Introduction to Environmental Toxicology 1789245184, 9781789245189

Table of contents :
Cover
Introduction to Environmental Toxicology
Copyright
Contents
Preface
Glossary
1 Introduction
1.1 Overview
1.2 Three Environmental Emergencies: Climate Change,Increased Human Morbidity and Ecotoxicity
1.3 Outline of Chapters
1.4 Methodology
1.5 Exposure Pathways
1.6 Interactions
1.7 Metabolic Responses
1.8 Environmental Fate
1.9 Risk Assessment
1.10 Key Issues
1.11 References
1.12 Exercises
2 Biogenic Contaminants
2.1 Overview
2.2 Algal Toxins
2.3 Mycotoxins
2.4 Phytotoxins
2.5 Key Issues
2.6 References
2.7 Exercises
3 Ambient Gases and Particulates
3.1 Overview
3.2 Ozone
3.3 Nitrogen Dioxide
3.4 Sulfur Dioxide
3.5 Particulate Matter
3.6 Key Issues
3.7 References
3.8 Exercises
4 Persistent Organic Pollutants
4.1 Overview
4.2 Polycyclic Aromatic Hydrocarbons
4.3 Polychlorinated Biphenyls
4.4 Dioxins and Furans
4.5 Organochlorine Insecticides
4.6 Organophosphate Compounds
4.7 Fungicides
4.8 Herbicides
4.9 POPs Associated with Endocrine Disruption
4.10 Assessment and Management of Risk
4.11 Ecotoxicity of POPs, Biomagnification and Collateral Damage
4.12 Key Issues
4.13 References
4.14 Exercises
5 Fossil Fuel Pollutants
5.1 Overview
5.2 Crude Oil
5.3 Shale Oil and Gas
5.4 Coal
5.5 Key Issues
5.6 References
5.7 Exercises
6 Metallic Elements
6.1 Overview
6.2 Mercury
6.3 Lead
6.4 Cadmium
6.5 Arsenic
6.6 Electronic Waste Recycling
6.7 Ecotoxicity
6.8 Key Issues
6.9 References
6.10 Exercises
7 Consumerism and Lifestyle Choices: Toxicological Perspectives
7.1 Overview
7.2 Plastics and Synthetic Fibres
7.3 Pharmaceuticals
7.4 Personal Care Products
7.5 Key Issues
7.6 References
7.7 Exercises
8 Radiation
8.1 Overview
8.2 Ionizing Radiation
8.3 Radon
8.4 Ultraviolet Radiation
8.5 Key Issues
8.6 References
8.7 Exercises
9 Adaptation in Microbes and Higher Plants
9.1 Overview
9.2 Microbes
9.3 Higher Plants
9.4 Key Issues
9.5 References
9.6 Exercises
10 Discussion
10.1 Overview
10.2 Contaminants in Diverse Ecosystems
10.3 Human Health Emergency: Environmental Pollutants Contributing to Increased Morbidity and Premature Fatalities
10.4 Ecological Emergency: Wildlife in Peril
10.5 Constraints in Risk Management
10.6 Implications
10.7 Conclusions
10.8 References
10.9 Exercises
Index
Back Cover

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Introduction to Environmental Toxicology

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Introduction to Environmental Toxicology by

J.P.F. D’Mello Formerly of SAC, University of Edinburgh King’s Buildings Campus, Edinburgh, UK

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CABI is a trading name of CAB International CABI Nosworthy Way Wallingford Oxfordshire OX10 8DE UK Tel: +44 (0)1491 832111 Fax: +44 (0)1491 833508 E-mail: [email protected] Website: www.cabi.org

CABI WeWork One Lincoln St 24th Floor Boston, MA 02111 USA Tel: +1 (617)682-9015 E-mail: [email protected]

© J.P.F. D’Mello 2020. All rights reserved. No part of this publication may be r­ eproduced in any form or by any means, electronically, mechanically, by ­photocopying, recording or otherwise, without the prior permission of the copyright owners. A catalogue record for this book is available from the British Library, London, UK. Library of Congress Cataloging-in-Publication Data Names: D’Mello, J. P. Felix, author. Title: Introduction to environmental toxicology / by J.P.F. D’Mello, formerly of SAC, University of Edinburgh King’s Buildings Campus, Edinburgh, UK. Description: Wallingford, Oxfordshire ; Boston, MA : CAB International, [2020] | Includes bibliographical references and index. | Summary: “This book covers the origin, characterization and environmental distribution of the major pollutants, providing explanations of the implications for human morbidity, biodiversity, and food and water safety. Including questions, further reading and case studies to spark classroom discussion, it forms a true introduction for undergraduates”-- Provided by publisher. Identifiers: LCCN 2020023625 (print) | LCCN 2020023626 (ebook) | ISBN 9781789245189 (paperback) | ISBN 9781789245196 (ebook) | ISBN 9781789245202 (epub) Subjects: LCSH: Environmental toxicology. Classification: LCC RA1226 .D64 2020 (print) | LCC RA1226 (ebook) | DDC 615.9/02--dc23 LC record available at https://lccn.loc.gov/2020023625 LC ebook record available at https://lccn.loc.gov/2020023626 References to Internet websites (URLs) were accurate at the time of writing. ISBN-13: 9781789245189 (paperback) 9781789245196 (ePDF) 9781789245202 (ePub) Commissioning Editor: Alexandra Lainsbury Editorial Assistant: Lauren Davies Production Editor: James Bishop Typeset by SPi, Pondicherry India Printed and bound in the UK by Severn, Gloucester

