids will be selected for replacement of both parental population.

Genetic Drift Genetic drift refers to changes in the frequency of a gene in a population as a result of chance rather than other processes of biological evolution. It is more prominent in small populations. When individuals are isolated in a small group from a larger population, there is a considerable decrease in the number of genes available to the main body of the species, as no individual or small group of individuals can possess all the genes that occur within the species pool. In this case, the individuals of small groups may not be better adapted to the environment, because the genetic variability of the species is greatly reduced. But in large population, if the offspring of one pair of parents under represents an allele it is likely that other will over represent it. Thus, genetic drift is the establishment of restricted genotypes in small populations by drifting the allele (certain genes) frequencies away from their starting values. Successive fixation (random changes in allele frequency) events will lead to the progressive loss of genetic variation, often completely from the population.

Biodiversity Biodiversity refers to the variety of organisms, number of organisms and complex ecological relationships between organisms or group of organisms and their environment. Biological diversity involves three important concepts such as: (i) Genetic diversity which refers to the number of genetic variations present in a particular habitat.

16.18

TOXICOLOGY

(ii) Species diversity describes the number of different kinds of organisms within individual community or ecosystem. (iii) Ecological diversity includes ecological niches, number of habitats, trophic levels, complexity of a biological community and recycle materials within the ecosystem. The restriction of a species to a particular ecological niche depends on its structural adaptations, physiological adjustments and tolerances and behaviour patterns. The ecological niche is a particular combination of physical factors (microhabitat) and biotic relations (role) required by a species for its life activities and continued existence in a community. The species refer to all organisms of the same kind that are generally similar enough to breed in nature and produce life and next generation. The variety of species living together in different biological niches results in species diversity of that ecosystem.

Interactions between Species Interactions may take place between individuals within and between species. These interactions are known as population ecology. The interactions may be interspecific or intraspecific. Interspecific interactions include mutualism, commensalism and predation-parasitism. The intraspecific interactions include colonization, aggregation and social organization [Fig. 16.9 (a)]

Fig.16.9 (a) Interactions of macro and microoranisms.

ECOTOXICOLOGY

16.19

Interspecific Interaction Mutualism

Mutualism is an association between two or more species in which all participant species are benefitted. Sometimes the term symbiosis is used to define this relationship. For example, nitrogen fixing bacteria with roots of legumes, lichens contain algae and fungi that require each other to persist. Commensalism

Commensalism defines the interactions in which one species is benefitted and other species is neither benefitted nor harmed. For example, the saps drive the insects from grasses that are fed on extensively by other birds, many microorganisms take shelter in canal system of sponges. Predation-Parasitism

In this type of interaction, one species is benefitted and the other one is harmed. Parasitism is the relation between two individuals in which the parasite is benefitted and the host is harmed. In predation relation one species kills the other.

Intraspecific Interactions Colonization

Colonization is the interaction of species within themselves to form colonies for their own survival. They form colonies for better protection from other predator or environmental condition, improved utilization of food supplies or more efficient reproduction. For example, the herd of elephants form the colony in which the young ones are at the centre and then the females. At the outer ring the males are there to protect the younger elephants. Aggregation

The aggregation of individuals must have survival value because it persists. For example, mayflies, midges and mosquitoes swarm for mating purposes. In honey bees when hive temperatures drop below 14°C during winter days, they form clusters and maintain a mass temperature several degrees above the atmospheric temperature. Social Organization

In this type of interaction the species are well organized to protect, to feed and to reproduce themselves for their survival. For example, the three primary organizations of ants are the winged reproductive males and females, the wingless sterile soldiers and smaller wingless workers.

16.5

BIOLOGICAL PRODUCTIVITY

The rate of biomass production per unit area per unit time is called productivity. The total amount of organic matter on any particular ecosystem is called

16.20

TOXICOLOGY

biomass. Biomass is increased through the biological production or growth, the change in biomass over a given period of time is called net production. There are two kinds of production such as: (i) Primary production, and (ii) Secondary production. Primary productivity is the rate of biomass production of a community. The primary productivity process is carried out by autotrophs by forming sugar from sunlight, carbon dioxide, and water through photosynthesis process. The energy left after respiration is net primary production (Fig. 16) C6H12O6 + 6O2 (Photosynthesis) (i) 6CO2 + 6H2O 6CO2 + 6H2O + Energy (Respiration) (ii) C6H12O6 + 6O2 Net Production = Gross Production – Respiration (Photosynthesis) The secondary productivity process is carried out by the hetrotrophs which cannot make their own food but must feed on other living organisms. The production by hetrotrophs is called secondary production as it is derived from the primary production. Secondary production is the rate of energy transferred and stored at consumer levels over a period of time (Fig. 16.9 (b)) Primary production

Secondary production Animals Photosynthesis

Fig. 16.9(b)

16.6

Primary and secondary productivity.

ENERGY FLOW

Energy flow is the flow of energy through an ecosystem from the external source or environment (solar energy) through a series of organisms and back to the external environment (sink or outer space). Organisms use carbon dioxide, water and sunlight and then return them into the environment in altered forms as byproducts of their metabolic processes. In the ecosystem energy flows in a unidirectional path and eventually into some low temperature sink such as outer space. For example, lions eat deers to get energy but deers cannot eat lions, thus flow of energy is unidirectional in an ecosystem. The second law of thermodynamics states that energy always changes from a more useful and more highly organized form to a less useful and disorganized

ECOTOXICOLOGY

16.21

form. The ecosystem is said to be the intermediate between the energy source (sun) and the energy sink (outer space). The energy efficiency flow in an ecosystem is commonly known as trophic level efficiency which is the ratio of production of one trophic level to the production of the next lower trophic level which is never high. The flow of enegy starts from the green plants to next trophic level and so on. Green plants are able to covert 1 to 3% of the energy received from the sun into plant energy. Then the herbivores convert the potentially available plant energy into herbivorous energy which may be converted into carnivorous energy by carnivores. It is found that the transfer of total energy from one trophic level to another is only 10% of the gross productivity of producers. This is known as 10 per cent low [Fig.16.10(a)]. The energy flow in an ecosystem through a linked path is known as food chain or food web [Fig.16.10 (b & c)].

Sun

Primary consumers

Plant producers

Fig. 16.10(a)

Secondary consumers

Energy flow.

Third trophic Fourth trophic t t

Fig. 16.10(b) Terrestrial food chain.

16.22

TOXICOLOGY

Grass

Mouse

Snake Hawk

Fig. 16.10(c) Terrestrial food chain.

16.7

DISTRIBUTION OF TOXICANTS IN THE ECOSYSTEM

The various human activities and the advent of science and technology cause the release of harmful substances into the ecosystem. Out of these, certain toxic elements may be toxic in certain concentrations, but are required in small quantity for metabolism. There are certain elements required in large quantity by certain organisms for their metabolic processes. Those elements required in small quantity are called micro-elements and elements required in large quantity are called macro-elements. Both macro-, and micro-elements are necessary for the growth and normal development of an organism. There are nine macro-elements such as Carbon (C), Oxygen (O), hydrogen (H), Nitrogen (N), Phosphorus (P), Sulphur (S), Potassium (K), Calcium (Ca) and Magnesium (Mg). In addition, there are seventeen (17) micro-elements such as Na, Cl, Si, V, Cr, Mo, Mn, Fe, Co, Ni, Cu, Zn, B, Sn, Se, F and I. The substances are released into the environment, their behaviour depends on many factors like physical, chemical and/or biological. The released harmful substances or toxicants can enter the ecosystem in any of the four matrices such as the atmosphere by evaporation, the lithosphere or soil by adsorption, the hydrosphere by dissolution or the biosphere by absorption, inhalation, ingestion. In this section, we will give emphasis on the absorption of harmful substances by biota. The various environmental transport processes lead to exposure of organisms and uptake of the harmful substances. In the environment, only a portion of the total quantity of chemical present is potentially available for uptake by organisms. This is known as the bioavailability. The bioavailable fraction of toxic substances may increase or decrease due to the change in factors like solubility,

ECOTOXICOLOGY

16.23

chemical and thermal stability of substances. For example, the heavy metals are released from the soil into surrounding or interstitial water through the activity of microorganisms (Haddadin et al. 1995). In soils, sorption controls the bioavailability of toxic substances. This distribution primarily determined by substance properties such as volatility, water solubility and affinity for lipids and dead organic material. The tight sorption of contaminants increase the residence time of the toxic substances in the soil. Slowly these contaminants are released into other ecosystem due to chemical action and/or microbial activities.

16.8

TERRESTRIAL ECOTOXICOLOGY

Ecosystem comprises all types of organisms or group of organisms that function together and interact with physical environment. There is a correlation among different organisms and non-living components through energy flow and material cycles (Odum, 1983). The toxic substances can affect the ecosystems over a large area mainly because of a high degree of functional redundancy of the ecosystems. This can be explained as the organisms can take over each other’s function through food chains which run parallel to each other and are linked to form food webs in various ways. Movement of biotic and abiotic components within the large ecosystems varies depending on several factors, including the species of animals and physical components of the surroundings. Terrestrial ecotoxicology is restricted to the exposure and effects of toxic substances to the terrestrial ecosystems only. Most of the terrestrial organisms are very mobile, covering a large area through migration and dispersion. In this way, all organisms contribute to the diffuse stability of an ecosystem. Toxic substances can cause effects within terrestrial ecosystems at suborganisms to superorganismic levels. For example, residues of DDT, other chlorinated hydrocarbon insecticides, industrial chemicals including PCBs can influence molecules, tissues, organs, individuals, populations and even whole communities. Terrestrial ecotoxicological tests have to be performed at different levels of organization, from molecule to ecosystems because of the dynamical population systems, interacting biological communities or even whole ecosystem makes it more complex. The toxic effects of chemicals on terrestrial organisms observed in some avian species like Bermuda petrels, brown pelicans, etc. (Peterle, 1991; Kendall and Akerman, 1992). The problem of chemicals effects on avian population became more apparent as the relationship between DDT contamination and declining bird population was established. The study by Ratcliffe (1967) had established the cause of declining of peregrine falcon and sparrow hawk that the toxic substances (DDT) caused the eggshell thinning. These toxic elements also affect the reproductive systems of avian species, resulting from eggshell thinning and decreased hatching success. The ecosystems become unbalanced through the effects of toxic elements. The selective action of toxicants affect different species in different ways to

16.24

TOXICOLOGY

different extent at different concentrations. The toxic effects may be lethal to kill the species or may be sublethal where species remain alive but reduced developmental and reproductive ability. All the toxicants present in the ecosystem may not be directly toxic. These toxicants may have secondary toxic effect. For example, plant nutrients like nitrogen and phosphorus cause eutrophication.