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Contents

Preface

vii

Glossary

xi

1  Introduction

1

2  Biogenic Contaminants

16

3  Ambient Gases and Particulates

30

4  Persistent Organic Pollutants

42

5  Fossil Fuel Pollutants

70

6  Metallic Elements

82

7  Consumerism and Lifestyle Choices: Toxicological Perspectives

97

8  Radiation

106

9  Adaptation in Microbes and Higher Plants

116

10  Discussion

124

Index

141

v

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Preface

We are on the verge of an environmental catastrophe. International agencies and high-profile pressure groups regularly highlight climate change as the primary manifestation of this crisis. I am profoundly dismayed to observe that the current risk-management agenda is almost entirely dictated by efforts to curb the emissions of detrimental greenhouse gases, whereas there is a critical need also to consider the anthropogenic production of a diverse range of other pollutants now unequivocally associated with human health disorders and ecotoxicity. The prevailing consensus implies that ‘carbon footprint’ assessments and the ‘carbon-neutral’ strategy should focus solely on monitoring and limiting tropospheric concentrations of carbon dioxide and methane. However, existing scientific evidence indicates that surveillance and regulations should be extended to a wide range of other contaminants in order to reduce pollution in diverse ecosystems. A significant proportion of complex pollutants contain carbon and thus the carbon trail should be viewed in a more comprehensive perspective in order to mitigate risks for human health and survival of endangered wildlife species. In addition, emissions of nitrogen dioxide, sulfur dioxide, ozone, particulates, heavy metals and radiation are definitively associated with morbidity in humans. Recent estimates by the Lancet Commission suggest that human diseases caused by environmental pollution accounted for about 9 million excess deaths worldwide in 2015 (Landrigan et al., 2018). The European Environment Agency estimated that air pollution caused 400,000 preventable deaths in Europe in 2016. In addition, it is widely believed that entire species of beneficial insects and marine predators are on the verge of extinction due to environmental exposures to persistent organic pollutants and heavy metals. In other words, there is no justification for separating the climate change crisis from the health and ecological emergencies, particularly since the pathways of the former can determine the extent of exposure of humans and wildlife to harmful pollutants. vii

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viii Preface

For example, the arid conditions now emerging in different ecosystems attributed, partly at least, to climatic factors favour the incidence of wildfires, resulting in the production of particulates capable of traversing the blood–brain and placental barriers, with harmful consequences, in addition to the direct effects on the respiratory system. Ecological degradation brought about by climate change may also impact on biodiversity in species compromised by toxicity of persistent organic pollutants and heavy metals (Noel et al., 2018). Thus, there is a strong case for a unified approach in environmental protection and management. Recent applications of robust quantitative methodologies in place of qualitative description have provided renewed impetus for assessing the impact of environmental contaminants and pollutants. In addition, the development of improved and more reliable biological models to predict likely outcomes for humans and endangered wildlife species has increased confidence in emerging data, although some public opinion remains unconvinced by factual information, as distrust of science becomes more common. The continuing risks associated with legacy contaminants, together with ongoing concerns over the absence of thresholds for a variety of environmental carcinogens and endocrine disruptors, have served to realign priorities in current investigations. Furthermore, recent evidence highlights clearly the absence of comprehensive risk assessments by expert groups sponsored by WHO in respect of neuro-behavioural and endocrine disruption risks for individuals and communities exposed to a wide array of urban and rural pollutants. Meanwhile, environmental toxicologists have to contend with confused rhetoric or outright indifference among political leaders who are guided solely by self-interest and electoral success. Complications also arise as a result of inconsistent application of toxicological data and in ensuring compliance with existing regulations which may be impacted by austerity measures. The need for vigilance in a wide range of toxicological issues has been highlighted by the numerous cases of corporate negligence and wilful transgressions, attracting severe penalties from the different authorities. Furthermore, the intervention of the judiciary in empowering vulnerable individuals and communities is emerging as a decisive factor in environmental toxicology. This edition of Introduction to Environmental Toxicology is designed to serve as a basic text for students in the first 2 years of undergraduate degree courses in environmental science, ecology and medical toxicology. Other potential readers might include geography, geology and agriculture graduates wishing to transfer to Masters courses in environmental science. This book represents a simpler version of the more advanced CABI text A Handbook of Environmental Toxicology: Human Disorders and Ecotoxicology (D’Mello, 2020). It is perceived that Introduction to Environmental Toxicology represents a user-friendly edition, enabling students with appropriate university-entrance qualifications to integrate fundamental concepts within modules of existing BSc/BS degree courses. For maximum benefit, students should have prior knowledge of chemistry and biology to advanced level in the UK, or equivalent for other countries. The outline of chapters and the underlying rationale appear in Chapter 1.

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Preface

ix

The approach herein comprises conventional textual material outlining fundamental facts, evidence and interpretation pertinent to environmental toxicology. In addition, a number of case studies are presented for in-depth evaluation of contamination incidents following global catastrophes exemplified, for example, in the Chernobyl nuclear explosion and the Deepwater Horizon oil spill. I have also included examples of environmental failures at local levels, such as the disturbance and potential toxicity caused by petrochemical installations on both sides of the Atlantic. Figures presented in this edition are designed to highlight major impacts of pollutants on human health and wildlife vulnerabilities. A further approach involves the use of questions similar to those I set in examination papers for the toxicology section of my course in Environmental Protection and Management, validated by the University of Edinburgh. This volume necessarily contains information about commercial products which is presented in good faith and in accordance with my understanding of the principles of ‘best practice’ and ‘due diligence’. Every effort has been made to verify the facts and figures relating to the evidence appearing in this book. It is particularly emphasized that data in Introduction to Environmental Toxicology should not be used to extol or discredit the efficacy of any proprietary product cited in the following pages. I have been guided entirely by the need to explore diverse issues in environmental toxicology wherever it takes us, however unpalatable, but always based on robust evidence available in reputable research journals. This Introduction is, therefore, intended exclusively for use as a text in education and research in my effort to protect and enhance human welfare and endangered habitats, since ecology is the very foundation of our society.

References D’Mello, J.P.F. (2020) A Handbook of Environmental Toxicology: Human Disorders and Ecotoxicology. CABI, Wallingford, UK. Landrigan, P.J., Fuller, R. and Acosta, N.J.R. (2018) The Lancet Commission on pollution and health. Lancet 391, 462–512. Noel, M., Loseto, L.L. and Stem, G. (2018) Legacy contaminants in the eastern Beaufort Sea beluga whales (Delphinapterus leucas): are temporal trends reflecting regulations? Arctic Science 4, 373–387.

Acknowledgement I wish to record here my sincere gratitude to Alex Lainsbury, the commissioning editor at CABI, for her expert guidance during the preparation of this book.