16.8.1 Lethal Effect When toxicity is described in quantitative terms, the concept of Lethal Dose is used from where the lethal effect is derived. The toxic effect may be measured as the toxicological response level of individuals to exposure is calculated as the dose of a chemical substance which causes death of a part of or the whole population. The lethal dose and effect is said to be 100% when all the organisms die. It is known as LD100. When 50% of the population die after certain period of exposure the lethal dose is LD50. Lethal doses (LD) are usually included in irreversible effect which is also known as lethal effect. When the effect of a toxicant in organism is permanent, i.e., even if there is a complete elimination of toxic elements from the organism, still then the effect of toxicant exposure persists it is known as irreversible effect.

16.8.2 Sublethal Effect The effective dose-50 (E D50) is the dose that cause an effect in 50% of the population. Similarly, the toxic dose-50 (TD50) is the dose that causes toxic effect to 50% of the population. In case of ED50 and TD50, the response is that none will die by the exposure of the toxicants. These two ED50 and TD50 show some positive response, i.e., the ultimate effect is not death of the organism. In many cases, the effective doses and toxic doses are detrimental as well as beneficial. When the effect from toxicant exposure is a temporary one and the effects are not observed after the elimination of toxic substances from the organism, the effect is said to be reversible or sublethal effect. Organism on exposure to toxicants with reversible effects do not die, these effects may be called as sublethal. The sublethal doses of most toxic substances are eventually eliminated from an organism’s system.

16.8.3 Non-lethal Effect The animals are randomly distributed over a number of groups. All animals in sometimes in the same ecosystem, a particular toxicant produces toxic effects to one kind of living organism without harming another form of life even though the two may exist in intimate contact (Albert, 1973). Every population will not react with equal sensitivity to the toxicants. The reaction depends on the way in which

ECOTOXICOLOGY

16.25

a population is regulated and on the effect of the substance. There are two different types of effects observed such as effects on reproduction and predatorregulated population. The predator-regulated populations are more sensitive to the toxicants which affect reproduction whereas food-regulated populations are susceptible mainly to the substances which influence survival. For example, the organisms at the top of food web (carnivores) are food regulated and the lower food web organisms (herbivores) are predator regulated populations. The organisms at the base of the food chain or food web are the most affected by the toxicant on reproduction, because this is of great importance to the persistence of such populations. The carnivores will depend on the lower organisms for food. If the population of the lower organisms is reduced, then there will be shortage of food for top carnivores so that they will be affected for their survival.

16.9

AQUATIC ECOTOXICOLOGY

Water is the largest sink for many chemicals of anthropogenic sources. Aquatic ecosystem is very important and complicated because most of the toxicants are easily soluble in water. The aquatic toxicology deals with the effects of toxicants on the living organisms in the aquatic environment. The major sources of toxicants to the aquatic environment are anthropogenic sources such as group receive the same dose of a particular toxicant and for other group the dosage is gradually increased considering that all animals were equally sensitive to that toxicant. Then there would be a threshold dose below which all animals would remain alive without any major toxic effect is said to be non-lethal effect.

16.10

EFFECTS OF TOXICANTS ON TERRESTRIAL ECOSYSTEM

The structure and functioning of the terrestrial ecosystems are so complicated that it is very difficult to predit effects of toxic substances on populations, communities and ecosystems. For example, the individuals within a population may show grant differences in sensitivity to a toxicant because of various factors like age, nutritional state, sex, body structure and other physical factors. There are also genetically differences in sensitivity between individuals to certain toxicants. In case of an essential element to living organisms display bimodality in terms of dose-response relationship. At a very low supply of an essential chemical element, the plant suffers from a shortage of nutrients which may cause death to the plant. If the concentration of the same chemical element surpasses the optimum level for plant growth it causes adverse effects which may result in death due to toxicity. The effects of toxicants on terrestrial ecosystem are not primarily at the shortage site, but rather at the surplus site of the plant (Ernst, 1994). Thus, the response of a plant exposed to a surplus of a chemical element is considered for the toxicity effects industrial effluents, domestic and commercial

16.26

TOXICOLOGY

sewages, etc. and from terrestrial run-off and atmospheric deposition generally known as secondary pollutants. There are large number of parameters which are different from terrestrial ones control the fate of the toxicants in the aquatic environment. Some important parameters are temperature, light, biological oxygen demand (BOD), chemical oxygen demand (COD), dissolved oxygen (DO), acidity and alkalinity. In the terrestrial ecosystem many toxicants are subjected to aerobic degradation whereas in aquatic system oxygen is not available in sufficient amount so little aerobic degradation occurs in that ecosystem. Many toxicants can persist in aquatic ecosystems for longer than in terrestial systems (Ashok and Saxena, 1995). In comparison to terrestrial animals, aquatic animals are more susceptible to toxicants because aquatic organisms have highly permeable skin and gills through which toxicants enter into aquatic organisms easily (Pritchard, 1993). The temperature of the aquatic system controls the metabolic activities of aquatic organisms like fishes, invertebrates and amphibians. The temperature also controls the solubility of toxicants in the aquatic. Thus, the accumulation and penetration of toxicants in the aquatic organisms is largely influenced by water temperature. The other important factor in aquatic ecosystem is pH value because most of metal toxicants or metal bound toxicants are easily soluble in acidic condition, i.e., at very low value of pH, most of metals are soluble in water. Acid deposition may be stored up in the snow and released during the summer days when the snow melts resulting in increase of acidity of the water. Thus, more soluble metals are available to aquatic organisms.

16.11

GENOTOXICITY

Genotoxicity is the study of toxic effects of toxicants like mutagens, clastogens, aneuogens, and teratogens on the genetic material of living organisms was originated with the experiments of Miller (1926). Life and propagation of life are determined by the information stored in the genes which is carried by deoxyribonucleic acid (DNA). The genotoxic compounds, either directly or indirectly (biotransformation) can bind to the DNA molecule in different ways. The most important attacking sites are the nucleotide bases which leads to mutagenicity. Mutagenicity is the process by which the genetic information for determining and maintaining the integrity, functions and relationships of living cells is permanently changed. Such effects may be observed as DNA strand breaks, base modifications, chromosomal rearrangements or fragmentation and/ aneuploidy (Shugart and Theodorakis, 1994). The principal target for mutagenic damage is DNA which is not only confined to nuclear chromosomes, but also occurs outside the nucleus, in mitochondria and in the choloroplasts of plants. If the toxic effects occur in

ECOTOXICOLOGY

16.27

germinal tissues, this can result in heritable effects and there is increase in genetic load. Mutations can arise spontaneously but they can also be induced by physical and chemical factors. The huge amount of toxicants released into environment due to human activities lead to an enormous rise in the mutation pressure. Mutagenic pressure greatly depends on the moment of action of mutation inducing factors. Chromosomal damage is defined as the modification of the number or structure of chromosomes. Variations in the number of chromosomes may involve the complete complement (polyploidy) or only some of the chromosomes (aneuploidy). The interaction between the bases of the DNA or electrophilic substances may form covalent bonds with nucleophilic bases, thus, leading to DNA abducts, etc (Walum et al. 1990; Shugart 1995). DNA abduct formation is the genotoxic end point. Non-lethal genetic alterations in dividing somatic cells may ultimately result in the development of cancer (Maccubin 1994). The DNA abducts can result in mispairing during subsequent replication or clastogenic changes such as strand breaks which are thought to play a key role in initiation, early propagation and in later stages of tumour progression (Harrish 1991).

16.11.1 Types of Mutation There are three groups of mutation observed as follows: Gene Mutations

Gene mutations are small changes in the bases of DNA which are invisible in light microscope. These are also called single point mutations. These single point mutations can be based on changes in the sequence of nitrogen bases, although phosphate oxygen is also a target. These changes occur due to addition or deletion of bases. Base change may result in the coding of a different amino acid. This type of change is a miss-sense mutation. Structural Chromosomal Aberrations

Chemicals or toxicants which cause structural chromosomal aberrations are also known as clastogenes. Clastogenesis refers to the process resulting in additions, deletions, or rearrangements of parts of the chromosomes that are detectable by light microscope. Deletion or insertion of bases in a gene may be large or small. Chromatid gaps which are achromatic lesions in a chromosome, may vary in length and are thought to be due to loss of DNA. Similarly, Breaks are broken ends of chromatids that are dislocated but still contained within the metaphase. Terminal deletions are when the chromosomal materials are spilt off at the end of both chromatids at homologous places resulting in the formation of two chromatid fragments. Centric ring chromosomes in which chromatid segments are centromeres and joined to form a ring. The ring chromosomes without centromere are called acentric chromosomes. In chromatid exchanges the chromosome breaks and exchanges between chromatids which can give rise to symmetrical or/and assymetrical shapes.

16.28

TOXICOLOGY

Chromatid type aberrations Intrachromatid aberrations

Interchromatid aberrations

Chromosome type aberrations Intrachromosomal aberrations

Interchromosomal aberrations

Normal

Gap Isochromatid gap

Normal

Exchange

Normal

Terminal Interstitial deletion deletion

Normal

Bicentric and fragment

Break

Centric Acentric ring and Ring fragment

Pericentric Inversion

Symmetrical exchange

Fig.16.11 Schematic representation of chromosome type and chromatid type aberrations.

Genome Mutations

In these mutations abnormalities occur in the number of chromosomes which is also known as aneuploidy. The chemicals or toxicants which cause aneuploidy are known as aneugenes. Genome mutations occur due to unequal division of chromosomes and result in a cell with either more or fewer chromosomes than normal. Variations in the number of chromosomes may involve multiples of complete complement known as polyploidy or the elimination or multiplication of only some of the chromosomes are called aneuploidy. Several chemicals, for example colchicine induces polyploidy by stopping the mitosis at metaphase, leaving the cell with the doubled quantity of chromosomal material, resulting in a polyploid cell. The other compounds cause polyploidy are vinca alkaloids, vincristine and vinblastine and podophyllotoxin. Teratogenesis

Teratogenesis is the science of birth defects due to structural malformation caused by radiations, viruses and toxicants, including drugs (Imlay et. al. 1988). The agent that when administered prenatally, induces permanent structural malformations or defects in the offspring are called teratogens. Teratogens affect developing embryos adversely when exposed. Structural malformation occurs due to damage of embryonic or foetal cells.

ECOTOXICOLOGY

16.29

-:-4+151. What is ecosystem? Define the terms used in ecosystems as: (a) Community. (b) Habitat. (c) Ecological community. 2. Discuss about the structure and community dynamics of the ecosystem. 3. Define the term terrestrial ecosytem. What are the different types of terrestrial ecosystem? 4. Write short notes on: (a) Grassland ecosystem. (b) Forest ecosystem. (c) Desert ecosystem. 5. Different between (a) Closed canopy and open woodland forest. (b) Deciduous and coniferous forest. (c) Lotic and lentic habitat. 6. What are the different types of aquatic ecosystems? Explain them. 7. Discuss about the lentic ecosystem.’ 8. Explain about the different zones of benthos. 9. Give the importance of marine ecosystems. 10. What are the different zones of habitat of aquatic animals in marine ecosystem? 11. What do you mean by marine biocies? Explain their distribution in the marine ecosystem. 12. What is evolutionary ecology? 13. Write notes on:

14. 15. 16. 17. 18. 19. 20.

(a) Mutation. (b) Genetic drift. (c) Biodiversity. (d) Migration. What is interaction between the species? Differentiate between the interspecific and intraspecific interactions among species. What do you mean by biological productivity? What is 10 per cent law? Explain it with example. Discuss about the distribution of oxicants in the ecosystem. Give comparative statements between terrestrial and aquatic toxicology. Explain the toxic effects of toxicants on terrestrial ecosystem. What is genotoxicity? Discuss the different types of mutation.

CHAPTER

17

Mechanisms for Minimizing Toxic Effects 17.1

INTRODUCTION

The substances taken in with the diet or in the preparation process may accumulate in the body depending on their physico-chemical properties. If the concentration of any substance in an organism is very high, then it will have harmful effect on the body. For example, the lipophilic compounds (fat soluble) have the greater tendencies to accumulate in the body. The unwnated substances must be eliminated from the body to make it safe and balance. It has become apparent that the xenobiotics or toxicants are not readily eliminated from the body to make it safe and balance. It has become apparent that the xenobiotics or toxicants are not readily eliminated from the body until they are in a form similar to that utilized for the elimination of endogenous substances for example, the lipophilic substances are metabolised to from hydrophilic, so that they can be eliminated very easily. For this, the observed xenobiotics or substances (toxicants) are metabolized by are or more chemical or enzymatic reactions to form more polar substance so that they can be excreted by the excretory organs such as liver, lungs and kidneys. All the living organisms can usually eliminate a xenobiotic in two different ways such as; • Direct excretion, and • Metabolic transformation of the parent substance. The metabolic system responsible for such transformation is called biotransformation.

17.2

DETOXIFICATION (BIOINACTIVATION)

Biotransformation of the xenobiotics often leads to changes in the molecule so that they are converted into more polar form which increases its water solubility. This process will improve the excretion or elimination of xenobiotics in the body.

17.2

TOXICOLOGY

Thus, conversion of a bioactive parent compound into less bioactive or inactive metabolites that easily excreted or eliminated body through renal and hepatic routes. This process decreases the toxic effects of the toxicants and is known as detoxification or metabolic inactivation. There is a relationship between the concentration of a substance and the intensity of its toxic effects. The bioinactivation process decreases the intensity of the toxic effects the biotransformation reactions which yield products having a lower toxicity than the parent compound are referred to as bioinactivation or detoxification on reactions. For example, toluene accumulates in neuronal membranes and inhibits their functions. Toluene is metabolized to form more polar molecules such as hydroxyl and carboxyl metabolites which are water soluble. These substances can be eliminated from the body easily. Thus, metabolism serves to detoxify or inactivate the xenobiotics and to accelerate the elimination of toluene. In the phase I biotransformation system the enzymes that often convert xenobiotics to reactive electrophile metabolites which have more intrinsic toxicity than the parent compound. In phase II, the xenobiotics are combined with hydrophilic endogenous compounds and thereby enhance excretion of xenobiotics from the body. Thus, the toxic effect is reduced and detoxified. Most of the phase II reactions are bioinactivations. Benzene and many volatile organic carbons (VOC) are converted through multiple metabolic pathways to products that are less toxic than the parent compounds.

17.3

ELIMINATION

The substances which are absorbed by the organism and distributed throughout the various tissues and organs will be removed or eliminated from the body by various means. Elimination includes all the processes in the body such as biotransformation, excretion (renal and hepatic) and exhalation. All the elimination processes usually lead to decrease the concentration of toxicants in the body of an organism. The major organs through which important excretion process takes place are kidneys and liver. The elimination of the xenobiotics from the body occurs through first order process, i.e., the rate of elimination at any time is proportional to the amount of the chemical in the body at that time.

dc = –kel C dt taming log value where

log C =

-kel t + log Co 2.303

C ® Concentration of toxicants at time ‘t’ initial Co ® concentration of toxicants kel ® Rate constant of elimination.

MECHANISMS FOR MINIMIZING TOXIC EFFECTS

17.4

17.3

EXCRETION OF TOXICANTS

The absorbed substances or xenobiotics are eliminated from the body by several routes. Excretion is the process of removal of xenobiotics or metabolites from the body. Excretion mechanisms are responsible for most of the elimination process. The most excretion routes are renal and hepatic routes, the other minor routes of excretion are alimentary excretion, sweet, hair, lungs, milk, nasal mucus and saliva. Most of the volatile or grocer’s substances excretion takes place through the lungs. Kidney is the most important excretory organ in the body through which more chemicals are eliminated from the body.

17.4.1 Renal Excretion Renal excretion is one of the most important excretion routes for xenobiotics or metabolites. The kidney is a very efficient organ for excretion. Most of the byproducts of normal metabolism, polar xenobiotics and the hydrophilic metabolites of any lipophilic xenobiotics are eliminated by this route. Toxic compounds are excreted with urine by the mechanisms such as glomerular filtration, tubular reabsorption and tubular secretion. Glomerular Filtration Glomerular filtration involves ultrafiltration. The structure of the glomelur membranes have large pore (70 mm), this virtually allows the passage of compounds with a molecular weight 50,000 (proteins). The system is under pressure generated by heart. The kidney receives about 25 percent of the cardiac output. The rate of glomerular filtration is about 180L/day in an average man. The rate of filtration is affected by the degree of plasma protein binding, because the size becomes too large to pass through the membrane. Any factor that affects the hydrostatic pressure of the glomerulus may affect the route of filtration. The rate of glomerular filtration is proportional to the free plasma concentration. The free plasma proteins, thus, there is an equilibrium between free plasma concentration and plasma-protein binding concentration, which may be influenced by pka the solubility of the toxicant at the certain pH value of plasma. Tubular Reabsorption The glomerular filtrate contains a large number of materials such as water, amino acids, glucose, salts etc along with toxicants and may remain in the tubular lumen and be excreted with urine. The necessary solutes required for normal body functions such as water, glucose, salts, etc. must be recovered from the filtrate during the elimination process. Depending on the physico-chemical properties of a compound, the reabsorption process will be influenced. The passive diffusion across the cell membrane is the basic principle of the reabsorption of toxicants across the kidney tubules. Thus, the toxicants with a high lipid/water partition

17.4

TOXICOLOGY

coefficient reabsorbed efficiently. The polar compound and water soluble ions are excreted with urine thus, most of the xenobiotics or toxicants are reabsorbed by passive diffusion driven by a concentration gradient. The body cannot excrete non-volatile, lipophilic compounds easily. When these substances are metabolised to form more polar metabolites than can be excreted through urine. Tubular Secretion Xenobiotics can be excreted into urine by either active or passive tubular secretion. These two tubular secretions (from the plasma onto the tubule systems transports acids (anions) and bases (cartions). The active tubular secretion system permits a secretion of a large number of organic acids (weak) including glucuronide and sulphate conjugates and the strong organic bases. The passive tubular secretion system allows the secretion of week basic and strong acidic organic compounds from the body. The affinity of the active secretion systems of the proximal tubular cells for various compounds is usually higher than the affinity of plasma protein. Thus, some protein-bound toxicants are available to active secretion system.

17.4.2 Fecal Excretion Fecal excretion is other important pathway for the elimination of xenobiotics from the body. This process may be direct if the absorption of substance after and ingestion is incomplete or has not taken place at all. The excretion toxicants via the feces is the result of biliary excretion. The xenobiotics, and the undergested food material can pass through the alimentary canal unabsorbed and contribute to fecal excretion. The non-absorbed portion of the xenobiotics contributes to the fecal excretion also.