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Glossary

The acronyms appearing in this volume are listed and explained in Table G.1. Only essential abbreviations have been included in Introduction to Environmental Toxicology to ensure that the text is presented in a student-friendly style rather than in a research format. Table G.1.  Explanation of acronyms used in Introduction to Environmental Toxicology. Abbreviation

Definition

AchE CNS COPD CVD DDT DNA EPA IARC NOAEL NOEL PAHs PCBs POPs ROS TCDD UV VOCs WHO

Acetylcholine esterase Central nervous system Chronic obstructive pulmonary disease Cardiovascular disease Dichlorodiphenyltrichloroethane Deoxyribonucleic acid Environmental Protection Agency (UK and USA) International Agency for Research in Cancer No observable adverse effect level No observable effect level Polycyclic aromatic hydrocarbons Polychlorinated biphenyls Persistent organic pollutants Reactive oxygen species 2,3,7,8-tetrachlorodibenzo-ρ-dioxin Ultraviolet Volatile organic compounds World Health Organization

xi

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1

Introduction

1.1 Overview Although global pollution has been an ongoing phenomenon since Roman times, environmental toxicology as a formal discipline emerged relatively recently. It can be argued that major pollution and contamination episodes around the world provided the impetus for a scientific recording and analysis of the impact on society and on the ecology of pristine and damaged habitats. A convenient but important historical point is undeniably the deployment of two atomic weapons at Hiroshima and Nagasaki in Japan in 1945. The physical devastation caused by the detonation of these two atomic devices will forever represent an ignominious phase in human history. In addition, however, whereas the infrastructure has now been restored in both cities, the toxic legacy remains to the present time, representing the most cogent exemplification of ‘Man’s inhumanity to man’. A significant development in the UK occurred in 1952 with an event generally known as the ‘Great Smog of London’. The roles of particulates caused by coal-burning and a mixture of gaseous pollutants were clearly identified as the underlying features. The headline that annual air pollution limits for London were breached within the first week of January 2017 demonstrated that meagre progress has been achieved since 1952. However, the Mayor of London claimed that limited progress on nitrogen dioxide emissions has been recorded since 2017 (Khan, 2018). Meanwhile, the New Delhi smog of 2019 will be recorded in history as another example of political apathy and regulatory failure, resulting in severe health risks for vulnerable residents. In 1967 and subsequently, pollution events were characterized by major oil spills in various accidents worldwide, raising new challenges in terms of



1

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2 Introduction

chemical and physical effects, with profound implications for ecotoxicity. The toxic legacy associated with crude oil pollution in the Exxon Valdez oil spill in 1989 with respect to wildlife recovery remains to the present time. Meanwhile, the Deepwater Horizon oil spill in 2010 represents a more modern beacon of ecotoxicity, with implications resonating long into the future. Another major environmental contamination incident relates to the accidental emissions of radioactive substances from nuclear power stations in the USA (Three Mile Island), Ukraine (Chernobyl) and Japan (Fukushima). In addition, there are regular reports of radiation leaks from nuclear plants and submarines as well as storage facilities on both sides of the Atlantic. A number of these and other case studies will be presented for analysis in the following chapters.

1.2 Three Environmental Emergencies: Climate Change, Increased Human Morbidity and Ecotoxicity The disproportionate emphasis on climate change, relative to environmental toxicology of pollutants, can no longer be justified in the light of unequivocal evidence of the profound risks consistently linked to human health and ecological emergencies (Fig. 1.1). The current environmental debate, focusing on the failure to reduce agreed global greenhouse gas emissions, has, to an alarming extent, overshadowed the urgent need to curb exposures of humans and wildlife to major pollutants, including nitrogen dioxide, sulfur dioxide, POPs, pesticides, heavy metals and radionuclides. This situation has to change to rebalance the debate and to ensure formulation and enforcement of a comprehensive and legally binding set of regulations for damage limitation. It is well known that biological systems are influenced by physical factors, and photosynthesis in plants is the prime example of this effect. It is therefore important to recognize that climate change may impact on the emission of certain contaminants and pollutants that adversely affect living organisms, resulting in unintended consequences. For example, increased drought may be a predisposing factor in the incidence of spontaneous or accidental wildfires (as in California, USA, and Australia), thereby resulting in increased exposure of local residents to harmful particulates. Again, if the recommendation to consume less meat to control methane emissions is adopted, then the reliance on plant-based foods would inevitably lead to increased applications of fertilizers and pesticides, while land use and water resources would impose additional constraints. Excessive use of fertilizers has been associated with increased occurrence of toxic algal blooms, while pesticides have long been recognized as outright poisons, endangering human health and survival of wildlife species, including insects, birds, reptiles and marine animals. Furthermore, the use of genetically modified crops might then become inevitable. It is doubtful whether society is ready for such an innovation, given that the full ecological implications remain obscure.

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Introduction

3 Pollutants

Microbial toxins Carbon dioxide Methane

Sulfur dioxide Ozone Nitrogen dioxide Particulates PCBs

Climate Change

Dioxins Pesticides

Ecotoxicity: Wildlife in Peril

Endocrine disruptors Plastics Heavy metals Radiation Light and noise

Increased Human Morbidity

Fig. 1.1.  Pathways to three environmental emergencies: climate change, increased human morbidity and ecotoxicity as affected by specific pollutants. Cross-linking shown above is designed to illustrate the impact of climatic factors on the generation of contaminants or pollutants harmful to human health and wildlife. Presentation of pollutants in red is designed to highlight the pathway of carbon to the three environmental emergencies, emphasizing the need to expand global objectives in the pursuit of carbon neutrality. Not shown is the direct effect of climate change on habitat degradation, which may exacerbate risks for wildlife species.

1.3  Outline of Chapters Both chemical and physical factors that contribute to human morbidity and ecological degradation are presented in this volume. The contaminants and pollutants considered here are classified within a conventional system to include biogenic compounds, ambient gases and particulates, persistent organic pollutants, fossil fuel constituents, heavy metals and complex polymers. In addition, the impacts of radiation from specific sources are presented to exemplify the wide spectrum of effects on human health and ecological biodiversity. The biogenic compounds include secondary metabolites synthesized by specific plants, fungi and algae. Consideration of these toxins is justified as