17.5

HEPATIC EXCRETION

Hepatic excretion is also known as biliary excretion which is the second most significant route of elimination. Biliary excretion is also the most important contributing source to the fecal excretion. The liver is interposed between the intestinal tract and the general blood circulation and is located in a very advantageous position for removing the toxic agents from blood after absorption from the gastrointestinal tract. The by-products or metabolites from the GI tract may be released into the circulating blood circulation. Thus, the liver can extract the toxicants from the blood through its hepatic cells arranged in plates of two cells thick. The xenobiotics which undergo metabolic process directly in the liver, the metabolites entering the intestine with bile which may be excreted through feces. Excretion of xenobiotics through biliary excretion is complementary to the renal excretion. The smaller molecules are eliminated through urine (renal) whereas the larger compounds are eliminated viabile. Thus, the xenobiotic

MECHANISMS FOR MINIMIZING TOXIC EFFECTS

17.5

compounds such as proteins, sugars, ions and many non-metabolized substances etc. can easily excreted through biliary excretion system. The toxic agents bound to plasma proteins are readily available for active biliary excretion. The toxicants excreted into the bile may be categorised into three important groups based on their concentration ratio in bile to plasma. Class A ® = 1

where

Class B ® > 1

Cb ® Concentration of toxicants in bile.

Class C ® < 1

Cp ® Concentration of toxicants in plasma.

Generally the compounds rapidly excreted into bile are most likely to be in class B toxicants. The products formed in enzymatic conversion in the intestine can be excreted directly with the feces or reabsorbed from the intestine. The consequence of these events may be enterohepatic circulation. If there is any reabsorption of the metabolites which are more toxic than the parent compounds then enterohepatic circulation may have adverse liver effects (toxicological problem) and the half life period of the xenobiotics in the body may also increase. There are certain substances which can be removed from the body exclusively by biliary excretion, hence it reduces the bile secretion. As a result hepatic disorders and inactivation of liver may occur.

17.6

EXHALATION (PULMONARY EXCRETION)

The gaseous and most volatile substances are excreted or eliminated through respiratory system involving lungs. In the alveoli, there is an equilibrium between volatile liquids and their gaseous phase. It is the basic principle that the amount of volatile liquid eliminated through lungs is proportional to its vapour pressure. The highly specialised part of the lungs with its great surface area and thin membranes has the primary function of exchanging O2 from air to blood and CO2 from blood to air. In lungs, the elimination simply takes place by diffusion. The gases which do not dissolve well in blood like ethylene, are excreted very easily whereas the well dissolved gases in blood such as chloroform are excreted with much difficulty. Thus, the elimination of gases is roughly inversely proportional to the rate of their absorption.

17.7

OTHER EXCRETORY ROUTES

Sweat and Saliva

Excretion through sweat and saliva depends on the diffusion of the non-ionised, lipophilic form of substances. Thus excretion process has very little importance. The toxic compounds excreted into sweat may cause dermatitis and other dermatological disorders. Toxicants excreted in saliva enter the mouth where they are swallowed and pass into the GI absorption.

17.6

TOXICOLOGY

Milk

Many xenobiotics such as drugs, pesticides etc. are excreted via milk which can be passed to the nurshing of springs or through the dairy products into the humans. The toxicants are excreted into milk by passive diffusion of the nonionised compounds. This diffusion depends on the pH value of both milk and plasma and the pka value of the foreign substances. Generally, milk is more acidic (pH = 6.6) than that plasma (pH = 7.4). Thus, the basic compounds have higher concentration in milk than plasma and acidic compounds have higher concentration in plasma. The lipophilic substances diffuse along with fat from plasma into the milk. Some metals such as calcium, lead and chelating agents may also be excreted into the milk. Excretion through Obscure Routes

Elimination of toxicants may also take place through obscure routes such as hair, nails and skin, through the excretion is negligible in terms of quantity. The toxic metals exposure may be responsible for the accumulation of these metals such as selenium, arsenic and mercury in these tissues. Eggs

The elimination of xebotiotics via eggs follows the same mechanism in the elimination process via milk. The egg has two parts such as one is the lipid containing part called yolk and the other aqueous containing part in which proteins are dissolved looks white. Generally, the polar toxicants and metabolitics may be eliminated through the egg white. Whereas the lipophilic xenobiotics are eliminated via yolk. Fetus

Many xenobiotics are accumulated and excreted via fetus as these toxic elements pass across the placenta during the pregnancy. The functions of placenta is an intermediary organ between the mother and fetus. The toxic elements such as carbon dioxide, urea, uric acid and creatinine may pass across the placenta.

-:-4+151. What is detoxification? How does it occur? 2. Derive the equation for the elimination of toxicants from the body. 3. Write short notes on (a) Glomerular filtration, (b) Tubular reabsorption, (c) Tubular secretion. 4. 5. 6. 7.

Differentiate between renal and faecal excretion. What do you mean by hepatic excretion? Explain about the Exhalation. Discuss the excretions through (a) Sweat and saliva. (b) Milk. (c) Fetus. (d) Obscure routes.

CHAPTER

18

Applications of Toxicology 18.1

INTRODUCTION

The basic principle of toxicology may be applied for the protection of human health and the protection of the environment. Precautions and correct measures may be taken for the use of different chemicals or xenobiotics and for the development of new chemicals so that their use and exposure may be safe and effective for humans and environment. The studies of the mechanisms of toxic action, in vivo toxicity testing, and the principles of toxicology may help to develop new technologies and analytic methods to identify all types of toxin including specific and more sensitive chemicals so that human health and environment may be protected. The major sources of exposure and intake of xenobiotics or toxins are food, drugs and the working places. In this chapter, the applications of toxicology may give more emphasis on the food toxicology, clinical toxicology and occupational toxicology.

18.2

FOOD TOXICITY

The study of food toxicity is generally based on the properties and condition of foodstuff of food science such as chemical composition, the texture of food material and the microbiological features (presence of pathogenic microorganisms). Thus, food is an exceedingly complex of nutrients and non-nutrient substances. The substances which are not naturally present in food but added ingredient to improve its quality, the safety standard is quite different. If the food items contain any poisonous or deleterious substance that may have toxic effects, hence, food materials demand a very high safety standards.

18.2

TOXICOLOGY

18.2.1 Sources of Toxicants in Food The important sources of toxicants in food are divided into two groups such as natural and anthropological. The natural compounds which are present in the food material but have deleterious health effects on the organism are called natural sources of toxicants in food. Compounds which are added deliberately such as additives or the substances directly or indirectly enter the food material during industrial food processing, packaging, etc. are known as the anthropological sources of toxicants in food. For example, lectins are naturally toxic proteins found in the seeds of certain plants. Pesticides may be widely used in agriculture which have the adverse effects on human beings considered anthropological source of toxicants.

18.2.2 Food and Colour Additives Generally, additives are used in the food processing and packaging stage to improve the food texture, flavour, test and storage life. The additives are generally emulsifiers, antioxidants and preservatives. The colour additive refers to a dye pigment and other substances to impart the colour. The certain additives are considered to be non-toxic by the government agencies related to food science. These agencies certify that the food and colour additives have a low order of acute toxicity. The basic principle of use of additives in food materials that these additives are highly polar, which combined with their high molecular weight, prevents them from being absorbed by the gastrointestinal tract or entering cells. The intake of food and colour additives varies among individuals. The safety of ingredients, additives and contaminants additions must be established for human consumption based on the uses of food as follows: • The additives or ingredients are added to which food materials or foodstuffs. • The level of use (quantity) in such food. • The objective and purpose of addition of additives. • Specific consumers (age, sex and condition). The exposure to any additives or ingredients is referred to as an estimated daily intake (EDI) which is influenced by the concentration of the substance (additives) and the food which is consumed daily (daily intake of food). Thus, EDI = C × I I ® daily intake of food. C ® concentration of toxicants in the food take daily. For more than one food, the formula would be EDIA = (CAO × fo) + (CAP × fP) + (CAQ × fa) + (Ch...)

APPLICATIONS OF TOXICOLOGY

18.3

where CAO, CAP, CAQ, ... are the concentrations of A in food category O, P, Q... respectively. fo, fp and fq... are the daily intake of food category. The effects of additives on the human health depend on the following factors: • The daily intake of each food containing additives • The concentration of additives in each food. • The potential consumption of or exposure to the substance from non-food sources.

18.2.3 Effects of Food Additives Food Allergy

Food allergy sometimes refers to as food hypersensitivity which involves immunoglobulins, basophils or mast cells and the exposure to the allergen. Cutaneous reactions and anaphylaxis are the most common symptoms associated with food allergy. Most allergens in food are proteins in nature. Generally, children are most susceptible to food allergy with adverse effects.

18.3

MEDICAL AND CLINICAL TOXICOLOGY

Medical toxicology refers to the study of activities aimed at the protection of heath, risk assessment related to health and doing research activities to improve these conditions. The clinical toxicology is the application of toxicology in which the direct diagnosis and treatment of patients who have been the victims of poisoning. Victims of intoxication may require immediate following general steps so that the patient can respond well and safe from any eventuality. • Stabilization of the patient: The first priority in the treatment of a patient who has suffered poisoning, must be established by assessing the vital signs and the effectiveness of respiratory and circulatory systems. Once the poisoned patient is clinically stabilized in terms of ventilation, circulation and oxygenation, the further treatment may be followed. • Clinical Evaluation: It involves various tests including laboratory and radiology to determine the dose and time of exposure relationship so that the effect of poison may be determined. • Prevention of further toxin absorption: Prevention of further toxin absorption is very essential by minimizing the total amount that reaches the systemic circulation. To prevent further toxin absorption, it is necessary to identify the route of exposure. For example, if the exposure route is inhalation, then keep the patient away from that environment where the toxins are present. Sometimes, the patient is induced to vomit (emesis).