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4 Introduction

their occurrence may be influenced by environmental factors, for example global climate change. In addition, plant secondary compounds are attributed with the potential to replace existing harmful synthetic pesticides. The toxicology of biogenic substances is characterized by diverse and profound effects in humans and other vertebrates following intake via contaminated food and water or exposure in damp dwellings characterized by the ‘sick building syndrome’. Plants and microbes may also exert physical effects affecting, for example, habitat selection by vectors or efficacy of oceans to serve as carbon sinks. However, such issues are outside the scope of this volume, but should nevertheless be considered in the general model of biological–environmental interactions. Ambient gases associated with human morbidity include ozone, nitrogen dioxide and sulfur dioxide, but the effects may be compounded by interactions with other pollutants, including polyaromatic hydrocarbons and particulates. Specific conditions currently under investigation include exacerbation of idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), asthma, cardiovascular disease, metabolic syndromes (particularly childhood obesity and type 2 diabetes), as well as diverse forms of cancer. The cognitive and neurological effects of air pollutants are an additional source of concern and in utero exposure may be a contributory feature in certain cases, such as the incidence of autism (Becerra et al., 2013). Interactions between certain gaseous pollutants and other ambient air contaminants, for example particulates, inevitably add to the complexities of interpretation of emerging data for the above-mentioned conditions. The diverse effects of acid rain on adaptation mechanisms in higher plants are relevant here, due to interactions with oxides of nitrogen and sulfur. Responses in plants include modulation in morphology, nutrient uptake, primary metabolism and oxidative status. Persistent organic pollutants are of immense significance due to low environmental degradability, presenting long-term risks for human health and biodiversity in the major ecosystems. The anthropogenic derivation of these compounds, including polychlorinated biphenyls, dioxins, pesticides and endocrine disruptors, only adds to public disquiet over their distribution in different matrices such as food, water and sediments. Issues of particular concern in relation to human morbidity include consequences of maternal exposure, transgenerational effects, reproductive dysfunction and relationship to carcinogenesis. Also under consideration is the possible link to asthma and diabetes. Furthermore, the biochemical mechanisms underlying the toxicity of these pollutants remain complex issues, despite recent advances in activation of receptors, signalling pathways and gene expression. The extraction, transport, refining and combustion of fossil fuels are important stages in environmental pollution, presenting diverse human health and habitat risks. The Torrey Canyon oil spill of 1967 remains the worst marine contamination incident in UK history, but images of the Exxon Valdez oil spill in 1989 off the coast of Alaska will readily be recalled by observers of marine pollution. However, the effects of the 2010 Deepwater Horizon oil discharge in the Gulf of Mexico continues to reverberate in ecological, regulatory and legal circles to the present time. It should be noted that oil leaks on a smaller

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Introduction

5

scale occur regularly, affecting sensitive ecosystems around extraction wells. Consequently, it is important to determine the extent to which coastal and marine species can recover after oil contamination events, minor or major. Similarly, human health and ecological risks associated with fracking technologies and coal combustion need to be evaluated in the light of emerging evidence of detrimental effects for human health and biodiversity. The toxicology of heavy metals has not been consigned to history but continues to cause concern due to increasing exposures associated with mining, coal combustion, deforestation and accidental discharges. Mercury pollution is still a persistent issue worldwide, following identification of this heavy metal in the Minamata poisoning episode some 60 years ago. This incident occurred in Japan following the consumption by entire coastal communities of seafood contaminated with industrial sources of mercury. In addition, the burgeoning global accumulation of electronic waste is creating toxic burdens for communities in developing countries where small-scale processing is performed on behalf of affluent customers elsewhere. In this chapter, particular emphasis will be given to methyl mercury, lead, cadmium and arsenic, reviewing diverse physiological and behavioural changes as well as ecotoxicological implications. Global consumerism and lifestyle choices threaten the well-being and, indeed, survival of numerous marine species due to inappropriate disposal of plastics, pharmaceuticals and personal care products. It is opportune to consider the wide-ranging physical and physiological effects caused by these disparate environmental contaminants. This chapter will reflect the need for immediate action, particularly since endangered species are already subjected to a variety of other pollutants while simultaneously attempting to adapt to climate change and habitat deterioration. Three major classes of human health risks associated with radiation are presented in this volume, covering radionuclide contamination (underlining in particular the Chernobyl and Fukushima nuclear plant accidents), as well as exposures to radon and ultraviolet light. Although common themes in adverse effects can be discerned, unique manifestations are also emerging which may determine future lines of investigation. The penultimate chapter is devoted to a consideration of the mechanisms of adaptation in microbes and higher plants in response to abiotic stresses imposed by adverse environmental conditions. Exposure to low pH, water deficit and organic and inorganic contaminants can affect biological systems and instigate adaptive mechanisms. It is widely acknowledged that these responses are maximal in microbes, compared with higher plants. Understanding these mechanisms may provide insight into the potential for bioremediation in contaminated ecosystems. The final chapter is designed to use the basic toxicology of contaminants and pollutants to address real-time human health and ecological risks associated with vehicle emissions, industrial legacies, fuel extraction and transport, metal recycling, consumerism and radiation. It is also important to examine the constraints in the monitoring and regulation of emission of toxic compounds into the environment, given the duplicity and lack of disclosure among the

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6 Introduction

major contributors to pollution. The successes and failures of environmental protection agencies are presented in the form of specific case studies.

1.4 Methodology Well-established protocols exist to evaluate the toxic potential of contaminants and pollutants. These focus principally on the assessment of acute toxicity or effects induced by chronic exposure and are derived from methods used in the design of pharmaceuticals and pesticides. The passage of time has done little to remove the major limitations in the systems employed in the determination of potential harm attributed to specific contaminants and pollutants. It is important to bear in mind that a particular compound may be associated with both acute and chronic effects and that biological species is invariably a critical factor in the interpretation of results. Acute toxicity assessments are based on quantitative lethality data obtained with a population of test organisms in a dose–response trial. Graded doses of the toxin under investigation are used to determine the effects on potential lethality for the test organisms. The dose–response so obtained will correspond to a sigmoid shape, with low doses causing small but perceptible effects, followed by a steep increase in lethality up to an asymptote of 100% mortality in the population of organisms. It is conventional to express the results as lethal dose values (LD50), in other words, the dose required to kill 50% of the population of test organisms. In an ecological context the results are reported as lethal concentration values (LC50) and relate to the concentration of the test compound required to kill 50% of the population in aquatic or atmospheric systems. These determinations are typically short-term, over a few hours or days, providing insufficient data to assess long-term effects at lower doses or concentration; in addition, mechanisms of action of the test compound remain obscure. Nevertheless, LD50 and LC50 data are a useful first step in determining potential toxicity. It is helpful to note that examples of acute toxicity are not confined merely to laboratory investigations (see Case Study 1.1). Lethality is a fundamental criterion used to determine the efficacy of pesticides. Toxicity evaluations by manufacturers typically focus on relatively short-term tests with mammalian models (rodents) to establish risks for humans consuming pesticide-treated foods. However, the impact on invertebrates, aquatic animals and other non-target species is often not considered. A recent investigation illustrates the point regarding a widely used neonicotinoid insecticide introduced into Japan in 1993. Numbers of arthropods in Lake Shinji were decimated almost immediately, leading to a collapse of the food web in the aquatic ecosystem and the associated population of fish. These effects were attributed to leaching of the pesticide into the lake. Neonicotinoids are fatal for bees and butterflies, while other evidence implies detrimental effects on bird populations. More significantly, lethality tests cannot determine effects of pesticides as carcinogens or as agents promoting or facilitating the development of neurodegenerative disorders in humans. Furthermore, acute toxicity tests cannot estimate potential legacy effects arising from persistence in the soil

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Introduction

7

Case Study 1.1.  Acute toxicity in Salisbury (UK) and in aquatic ecosystems LD50 and LC50 determinations are valuable tools in the assessment of the potential efficacy of compounds intended for pharmaceutical and pesticide formulations with respect to human health and environmental impact. Such bioassays are also employed in evaluating the safety of a wide range of contaminants in food and water. Although these data of lethality are normally obtained under relatively stringent laboratory conditions, the poisoning of five individuals in Salisbury brought into sharp focus, once again, a real-life example of acute toxicity among innocent civilians. This attack in March 2018 resulted in the death of one person and intensive care of the four survivors. It has been confirmed that the agent used in the Salisbury incident was Novichok, one of a class of highly potent organophosphate (OP) nerve poisons, developed specifically as a lethal weapon. It has been assumed that Novichok was prepared in the binary form based on two innocuous compounds which were mixed just prior to deployment. Anecdotal evidence indicates that the routes of exposure in the Salisbury included skin absorption, inhalation and ingestion with food and drink. The LD50 value has been estimated at 0.22 μg kg–1 for humans. The expression of toxicity is progressive and extremely rapid, proceeding from neurotoxicity, seizures, severe respiratory distress, coma and death. The mechanism of action, as with all OP compounds, is via the irreversible binding of the agent with acetylcholinesterase to produce a cholinergic toxidrome in affected individuals. Inhibition of this critical enzyme prevents the physiological breakdown of acetylcholine, thus interfering with normal neurotransmission. The treatment protocol involves immediate provision of oxygen, resuscitation and decontamination of patients and the local environment to prevent further exposure and dispersal of the nerve poison. The prophylactic measures include the administration of anticholinergic drugs, anticonvulsants and reactivation of the acetylcholinesterase system through the use of oximes. Specifically, intravenous provision of atropine and pralidoxime have been cited in the medical literature. It is assumed that such procedures were adopted in the Salisbury poisoning, but in any case, the resuscitation strategies and clinical approach have been well rehearsed following numerous incidents of serious OP pesticide intoxication in human subjects over several decades. Malathion has emerged as a prominent example of an OP insecticide in common use worldwide. It is well recognized for its high lethality towards target insects and low to moderate toxicity in humans and other mammals. However, malathion is associated with severe detrimental effects in aquatic ecosystems. For example, it is highly toxic to freshwater invertebrates as demonstrated in bioassays with the test species Daphnia magna. Malathion is also lethal towards fish and there is, therefore, widespread concern about the general environmental implications of continuing use of this pesticide in intensive farming.

•• Can you summarize the circumstances surrounding the fatal ricin poisoning near Waterloo Bridge in London in 1978?

•• How does this event compare with the sarin poisoning incident in a Tokyo subway in 1995?

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8 Introduction

or aquatic ecosystems. Nevertheless, it should be noted that premature mortality is an important outcome in the long-term toxicity of several pollutants described in this volume. Chronic toxicity is, by definition, based on assessment of adverse effects following long-term exposure to a particular contaminant or other potentially harmful substance. Such procedures provide a more realistic appreciation of deleterious consequences to individuals or populations and there is also scope for elucidating the mechanisms underlying these manifestations. Although chronic toxicity may be determined under laboratory conditions, more typically they are linked with epidemiological studies using a variety of correlation models. For example, the association of lung cancer with cigarette smoking was first established by epidemiology before confirmatory mechanistic evidence emerged in subsequent investigations. It will be apparent that long-term exposure to pollutants and other contaminants will result in a wide range of manifestations in individuals and populations of living organisms. In vertebrate animals (including humans), gross manifestations might include reduced growth and development usually accompanied by loss of appetite, but aberrations in organ morphology and functions may also occur. For example, the lungs are often affected by traffic pollutants, instigating or exacerbating pulmonary functions in disorders such as asthma, chronic obstructive pulmonary disease and cancer. Another target organ is the heart and there is accumulating evidence of the detrimental impact of common pollutants on cardiovascular disease. Although normally associated with extensive detoxification pathways, the liver can also be affected adversely by toxic contaminants and pollutants. A number of these compounds may also damage the kidney. Of increasing interest is the impact on the central nervous system, particularly the brain, but the peripheral system may also be affected. How conditions such as autism, cognitive impairments and related disorders are affected by pollutants is currently under active consideration. A matter of much concern is the disruption of the endocrine system and functions in humans and endangered animal species. At the subcellular level, DNA damage may result in the initiation and expression of mutational disorders. The production of characteristic metabolites and DNA adducts during metabolic processes can occasionally serve as biomarkers linking adverse effects with specific contaminants or pollutants. The procedures described above may be defined as in vivo studies. However, due to disquiet over the use of live animals in lethality tests, alternative methodologies have emerged over recent decades based on in vitro cytotoxicity assessments of contaminants and pollutants. For example, hepatocytes are frequently used, but it is important to recognize that such investigations cannot be used to predict the outcome for any resulting transformation metabolites in other tissues or organs such as the pulmonary, renal or central nervous systems. Integrated into the standard methodologies of toxicity assessments are additional terms applied widely for investigating the safety or otherwise of food contaminants and environmental pollutants. For example, LOAEL refers to the lowest observed adverse effect level, whereas NOAEL means no observable adverse effect level. In this volume a comprehensive range of adverse effects is considered in addition to questions of lethality and implications for individuals predisposed

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9

to conditions such as asthma, cystic fibrosis, COPD and cardiovascular disease. Thus, the impacts on sleep deprivation caused by light and noise pollution are relevant here.