18.4

TOXICOLOGY

One may administer apomerphine to induce vomit. Medical activated charcoal may be administered orally to prevent absorption in that area of GI which cannot be reached by gastric lavage which is used to wash the stomach. Laxatives are to prevent the lumen of intestine from toxic elements. • Elimination of Poison: Various methods may be applied to accelerate the process of elimination of poison from the absorbed system. The preliminary methods for this process are alkalization of urine, haemodialysis, haemoperfusion, haemofiltration, plasma exchange and serial oral activated charcoal. Urinary alkalization is used to remove weak acids by increasing the pH of urinary filtrate which prevents renal reabsorption. In haemodialysis method, the blood is pumped into the dialysis membrane which allows the toxic agents to pass through the membrane and reach equilibrium. The toxic agents with high water solubility, low molecular weight, low protein binding and low in concentration are very effectively eliminated by haemodialysis process. Haemoperfusion has the similar type of action for elimination of toxins. The high molecular weight and high protein binding toxins may be removed effectively through plasma exchange methods. • Administration of Antidote: Many intoxications can be treated by using antidotes which behave as a chelating agent so that they can physically bind the toxins. Thus, the adverse effects due to toxins may be eliminated. All the substances classified as antidotes exert their effect via one form of antagonism or another. For example, atropine is used to treat intoxication by cholinesterase inhibitors such as organophosphorus compounds such as parathion and carbamates. Sodium nitrite is given to patients poisoned with cyanide to cause formation of methemoglobin, which serves as an alternative binding site for the cyanide ion, thus making it less toxic to the body.

18.4

OCCUPATIONAL TOXICOLOGY

Occupational toxicology is the application of the principles of toxicology towards the toxic agents coming out of industries or any other workplace with the health hazards. The principal objectives of the occupational toxicology are as follows: • To prevent adverse health effects in workers arising from their work environment. • To eliminate established hazards as far as possible. • To identify and monitor the toxic hazards at work.

APPLICATIONS OF TOXICOLOGY

18.5

The occupational toxicology has two types of effects or influences on the worker at place. The effects are system linked and non-system linked stimuli. The system linked stimuli are light, noise, temperature, humidity, etc. These stimuli may have the lower and upper limit to tolerate. The non-system linked stimuli are mechanical vibrations, toxic chemicals and radiations. These stimuli have always adverse effects on human health. These stimuli do not have lower limit but only have the upper limit to tolerate. The main objective of occupational toxicology is to provide information about the dose and host factors so that exposure standards for workers may be established. Dose is a function of exposure concentration, exposure duration and exposure frequency. The exposures depend on the work conditions and ambient conditions of the site of work. Depending on the physico-chemical properties of the toxic elements in the workplace, the substances may be inhaled or absorbed through skin.

18.4.1 Toxin Exposure Routes Disease causing toxin from industries or other workplace involve exposure primarily through inhalation, ingestion and dermal absorption. Generally, the gaseous substances, volatile chemicals, aerosols, vapours, smoke and fumes can enter the body through inhalation. In the ingestion exposure, the toxic elements enter the body with the help of insect bite, venomous animals and plants. The dermal exposures can arise from airborne materials as well as liquids splashed onto the skin, immersion exposures, or from material handling.

18.4.2 Occupational Diseases Workers exposed to chemicals in the workplace are exposed principally by inhalation and dermal contact. Thus, the occupational toxicants may induce diseases in lungs and skins. The severe diseases like pneumoconiosis, silicosis, asbestosis, byssinosis and occupational asthma among coal workers lead to death. Several occupational diseases may affect the organs such as liver, kidney, heart, nervous system, immune system and reproductive system other than lungs and skin.

18.4.3 Permissible Levels of Exposure It is always necessary to define suitable permissible levels of exposure so that workers may take suitable measures for their safety. Some important terms related to permissible levels of exposure may be described as: Threshold-Limit Values (TLVs)

Threshold-limit values may be defined as the limit value to which workers may be repeatedly exposed to the certain toxicants without any adverse effect. TLVs generally refer to airborne concentrations of the substances exposed to the

18.6

TOXICOLOGY

workers. Threshold limits are based on the reliable available data from the workplace. There are three categories of TLVs such as: Threshold-limit value-time-weighted average (TLV-TWA)

The threshold limit value-time weighted average is the certain concentration of toxicents exposed for 8 hrs per day without any adverse effect. Threshold-limit value-short term exposure limit (TLV-STEL)

It is the maximal concentration of the toxicants to which the workers are exposed for a period of 15 minutes continuously without causing irritation, chronic or irreversible tissue change and narcosis. It is only permitted for 4 times, i.e., 60 minutes per day exposure. Threshold limit value-ceiling (TLV-C)

It is the concentration that should not be exceeded. If this value is exceeded, then the life is under threat. Below this value the workers may be exposed without any adverse effects.

-:-4+151. 2. 3. 4. 5.

Explain about the food toxicity. What are the different sources of toxicants in food? Explain the term estimated daily intake (EDI). Discuss about the medical and clinical toxicology. Write notes on occupational toxicology.

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71. Dauterman, Walter C. Metabolism of Toxicants, Phase II reactions, Chapter 5 in Introduction to Biochemical Toxicology, Ernest Hodgson and Frank E., Guthrie, Eds, Elsevier, New York pp. 92-105, 1980. 72. Carson R: Silent Spring. Boston: Houghton Mufflin, 1962. 73. Stopford, Woodhall, The Toxic Response of Pesticides,” Chapter ll in Industrial Toxicology, Phillip L. Williams and James L. Burson, Eds., Van Nostrand Reinhold Co., New York, pp. 211-229 (1985). 74. Hodgson, Ernest, “Metabolism of Toxicants, “Chapter 13 in A Textbook of Modern Toxicology. Ernest Hodgson and Patricia E. Levi, Eds., Elsevier, New York, pp. 5184, 1987. 75. Abou-Domia MB, Lapadula D: Mechanisms of Organophosphorus ester induced delayed neurotoxicity: Type I and II. Annu Rev Pharmacol Toxicol 50: 405-440, 1980. 76. Sako, MDN, AI-Sultan II, Saleem AN: Studies on sheep experimentally poisoned with Hypericum perforatum. Vet Hum Toxicol 35: 298-300, 1993. 77. Emboden, William, Narcotic Plants, Macmillan Publishing Co., New York, 1979. 78. Burkhard PR, Burkhard K., Haenggeli C.A.: Plant-induced seizures: Reappearance of an old problem. J. Neurol 246: 667-670, 1999. 79. Scheuplein RJ. Blank JH: Permeability of the skin. Physiol Rev. 51: 702-747, 1971 80. Bloom JC: Introduction to hematotoxicology, in spies IG, Mc Queen CA, Gandolfi AJ (Eds): Comprehensive Toxicology, vol. 4 Oxford: Pergamon Press, pp. 1-10, 1997 81. Agency for Toxic Substance and Disease Registry (ATSDR): Toxicological profile for 4,4¢-DDT, 4-4¢, DDE, 4-4¢, DDD, TP-93/05. Atlanta: U.S. Department of Health and Human Services, 1994. 82. NRC: Science and Judgement in Risk Assessment. Washington DC; National Academy Press, 1994. 83. Huff JE: Value, Validity and historical development of carcinogenesis studies for predicting and confirming carcinogenic risk to humans, in Kitchin KT (Ed): Carcinogenicity Testing: Predicting and interpreting chemical effects. New York: Marcel. Dekker pp. 21-123, 1999. 84. TGD, Technical Guidance Document in support of commission directive 93/67/ EEC on Risk Assessment for notified new substances, commission regulation (EC) No 1488/94 on Risk Assessment for existing substances and directive 98/8/EC of the European Parliament and Council concerned with the placing of Biocidal Products on the Market, 2nd ed., EUR 20418 EN/1, European Communities, 2003 (available online through the European Chemicals Bureau website) 85. IPCS (International Programme on Chemical Safety), Principles for the Assessment of Risks to Human Health from Exposure to Chemicals, Environmental Health Criteria 210, UNEP-ILO-WHO-IOME. World Health Organisation, Geneva, 1999 (available online through the IPCS-INCHEM website).

R.6

REFERENCES

86. UNECE (UN Economic Commission for Europe), UN Recommendations on the Transport of Dangerous Goods. Model Regulations, 13th ed, United Nations, New York and Geneva, 2003a (available online through the UNECE website. 87. UNECE (United Nations Economic Commission for Europe), Globally Harmonised System for the Classification of Chemicals (GHS), ST/SG/AC. 10/30. United Nations, New York and Geneva, 2003b (available online through the UNECE website). 88. Maudling, J.S. and Harris, R.H.(1968), Effect of Ionic Environment and Temperature on the Coagulation of color-cawring organic compounds with ferric sulphate. Jr. of American Water Works Association 60, 460. 89 Butterfield, C.T. (1943), Influence of pH and temperature on the survival of coliforms and enteric pathogens when exposed to free chlorine. Public Health Reports 58, 1837. 90. Mullen, E.D and Ritter, J.A.(1974), “Potable Water Corrosion Control”. Jr. of the American Water Works Association 66, 474. 91. American Water Works Association (1971), “Water Quality and Treatment”, 3rd, ed., Toronto, Mcgraw-Hill., pp. 89, 305. 92. Parker, F.L. and Krenkel, P.A. (1969), “Thermal Pollution”, Castle Housing Publication Ltd. 93. Jenkins, S.H. (1974), “Water Pollution Research”, Proceedings of 7th International Conference Paris, pp. 753.

Index

A Abyssal zone, 16.13, 16.15 Accidental intoxication, 8.5 Acetamide, 5.11 Acetonitrile, 5.11 Acetylation, 7.22 Acid anhydride, 5.8 Acid base strength, factors affecting, 3.46 Acid mine drainage, 14.14 Acid rain, 13.10, 13.25 effect of, 13.26, 15.10 Acids, 3.12 ionization of, 3.13 Acrylamide, 5.11 Acrylonitrite, 5.12 Active transport, 6.4 Acute effect, 1.3 Acute exposure, 2.17, 2.19 Acute toxicity tests, 12.3 Acute toxicity, 8.5 Acyclic saturated hydrocarbons, toxicity of, 5.3 Acylation, 7.21 Addition reaction, 3.53 Adiabatic cooling, 13.17 Adiabatic lapse rate, 13.18 Adiabatic process, 3.17 Adiabatic walls, 3.16 Aeration, 14.25 Aflatoxins, 9.22 Aggregation, 16.19

Agonist, 2.13 Agricultural wastes, 15.8 Air pollutants, dispersion of, 13.17 elevated sources of, 13.23 fate of, 13.17 health effects of, 13.38 properties of, 13.7 sources of, 13.38 transportation of, 13.17 types of, 13.3 Air pollution, control of, 13.17 problems of, 13.25 sources of, 13.2 Alcohol dehydrogenase, 7.6 Alcohols, 9.6 toxicity of, 5.6 Aldehyde dehydrogenase, 7.7 Aldehydes, 5.7 Aliphatic hydrocarbon, 9.3 Alkyl halides, toxicity of, 5.3 toxic effects of, 5.4 Allergic dermatitis, 10.4 Allergy, 1.6 Alpha (a) rays, 4.15 a-elimination, 3.53 Ames test, 12.4 Amides, toxicity of, 5.10

2

INDEXOXICOLOGY

Amines, toxicity of, 5.10 Amino acid conjugation, 7.22 Anabolism, 7.30 Anaemia, 10.6 Animal toxins, 9.23 Anionotropic transformations, 3.50 Antarctic ozone hole, 13.36 Anticonvulsants, 9.21 Antidote, administration of, 18.4 Antiepileptics, 9.21 Aquatic ecosystem, 16.8 Aquatic ecotoxicology, 16.25 Aromatic hydrocarbons, 9.8 Arsenic, 4.4 Arthropod toxins, 9.23 Artificial radioactivity, 4.17 Asthma, 10.17 Atom, electronic configurations of, 3.3 Atomic number, 3.1 Atomic radii, 3.5 Atomic structure, 3.1 Attacking reagent, types of, 3.54 Aufbau principle, 3.3 Axonopathies, 10.14 Azimuthal quantum numbers, 3.3 Azo-reduction, 7.10 B Bacteria, 14.6 Barbiturates, 9.18 Bases, 3.12 ionization of, 3.13 Beer’s law, 3.42 Behavioural tolerance, 1.4 Benthic zone, 16.15 Benthos, 16.12, 16.16 Benzene, 9.8

Benzodiazepines, 9.19 Beryllium (Be), 4.6 Beta (b) rays, 4.15 b-elimination, 3.53 Bioaccumulation, 7.25 Bioactivation, 8.1 Bioavailable substance, 7.28 Biochemical oxygen demand, 14.4 Biochemical reactions (on the body), 1.9 Biocides, toxic effects of, 9.10 Bioconcentration, 7.28, 7.29 Biodegradation, 7.29 Biodiversity, 16.17 Bioinactivation, 17.1 Biological evolution, 16.16 Biological monitoring, 11.2 Biomagnification, 7.25, 7.26 Biomarkers, adverse effects of, 11.4 aspects of, 11.1 classification of, 11.1 effect of, 11.3 exposure of, 11.2 genetic damage of, 11.4 in plants, 11.5 susceptibility of, 11.5 significance of, 11.6 Biomass production, 16.19 Biotic province, 16.3 Biotransformation, 4.5, 7.2, 7.30 Bipyridilium herbicides, 9.17 Bivariant, 3.27 Black alkali soil, 15.9 Blood cells, toxicity of, 10.6 Blood-to-gas partition coefficient, 6.7 Bond fission, 3.45 Bond, types of, 3.8

INDEX

Botanical insecticides, 9.15 Brooks, 16.9 Bucco-enteral circulation, 6.6 C Cadmium (Cd), 4.6, 10.13 Carbamate insecticides, 9.14 Carbanions, 3.52 Carbene, 3.53 Carbocations, 3.52 Carbon dioxide, 13.8 Carbon disulphide, 9.10 Carbon monoxide, 13.7 Carbon tetrachloride, 9.5 Carbonium ions, 3.52 Carbonyl reduction, 7.11 Carboxylic acids, 5.7 Carcinogenesis, 10.5, 8.6 Carcinogenicity tests, 12.4 Cardiac hypertrophy, 10.19 Cardiotoxicity, 10.19 Cardiovascular toxicology, 10.18 Catabolism, 7.30 Cathode, 3.33 Cationotropic transformations, 3.50 Cell death, 10.9 Cell membrane concept, 6.2 Cell necrosis, 10.9 Cell, EMF of, 3.36 Cellular cholestasis, 10.10 Charge neutralization, 14.33 Chelating agents, characteristics of, 4.4 Chemical antagonism, 2.22 Chemical bonding, 3.7 Chemical equilibrium, 3.18 Chemical kinetics, 3.37 Chemical oxygen demand, 14.5 Chemical reaction, rate of, 3.38

Chemical signal systems, disturbance of, 9.1 Chemiluminescence, 3.44 Chlorinated hydrocarbons, 9.3 Chlorination, 14.36 Chlorofluorocarbons, 13.8 Chloroform, 9.5 Chlorophenoxy herbicides, 9.17 Chromium (Cr), 4.7 Chronic effects, 1.3 Chronic exposure, 2.17, 2.19 Chronic toxicity tests, 12.3 Chronic toxicity, 8.6 Clinical toxicology, 1.2, 18.3 Closed system, 3.16 Coagulation, 14.32 Colloidal systems, 3.30 classification of, 3.31 Colloids, 3.30 Colonization, 16.19 Colour additives, 18.2 Commensalism, 16.19 Common ion effects, 3.14 Community dynamics, 16.2 Community, 16.2 Complete carcinogen, 8.8 Coniferous forests, 16.6 Conjugating agents, 7.16 Conjugation reaction, 7.16 Conjugation, 3.55 Conventional pollutants, 13.4 Coordinate bond, 3.11 formation of, 3.11 Coordinate compound, characteristics of, 3.11 Coordinate covalent bond, 3.11 Copper (Cu), 4.8 Cosmetics, toxic effects of, 9.25 Covalent bond, 3.10 Creeks, 16.9

3

4

INDEXOXICOLOGY

D Daniel cell, 3.36 Dative bond, 3.11 d-block elements, 3.5 Deciduous forest, 16.6 Deforestation, 15.2 Degrees of freedom, 3.27 Dehydrochlorinase, 7.15 Delayed toxic effects, 8.3 Delayed toxicity, 8.2 Deliberate intoxication, 8.5 Deposition, 2.21 Dermal exposure, 2.18 Dermatotoxicity, 10.1 Descriptive toxicology, 2.7 Desert ecosystem, 16.7 Desertification, 13.30 Detergent builder chemicals, 14.11 Detergents, 14.11 Detoxification, 17.1, 17.2 Developmental toxicity, 10.18 Developmental toxicology, 1.2 Diamine oxidases, 7.7 Diathermal walls, 3.16 Dichloromethane, 9.3 Diethyl sulphate, 5.16 Diethylene glycol, 9.8 Dimethyl sulphate, 5.16 Disease-causing agents, 14.5 Disinfectant, 14.36 Disinfection, 14.36 Dispersion models, 12.9 Dispersion, 13.21 Dispositional antagonism, 2.22 Dissolved oxygen wastes, 14.4 Distal tubular injury, 10.12 Disulphide reduction, 7.11 Disulphides, 5.15 DNA damage, 4.20 Dose-response assessment, 12.10

Dose-response concept, 2.10, 2.11 Dose-response curve, 2.12 Dose-response relationship, 2.11, 2.13, 2.14, 2.15 Double layer compression, 14.33 Droughts, 13.30, 13.31 Drugs, 9.21 toxic effects of, 9.18 Dual media filters, 14.35 E –E effect, 3.49 Ecological community, 16.2 Ecological gradients, 1.3 Economic toxicology, 1.2 Ecosystem, 16.2 components of, 16.3 structure of, 16.2 Ecotoxicology, 16.1 Electrochemical cell, 3.35 Electrochemistry, 3.32 Electrode potentials, 3.33 measurement of, 3.34 Electrolytes conductors, 3.32 Electrolytic cell, 3.35 Electrolytic conductors, 3.32 Electromeric effect, 3.48 Electron affinity, 3.7 Electronegativity, 3.7 Electronic conductors, 3.32 Electrons, 3.1 Electrophiles, 3.54 Electrovalent bond, 3.8 Elements, classification of (in the Periodic Table), 3.5 Elimination reaction, 3.53 Elimination, 17.2 Emission control, 12.12 Emission process, 2.21 Emphysema, 10.16

INDEX

Endocrine system, toxic effects on, 10.19 Endocrine toxicity, 10.19 Endogenous substances, 1.5 Energy flow, 16.20 Energy, 3.16 Enterohepatic circulation, 6.6 Enthalpy, 3.20 Entropy, 3.24 Environmental monitoring, 11.2 Environmental toxicology, 1.1, 1.2 Enzyme inhibition, 10.8 Enzyme inhibitors, 9.1 Epigenetic carcinogens, 8.8 Epoxidation, 7.3 Epoxide hydrolase, 7.14 Equilibrium models, 12.9 Ergot alkaloids, 9.22 Esterases, 7.13 Ethanol, 9.7 Ethylene glycol, 9.7 Eutrophication, 14.8, 14.23 Evolutionary ecology, 16.16 Exhalation, 17.5 Exposure assessment, 12.10 Exposure, control of, 12.12 duration of, 2.19 form of, 2.20 frequency of, 2.19 permissible levels of, 18.5 quantitative aspects of, 2.21 sites of, 2.17 Extensive property, 3.18 Extracellular reactions, 1.7 F Facilitated diffusion, 6.4 Fatty liver, 10.9 f-block elements, 3.5 Fecal excretion, 17.4