1.5  Exposure Pathways In the case of food and water contaminants, the primary route of entry would be oral intake. This would also apply to neonates reliant on mother’s milk, an exposure pathway continuing to cause concern among environmental scientists (Tsygankov et al., 2019). For a variety of gaseous pollutants and particulates, inhalation into the lungs would be the most important pathway. Absorption through the skin is another route of entry into the body. Of increasing concern is the development of disorders arising from inadvertent in utero exposure, adversely affecting health outcomes in offspring (Fig.1.2). In higher plants, the major routes of entry are the roots and the stomata in the leaves.

1.6 Interactions The difficulties with ascribing toxic effects to a particular contaminant or pollutant are amplified in cases involving complex interactions. It is important to distinguish between genuine and confounding factors that might contribute to toxicity, particularly when considering the impact of a cocktail of potentially harmful compounds. At the simplest level, the effects of the individual components in these mixtures might be additive, making interpretation relatively straightforward (Fig. 1.3). However, when the components act synergistically (Fig. 1.4) or via a potentiation mechanism, then risk assessment and prediction of likely outcomes becomes considerably more controversial. For example, evaluating the relative effects of gaseous pollutants and particulates in urban environments with heavy traffic is destined to challenge both toxicologists and regulators. Another example of interactions is the photoactivation of precursors to yield a toxic compound. This is particularly the case with certain biogenic compounds associated with forms of dermatitis. In environmental toxicology, two examples exemplify the difficulties in predicting or determining cause-and-effect issues and the impact of interactions. Of immense concern currently is the catastrophe labelled ‘the next ecological Chernobyl’ in the media. This case relates to large quantities of mercury as well as a pressurized storage container full of unknown hazardous chemicals in an abandoned Siberian factory (Balmforth and Heinrich, 2019). Oil waste presents an additional risk at that site, with the potential to pollute a nearby river, thereby jeopardizing the safety and health of local inhabitants and a part of the Russian wilderness renowned for its ecology and wildlife. The coastal green turtles foraging around the Great Barrier Reef in Australia endure a diverse burden of pollutants ranging from agricultural effluents, including pesticides, to industrial chemicals, pharmaceuticals and personal care products. It is, therefore, a challenge to apportion adverse effects on physiology and behaviour of these turtles (or other marine species) to a particular pollutant or to discern the

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10 Introduction

Fig. 1.2.  This is undeniably an image of contentment and pride, but also one of vulnerability. Maternal exposure to pollutants can adversely impact on the development and health of infants and older children. Key pathways include placental transport and feeding on mother’s or cow’s milk. Of immense concern is the WHO announcement in 2018 that 93% of all children below the age of 15 inhaled polluted air. Residential exposure to vehicle exhaust emissions can initiate or exacerbate conditions such as cystic fibrosis and childhood asthma. While toxic air quality is normally associated with cities such as New Delhi, Mexico City, Los Angeles and London, the British Lung Foundation estimated that children’s lives were reduced by 5 months due to pollution in Liverpool (UK, announced January 2020). Irreversible damage can be caused to immature and developing lungs in young children. It is appropriate to acknowledge here the role of mothers who, against all the odds, successfully secured environmental justice for communities and individuals exposed to lead in Flint, Michigan (USA), cadmium and other contaminants in Corby, Northamptonshire (UK) and air pollutants in Lewisham, London (UK). (Photograph ‘Golden Child’ by Garry Knight is licensed under CC BY 2.0.)

type of interactions involved in the manifestations of toxicity. Interpretation is further complicated when the effects of climate change are considered in conjunction with pollution associated with farming, sewage disposal and personal care products. For example, the extent to which ocean acidification (attributed to rising atmospheric concentrations of CO2) interacts with land-based sources of pollution in the degradation of the unique coral ecosystem (Fig. 1.5) still cannot be quantified with any degree of confidence.

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11 4.5 4

Toxic response

3.5 3 2.5 2 1.5 1 0.5 0 Pollutants A , B and A+B

Fig. 1.3.  Additive effects in the toxic response of an organism after exposure to pollutants A and B separately and in combination. Values shown are in arbitrary units. 9 8

Toxic response

7 6 5 4 3 2 1 0

Pollutants C, D and C+D

Fig. 1.4.  Synergistic effects in the toxic response of an organism after exposure to pollutants C and D separately and in combination. Values shown are in arbitrary units.

1.7  Metabolic Responses The entry of potentially harmful compounds almost invariably provokes a metabolic response in living organisms as pathways are activated to diminish or overcome any adverse effects. Microbes possess the greatest capacity to metabolize deleterious substances, occasionally yielding products of higher

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12 Introduction

Fig. 1.5.  Coral reefs support unique habitats for a diverse range of organisms in marine ecosystems. However, bleaching of corals is extensive due to rising sea temperatures and pollution caused by sewage and fertilizer discharges as well as use of sunscreens. (‘Emperor angelfish, goldies, corals and blue ocean at Elphinstone Reef, Red Sea, Egypt #SCUBA’ by Derek Keats is licensed under CC BY 2.0.)

­ otential toxicity. The induction of adverse effects is rarely a passive process p even in higher plants which might, superficially at least, appear to be defenceless. The metabolic machinery involved in defence or detoxification processes can be quite complex. For some pollutants, the response might entail the use of receptors, signalling pathways and gene expression for the synthesis of the appropriate metabolizing enzymes, usually in the liver of animals. This biotransformation normally proceeds in three steps. In Phase I, the toxin is modified in a process designed to make it more reactive, for example by hydroxylation catalysed by cytochrome P450 mixed-function oxidases. In Phase II, the modified molecule is conjugated with one of a variety of compounds, including glutathione, glycine or glucuronic acid. In Phase III, additional modifications may be introduced and the final product excreted in the urine via the kidneys. However, this process may also lead to the synthesis of reactive metabolites and adducts that may initiate chronic toxicity in the form of cancer and other conditions. There are also significant mechanisms in higher plants to reduce the impact of different types of abiotic stress. One may involve the mediation of specific amino acids such as proline and histidine. The physical properties of proline associated with its cyclic structure are believed to confer particular attributes

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in complex formation with toxic elements. Another mechanism centres on the synthesis of a wide array of peptides, known as phytochelatins, capable of conferring stress tolerance in the plant towards potentially toxic metals. In certain instances, these peptides may form part of a system that provides for chelation, transport and compartmental sequestration within the plant cell so that the offending compound cannot interfere with the primary metabolism of the plant. A mechanism frequently invoked to explain particular features of toxicity in both animals (including humans) and plants centres on the development of ‘oxidative stress’. In the processes of metabolism, reactive oxygen and n ­ itrogen species accumulate, but the adverse effects are offset by antioxidant defences. Oxidative stress results from an imbalance in favour of reactive radicals and has been implicated in several age-related conditions such as cardiovascular, pulmonary and neurodegenerative diseases that might be exacerbated by pollutants.