Fibrosis, 10.16 Filter media, 14.34 Filtration, 6.3, 14.34 First order kinetics, 2.4 Fluorescence, 3.44 Food additives, 18.2 effects of, 18.3 Food allergy, 18.3 Food chain, 7.26 Food toxicity, 18.1 Food web, 7.27 Forest ecosystem, 16.4 Free energy change, 3.36 Free radicals, 3.52 Freons, 13.34 Freshwater ecosystem, 16.8 Functional antagonism, 2.22 Fundamental reactions, 3.44 Fungicides, 9.17 G Galvanic cell, 3.35 g-elimination, 3.53 Gamma (g) rays, 4.15 Gastrointestinal exposure, 2.19 Gene mutations, 16.27 General dose-response curve, 2.11 Genetic drift, 16.17 Genetic tolerance, 1.4 Genome mutations, 16.28 Genotoxic carcinogens, 8.7 Genotoxicity, 16.26 Global warming, 13.31 effects of, 13.32 Glomerular filtration, 17.3 Glomerular injury, 10.12 Glucuronidation, 7.16 Glutathione conjugation, 7.23 Glycol ethers, 9.8 Grassland ecosystem, 16.4 Greenhouse effect, 13.8, 13.31

5

6

INDEXOXICOLOGY

Greenhouse gases, 13.32 sources of, 13.31 Grothus-Draper law, 3.42 Groundwater pollution, 14.21 Groundwater, pollutants in, 14.22 H Habitats, 16.2, 16.10 Haematotoxicity, 10.6 Hazard characterization, 12.7 Hazard identification, 12.7 Hazardous wastes, 15.8 Heat, 3.16 Helmholtz electrical double layer, 3.33 Hepatic excretion, 17.4 Hepatotoxicity, 10.7 Herbicides, 9.16 Heterolytic fission, 3.46 High level wastes, 14.17 Homeostasis, 2.15 Homolytic bond fission, 3.45 Hormesis, 2.15, 2.16 Human skin, cross-section of, 6.8 Hund’s rule of maximum multiplicity, 3.4 Hydrocarbons, 5.1, 13.11 toxicity of, 5.5 Hydrogen bond, 3.12 Hydrogen fluoride, 13.11 Hydrogen sulphide, 9.10 Hydroxylation, 7.4 Hyperconjugation, 3.55, 3.56 Hyperpigmentation, 10.5 Hypersensitivity, 1.6 Hyperthyroidism, 10.20 Hypochromasia, 10.6 Hypopigmentation, 10.5 Hyposensitivity, 1.6 Hypotonics, 9.18

I –I effect, 3.47 Immediate toxic effects, 8.2 Immediate toxicity, 8.2 Immune response, types of, 4.3 Immune system, toxic response of, 10.20 Immunosuppression, 1.6 Immuno-toxicology, 1.2, 10.20 Impaired bile flow, 10.10 Incomplete carcinogen, 8.8 Indoor air pollution, 13.37 Inductive effect, 3.47 Industrial wastes, 15.7 Ingestion exposure, 2.19 Inhalation exposure, 2.18 Initiation phase, 8.6 Inorganic element, types of, 4.1 Inorganic pollutants, 14.13 Inorganic toxicants (in soils), 15.5, 15.6 Insect vectors, 14.5 Insecticides, 9.11 Intensive property, 3.18 Intermediate level wastes, 14.17 Intermediates, formation of, 3.51 Internal energy, 3.18 Interspecific interactions, among species, 16.18, 16.19 Intertidal zone, 16.14 Intoxification, 7.3 Intracellular reactions, 1.8 Invariant, 3.27 Ionic bond, 3.8 Ionic compounds, characteristics of, 3.9 formation of, 3.9 Ionic radii, 3.5

INDEX

Ionization potential, 3.6 Iron (Fe), 4.9 Irreversible binding mechanism, 6.11 Irreversible effect, 16.24 Irreversible process, 3.17 Irreversible solutions, 3.31 Irreversible toxic effect, 1.6 Irreversible toxicity, 8.3 Irritant dermatitis, 10.4 Isobaric process, 3.17 Isochoric process, 3.17 Iso-electronic species, 3.5 Isolated system, 3.16 Isothermal process, 3.17 K Ketones, 5.7 Kidney nephron, 10.11 L Lambert’s law, 3.42 Land degradation, 15.2 Lapse rate, 13.17 Leachates, 14.22 Lead (Pb), 4.12 Lentic ecosystem, 16.10 Lethal dose, 16.24 Lethal effect, 16.24 Limnetic zone, 16.13 Lipid peroxidation, 10.8 Littoral zone, 16.13 Liver injury, types of, 10.8 Local toxicity, 8.2 Looping plume, 13.18 Lotic ecosystem, 16.9 Low level wastes, 14.17 Lung cancer, 10.17 Lung, toxic responses of, 10.16 Lyophilic sols, 3.31

7

Lyophobic sols, 3.31 M Macrohabitat, 16.2 Magnetic quantum numbers, 3.3 Major communities, 16.2 Manganese (Mn), 4.10 Marine biocies, 16.15 Marine pollution, 14.22 effects of, 14.23 Mechanical equilibrium, 3.18 Mechanistic toxicology, 2.2 Medical toxicology, 18.3 Mercury (Hg), 4.11 Mercury, 10.13 Metabolic activation, 7.8 Metabolic hydrolysis, 7.13 Metabolic inactivation, 17.2 Metabolic reduction, 7.10 Metabolic toxicology, 2.2 Metal reduction, 7.13 Metal toxicity (with multiple effects), 4.2, 4.4 Metal toxicology, 10.13 Metallic conductors, 3.32 Metallothionein, 6.11 Metals, 3.4 Methane, 13.8 Methanol, 9.6 Methylation, 7.19 Methylene chloride, 9.3 Microbial toxins, 9.23 Microhabitat, 16.2 Microorganism, 14.6 diseases caused by, 14.6 Microsomal oxidation, 7.2 Migration, 16.17 Mineralization, 7.29 Minor communities, 16.2 Mixed media filters, 14.35 Mixed-function oxidases, 7.2

8

INDEXOXICOLOGY

Mixtures, toxicity of, 8.3 Molecularty, 3.41 Mono aromatic hydrocarbons, toxicity of, 5.5 Monoamine oxidases, 7.7 Monovariant, 3.27 Municipal wastes, 15.7 Mutagenesis, 4.20, 4.21 Mutagenesis, 8.9 Mutagenicity tests, 12.4 Mutagenicity, 16.26 Mutagens, 4.21, 8.9 Mutation, 16.16 types of, 16.27 Mycotoxins, 9.22 Myelinopathies, 10.14 N Nanoplankton, 16.15 Narcotic analgesics, 9.20 Natural products, toxic effects of, 9.21 Natural selection process, 16.17 Natural water, classification of, 14.1 N-dealkylation, 7.5 Negative lapse rate, 13.18 Nektons, 16.16 Nephrotoxicity, 10.10 Net planktons, 16.12 Neuroleptics, 9.21 Neuronopathy, 10.14 Neurotoxicity, 10.13 Neutrons, 3.1 Nickel (Ni), 4.13 Nitriles, toxicity of, 5.11 Nitro compounds, toxicity of, 5.12 Nitrobenzene, 5.12

Nitrogen oxides, 13.9 Nitrogen-containing organic compounds, 5.9 Nitro-reduction, 7.10 Nitrosoamines, toxicity of, 5.13 Nitrous oxide, 13.9 N-methylation, 7.20 Noble gases, 3.4 Non-carbon elements, oxidation of, 7.8 Non-lethal effect, 16.24 Non-microsomal oxidation, 7.6 Non-variant, 3.27 Normal elements, 3.4 N-oxidation, 7.8 N-oxide reduction, 7.12 Nuclear fuel cycle, 4.18 Nuclear stability, 4.17 Nucleophiles, 3.55 Nucleophilicity order, 3.55 Nucleus, 3.1 Nutrients, 14.8 Nutritional toxicology, 1.2 O Occupational diseases, 18.5 Occupational toxicology, 1.2, 18.4 Octet theory, 3.10 O-dealkylation, 7.5 Oil, 14.13 Oligofication, 14.9 Oligophication, 14.24 O-methylation, 7.20 One component system, 3.27 One-compartment model, 2.3 Open system, 3.16 Opiates, 9.20 Order of reaction, 3.41 Organic acids, 5.7 Organic chemicals, 14.9

INDEX

Organic esters, 5.16 Organic pollutants, 14.4 Organochlorine insecticides, 9.11 Organomercury, 5.17 Organometallics, 5.16 Organometalloids, 5.16 Organophosphate insecticides, 9.13 Organophosphorus insecticides, 9.12 Organophosphorus, 5.13 Osmosis, 14.22 Overgrazing, 15.2 Oxidation potential, 3.34 Oxygen-containing organic compounds, 5.6 toxic effects of, 5.6 Oxygen-demanding, 14.4 Ozone depletion, effects of, 13.37 Ozone hole, 13.34 Ozone layer, depletion of, 13.33 Ozone shield, 13.33 Ozone, 13.9 P Papillary injury, 10.12 Parasites, diseases caused by, 14.7 Particulate matter, 13.12 Passive transport, 6.3 Pathogenic organisms, 14.5 Pathogens, 14.5 Pauli exclusion principle, 3.4 p-block elements, 3.5 Pelagic zone, 16.14 Percutaneous absorption, 10.3 Percutaneous exposure, 2.18 Perfect differentials, 3.19 Periodic properties, 3.5 Periods, 3.4 Periphytic, 16.15

9

Permanent effect, 3.47 Permeation, 10.3 Pesticidal toxicity, 15.3 Pesticide resistance, 15.3 Pesticides, 14.9 behaviour of, 15.4 effects of (on soil organisms), 15.5 in soil, 15.3 toxic effects of, 9.10 Phagocytosis, 2.18, 6.5 Pharmacokinetic models, 2.3 Phase rule, 3.25 Phase, 3.26 Phase-I biotransformation, 7.2 Phase-II reactions of toxicants (enzyme reactions), 7.15 Phosphine oxides, 5.14 Phosphine, 5.14 Phosphorescence, 3.44 Photochemical equilibrium, 3.44 Photochemical oxidants, 13.11 Photochemical reactions, 3.42 primary processes in, 3.43 Photochemical smog, 13.27 effects of, 13.30 Photochemistry, laws of, 3.42 Photoelectric effect, 3.2 Photosensitivity, 10.5 Phototoxicology, 10.4 Physico-chemical speciation, 2.20 Physiological tolerance, 1.4 Phytoplankton, 16.15 Pinocytosis, 6.5 Plankton, 16.15 Plant toxins, 9.24 +E effect, 3.48 +I effect, 3.47 Pneumoconiosis, 10.17 Point mutations, 8.9

10

INDEXOXICOLOGY

Point sources, 14.3 Poison, elimination of, 18.4 Polar night, 13.36 Polar stratospheric clouds, 13.36 Polar vortex, 13.36 Polar winter, 13.36 Polyamine oxidases, 7.7 Polychlorinated biphenyls, 14.12 Polycyclic aromatic hydrocarbons, toxicity of, 5.5 Population ecology, 16.18 Positive adiabatic lapse rate, 13.18 Potentiation, 2.23 P-oxidation, 7.9 Predation-parasitism, 16.19 Primary carcinogens, 8.7 Primary haematotoxicity, 10.6 Primary pollutants, 13.3 Primary productivity, 16.20 Primary quantum yield, 3.43 Principal quantum numbers, 3.3 Procarcinogen, 8.7 Profundal zone, 16.13 Progression phase, 8.6 Promotion phase, 8.6 Propylene glycol, 9.8 Protons, 3.1 Prototropic transformations, 3.50 Proximal tubule injury, 10.12 Proximate carcinogens, 8.7 Pulmonary excretion, 17.5 Pulmonary exposure, 2.18 Pulmonary oedema, 10.16 Q Quantum theory of radiation, 3.1 Quantitative exposure-response relationship, 2.21 Quantum numbers, 3.2

R Radiation, quantum theory of, 3.1 Radioactive decay kinetics, 4.15 Radioactive elements, effects of, 4.19 in aquatic environment, 4.18 Radioactive materials, 14.1 Radioactive toxicants, effects of, 4.19 Radioactive waste waters, 4.19 Radioactivity theory, 4.17 Radioisotopes, 4.17 Radionuclides, 15.8 Radium, 4.20 Radon, 4.20 Rapid sand filter, 14.36 Reaction intermediates, 3.51 Reactions, classification of, 3.53 molecularity of, 3.41 order of, 3.40 Reactive metabolites, toxicity of, 8.12 Reaeration, 14.4 Rearrangement reaction, 3.54 Recalcitrant compounds, 7.29 Receptor antagonism, 2.23 Receptor, 2.13 Recovery zone, 14.5 Redox reaction, 3.54 Reduction potential, 3.34 Regulatory toxicology, 2.7 Relative biological effectiveness, 14.17 Renal excretion, 17.3 Reproductive toxicity tests, 12.5 Reproductive toxicity, 10.17 Reproductive toxicology, 1.2 Resonance effect, 3.49 Respiratory toxicology, 10.15

INDEX

Reversible binding mechanism, 6.10 Reversible process, 3.17 Reversible solutions, 3.31 Reversible toxic effect, 1.6 Reversible toxicity, 8.3 Risk assessment, 12.7, 12.11 Risk characterization, 12.10 Risk monitoring, 12.12 Routes, sites of, 2.17 S Saline water ecosystem, 16.13 Salts, 3.12, 3.15 s-block elements, 3.5 Screening effect, 3.6 S-dealkylation, 7.6 Second order reaction, 3.40 Secondary haematotoxicity, 10.6 Secondary pollutants, 13.3 Secondary productivity, 16.20 Sedimentation, 14.28 Sediments, 14.15 Sensitivity, 1.6 Simple diffusion, 6.3 Simple dilution models, 12.9 Single electrode potential, 3.34 Slow sand filter, 14.36 S-methylation, 7.21 Soaps, 14.11 Social organization, 16.19 Soddy-Fajan group displacement law, 4.16 Soil erosion, 15.2 Soil salinity, 15.9 Soil toxicant, types of, 15.3 Soil toxicity, sources of, 15.1 Solid waste, soils in, 15.7 types of, 15.7

11

Solubility product, 3.14 Solvent, toxic effects of, 9.2 S-oxidation, 7.8 Special transport, 6.4 Spin quantum numbers, 3.3 Stable configuration, 3.7 Stark-Einstein law, 3.42 Steatosis, 10.9 Structural chromosomal aberrations, 16.27 Structure-activity relationship, 1.1 Subacute exposure, 2.19 Subchronic exposure, 2.19 Subchronic tests, 12.6 Sublethal effect, 16.24 Substitution reaction, 3.54 Sulphate conjugation, 7.18 Sulphation, 7.18 Sulphides, 5.15 Sulphoxide reduction, 7.12 Sulphur oxides, 13.10 Sulphuric acid, 5.16 Sulphurous smog, 13.29 Super adiabatic rate, 13.18 Surfactants, 14.11 Surroundings, 3.16 Synaptopathies, 10.15 Systemic effects, 8.2 Systemic toxicity, 8.2 T Tautomerism, 3.49 characteristics of, 3.50 Temperature inversion, 13.18 Temporary effect, 3.47 Teratogenesis, 8.11, 16.28 Teratogenicity tests, 12.5 Teratology, principles of, 8.11 Terrestrial ecosystem, 16.3 Terrestrial ecotoxicology, 16.23

12

INDEXOXICOLOGY

Terrestrial food chain, 16.21 Tetrachloroethylene, 9.4 Thermal equilibrium, 3.18 Thermal pollution, 14.18 effects of, 14.20 Thermochemistry, 3.21 Thermodynamic equilibrium, 3.18 Thermodynamic state, 3.17 Thermodynamic system, 3.16 Thermodynamics, 3.15 first law of, 3.19 second law of, 3.22 terminology of, 3.15 Thiols, 5.15 Threshold doses, 2.8, 2.14 Threshold effect, 1.3 Threshold frequency, 3.2 Tolerance gradients, 1.3 Toluene, 9.9 Toxic compounds, absorption of, 6.5 Toxic nephropathies, 10.12 Toxic radioactive elements, 4.14 Toxic responses, variation in, 8.4 Toxicants, absorption of (by gastrointestinal (GI) tract), 6.5 absorption of (by respiratory tract), 6.7 absorption of (through the skin), 6.7 accumulation of (in tissue), 6.10 additive effect of, 1.5 antagonistic effect of, 1.4 biochemical pathways of (on the body), 1.8 distribution mechanism of, 6.10 distribution of (in ecosystem), 16.22 distribution of (over the organism), 6.9

effects of (on terrestrial ecosystem), 16.25 excretion of, 17.3 interactive effects of, 2.21, 2.22 potentiative effect of, 1.5 sources of (in food), 18.2 synergistic effect of, 1.5 Toxicity evaluation, 12.1 Toxicity rating, 12.6 Toxicity, 8.1 Toxicodynamics, 2.6, 2.7 Toxicokinetics, 2.2, 2.7, 4.5 effects of, 4.19 Toxicological chemistry, 1.1, 1.7 Toxicology, classification of, 1.1 principles of, 2.1 subdisciplines of, 1.2 Toxin exposure routes, 18.5 Toxin exposure, 2.16 Toxins, transport mechanisms of, 6.2 Transition elements, 3.4 Transmission process, 2.21 Transport models, 12.9 Trichloroethylene, 9.4 Trichothecenes, 9.22 Tricyclic antidepressants, 9.19 Triple point, 3.28 Trophic level efficiency, 16.21 Tubular reabsorption, 17.3 Tubular secretion, 17.4 Tundra, 16.7 Two-compartment model, 2.5 graphs of 2.6 U Ultimate carcinogen, 8.7 Unconventional pollutants, 13.4

INDEX

Unsaturated hydrocarbons, toxicity of, 5.3 Urticaria, 10.5 V Vapours, toxic effects of, 9.2 Venomous animals, toxins of, 9.23 Vinyl chloride, 9.6 Viruses, 14.6 W Water pollutant, types of, 14.3 Water pollution control, engineered system for, 14.24

Water system, 3.27 Water, types of, 14.2 Water-brone insect vector, 14.5 diseases caused by, 14.7 Wind, 13.21 Woodland, 16.6 Work, 3.16 Xenobiotic substances, 1.5 Xenobiotics of the skin, toxic effects of, 10.3 Xenobiotics, biotransformation of, 7.1 Z Zero order reactions, 3.41 Zinc (Zn), 4.14

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Textbook of TM

Toxicology The book also provides the fundamental knowledge of the principles related to toxicology, chemical toxicology, environmental toxicology and related sciences so as to meet the challenging requirements of students as well as teachers in environmental sciences, pharmacological, medical, veterinary, biomedical science and toxicological sciences. All essential aspects of toxicology have been covered in this book. It comprises 18 chapters in a logical sequence. Toxicology is distinguished by up-to-date insight into the harmful interactions between chemicals (xenobiotics) and biological synthesis. It gives better understanding on acute toxicology risk assessment, toxicity testing and many other areas directly or indirectly related to toxicology. Balram Pani is a faculty in the Department of Chemistry at Bhaskaracharya College of Applied Sciences, Delhi University, New Delhi. He obtained his Ph.D. from Jawaharlal Nehru University. Dr. Pani has 20 years of research and teaching experience in the field of Chemistry and Environmental Science. He has also authored various books on Environmental Science and Engineering Chemistry, which have been adopted by several universities, and engineering and science colleges.

Textbook of Toxicology

Toxicology is an interdiscipline that requires the knowledge of many areas such as analytical chemistry both organic and inorganic, biochemistry, pathology and physiology. The book is designed to provide a wide ranging overview of the various toxicants and their effects on living organisms, particularly on human beings.

Textbook of

Toxicology

978-93-89520-27-9

Distributed by: 9 789389 520279

TM