1.8  Environmental Fate Understanding the dynamics of potentially toxic compounds and other contaminants after release into the environment and subsequent degradation or partition into different phases of air, soil, sediments and aquatic systems is of critical significance in protecting human health and ecological biodiversity. Environmental fate data are essential for the completion of environmental risk assessments, particularly for synthetic chemicals such as dioxins and pesticides. The major determinants of pathways and ultimate destination of these compounds will depend upon their physical characteristics and reactivity in different ecosystems. For example, the environmental fate of hydrophilic and lipophilic compounds will clearly be different. If the chemical in question readily submits to biotransformation reactions, then the outcome might be more favourable compared to a more recalcitrant substance. All of these factors will determine the persistence of a contaminant in the environment and potential risks to human health and biodiversity.

1.9  Risk Assessment Analysis of soil, air, water and foods provides a valuable insight into potential risks associated with environmental contaminants. In addition, certain living organisms may be suitable bioindicators, particularly in assessments of water quality and safety. For example, the use of eels has been advocated due to their relatively long lifespan, high fat content, sedentary existence at certain stages and feeding as benthic carnivores. Consequently, eels are able to carry significant burdens of contaminants in their body fat reserves. However, analyses of blood, breast milk, organ tissue, urine and stools give a more comprehensive picture of exposure reflecting metabolic changes and the potential for harmful physiological consequences in humans and endangered animal species. The identification of subcellular markers such as enzymes, DNA-adducts and signature

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14 Introduction

molecules is also possible with advancements in appropriate methodologies. An example of this approach is presented by Alves et al. (2016) relating to ozone stress in plants. The enzymes of particular significance in risk assessment are those associated with antioxidant protective mechanisms, including cytochrome P450, superoxide dismutase and reduced glutathione.

1.10  Key Issues Pollution results in three environmental emergencies: climate change, human health disorders and existential risks for biodiversity in a variety of ecosystems. Although there is a clear requirement to control greenhouse gas emissions, pulmonary and cardiovascular degeneration caused by vehicle combustion products can no longer be ignored, while hazards associated with persistent organic pollutants (POPs), recycling of heavy metals and radiation impose additional constraints for human health. Crude oil pollution, widespread distribution of endocrine disruptors and the indiscriminate use of pesticides have already contributed to the extinction of numerous wildlife species, while endangering the very survival of apex predators. Meanwhile, disposal of plastics and personal care products present substantial risks for a wide range of marine species.

1.11 References Alves, E.S., Moura, B.B., Pedroso, A.N.V., Tresmondi, F. and Machado, S.R. (2016) Cellular markers indicative of ozone stress on bioindicator plants growing in a tropical environment. Ecological Indicators 67, 417–424. Balmforth, T. and Heinrich, M. (2019) Abandoned Siberian factory could cause Chernobyl-style disaster, warns official. Yahoo News, 24 July 2019. Becerra, T.A., Wilhelm, M. and Ritz, B. (2013) Ambient air pollution and autism in Los Angeles County, California. Environmental Health Perspectives 121, 380–386. Khan, S. (2018) London air quality still within legal limits. Available at: https://www.london.gov. uk/press-releases/mayoral/londons-air-quality-still-within-legal-limits (15 January 2018, accessed 23 May 2020). Tsygankov, V.Y., Gumovskeya, A.H., Koval, I.P. and Boyarova, M.D. (2019) Bioaccumulation of POPs in human breast milk from south of the Russian Far East and exposure risk to breastfed infants. Environmental Science and Pollution Research 22, 14379–14382. doi: 10.1007/s11356-019-07394-y.

1.12 Exercises (i)  Using the format presented in Figs 1.3 and 1.4, indicate how pollutant E might potentiate the toxicity of pollutant F. (ii)  Indicate the criteria that might be used to determine the toxic responses presented in Figs 1.3 and 1.4. (iii)  Explain how antagonisms between pollutants might induce adverse effects in living organisms.

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(iv)  Comment on the difficulties in assessing the impact of interactions in environmental toxicology. (v)  What are the limitations of conventional acute and chronic tests in environmental toxicology? (vi)  Give examples of legacy pollutants and comment on the significance of these compounds in human morbidity and survival of endangered wildlife species.

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2



Biogenic Contaminants

2.1 Overview Microbes and plants contribute significantly to activities in the biosphere, conferring both physical and chemical impacts in global ecosystems. In addition, there is growing interest in the physical association of microbial-derived biofilms and plastic polymers in freshwater and marine environments. Such interactions may affect pathogen transfer, particle buoyancy and biodegradation of microplastics and adhering co-contaminants. Microbes are highly adaptable to varying environmental conditions, including, for example, water availability, pH and salinity. Recently, fungi have been observed thriving inside the abandoned nuclear reactor in Chernobyl, employing radiosynthesis to derive chemical energy from the intense gamma radiation still present in the system. The implications for bioremediation are clear. Evaluating the effects of climate change and other factors on the ecological distribution of specific chemical compounds remains a challenging but separate issue (Paerl et al., 2019). This chapter is concerned with the toxicological issues associated with microbial and plant metabolism. Three classes of biogenic compounds regularly occur in aquatic and agricultural ecosystems to contaminate food and water supplies (Table 2.1). These include: • algal toxins; • mycotoxins; and • phytotoxins. It is generally assumed that biogenic compounds arise as a result of secondary metabolism in microorganisms and plants. Such an assumption implies an inferior function to the primary metabolism involved in respiration, photosynthesis

16.

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Table 2.1.  General toxicology of biogenic compounds. (See text for effects association with specific toxins.) Class of compounds

Toxic properties

Cyanobacterial toxins Mycotoxins Phytotoxins

Hepatotoxic, cytotoxic, neurotoxic and dermatoxic Liver and kidney damage, carcinogenic Digestive dysfunction, allergic reactions, cognition defects, goitrogenic, reproductive abnormalities, carcinogenic

and protein accretion. However, there is accumulating evidence that secondary compounds serve crucial roles in defence and competition for survival and growth in particular niches and ecosystems. This aspect is viewed positively, for example, by those advocating the replacement of synthetic chemicals with an appropriate selection of plant secondary compounds to serve as environmentally friendly ‘biopesticides’ in arable farming. On the negative side, a relatively significant number of biogenic compounds are capable of inducing moderate to severe toxicity in humans and animals following contamination of staple foods and drinking water.

2.2  Algal Toxins The distribution of algal blooms is increasing at an unprecedent pace in response to climate change, higher rainfall and run-off of fertilizers from farmland. A recent survey indicated a significant increase in 33 countries worldwide. Algae emitting hydrogen sulfide contaminating the coastline around parts of Brittany in 2019 contributed to the deaths of three people inhaling the gas. In Bolivia, the first recorded algal bloom occurred in 2015 in a high-altitude lake which subsequently was observed to exacerbate hydrogen sulfide and methylmercury contamination in this remote aquatic ecosystem. A group of Gram-negative photosynthetic blue-green algae, named cyanobacteria, occur in a wide range of ecosystems, from freshwater rivers and lakes to oceans, but may also exist in hot springs and in arid regions such as deserts. They are frequently seen as blooms and scums within and on the surface of water, often appearing as macroscopic formations, visible to the naked eye and causing aesthetic issues as well as the potential to induce toxicity in humans and wildlife through exposure to cyanobacterial toxins (see Case Study 2.1 and Fig. 2.1). The cyanobacterial toxins are classified according to mode of action in ­humans and other living organisms. This group of compounds includes: • hepatotoxins; • cytotoxins; • neurotoxins; • lipopolysaccharide endotoxins; • dermatoxins; and • neuroactive amino acids.

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Case Study 2.1.  Big fun on the Bayou? Green with envy? Not likely on Lake Erie! In the summer of 2015, the Western Lake Erie Basin, situated between the USA and Canada, was subjected to significant nutrient loading from adjacent farmland leading to the formation of the largest algal bloom on record. The blue-green algae, generally known as cyanobacteria, are responsible for these blooms and form the basis of food chains and webs within aquatic environments, including inland lakes. The regular episodes of bloom incidence have caused concern due to potential adverse economic effects associated with loss of aesthetic attributes and odour formation, thus affecting tourism. In addition, human health and wildlife welfare may be at risk through the generation of different classes of cyanobacterial toxins. The main factor implicated in the development of these algae is phosphorus supply and availability. In particular, the extent of algal blooms in Lake Erie is strongly correlated with agricultural loading of phosphorus from the tributaries. Alterations in farming practices, including conservation methods aimed at reducing erosion such as minimal tillage and improved drainage, may have aggravated the problem by increasing soluble and reactive phosphorus loads reaching the Lake Erie Basin. There are other reports which indicate that managing organic nitrogen loads should be an integral component of a control system, as both algal bloom size and toxicity may be affected by this source of nutrient. In addition, organic phosphorus arising from farms and wastewater treatment plants may be a significant source of pollution in the tributaries. Despite considerable attention to the incidence of algal blooms, fundamental questions remain concerning appropriate fertilizer guidance for farmers, best practice to protect water quality, conservation recommendations and balancing economic outcomes with environmental quality. In this respect, it has been suggested that gypsum may serve as a soil amendment by reducing soluble phosphorus loading into the Lake Erie watershed. The need for monitoring is critical where water supplies for humans and wildlife are at risk of contamination with the algal toxins. Biomarkers such as chlorophyll and phycocyanin might serve as predictors of occurrence of algal blooms. An additional factor to be considered is the impact of climate change, particularly global warming, which may contribute to increases in the frequency and size of these blooms and may also lead to geographical spread to other aquatic ecosystems. Furthermore, as cyanobacterial blooms senesce, the decay of large quantities of organic matter can result in decreases in dissolved oxygen within the lake, thus affecting the overall ecology of the aquatic system. Press reports in 2019 indicated that residents in Toledo, Ohio, voted in favour of regulations that would allow them to sue polluters on behalf of Lake Erie. In effect, this measure represents a ‘right-of-nature’ law which might inspire others to protect sensitive ecosystems and endangered wildlife species. • What other gases should we expect from algal blooms? • How can we minimize the incidence of algal blooms? • Are there any toxic lakes or lagoons in your county?

The hepatotoxic microcystins and the related nodularins are cyclic peptides and are considered to be the most common forms of toxins synthesized by a number of genera of cyanobacteria. At least 200 microcystin and ten nodularin variants have been identified, each with differing toxicities. These compounds

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Fig. 2.1.  Algal blooms on Lake Erie in Canada. The occurrence of these blooms is associated with indiscriminate and excessive use of fertilizers on nearby farms and incidence is likely to increase with climate change factors, particularly higher environmental temperature and precipitation. (Photograph ‘Algal Bloom - Kelly’s Island, Lake Erie’ by NOAA Great Lakes Environmental Research Laboratory is licensed under a Creative Commons Public Domain Mark 1.0 License.)

act as potent protein phosphatase inhibitors, with high doses resulting in the degradation of liver cytoskeleton and macrostructure and even death. Regular low-dose exposure to microcystins and nodularins are, respectively, associated with tumour promotion and carcinogenesis. The cytotoxin, cylindrospermopsin, occurs as a low-molecular-weight geno­toxic alkaloid produced by many Australian strains and other genera of cyanobacteria. It inhibits protein synthesis in plants and in animals, with the liver and kidney being the main target organs but the lungs and intestines may also be affected. The neurotoxins include anatoxin-a, anatoxin-a(S) and the saxitoxins. Anatoxin-a is recognized to be an acetylcholine mimic. Anatoxin-a and its analogue homoanatoxin-a act at the cholinergic synapse, exerting its effects as a potent post-synaptic depolarizing neuromuscular inhibitor, binding to the nicotinic acetylcholine receptor at the neuromuscular interface, causing repeated stimulation and consequently blocking further electrical transmission. At high doses, anatoxin-a may induce paralysis, asphyxiation and death. Anatoxin-a(S) is a less common cyanobacterial compound, existing primarily in aquatic ecosystems, but assumed from enzyme inhibition tests to occur in desert environments. It is structurally unrelated to anatoxin-a, being a naturally occurring organophosphate (OP) and with more toxicological similarity to OP pesticides.

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Depending on dose level, therefore, anatoxin-a(S) is able to inhibit acetylcholine esterases, causing paralysis and death. This toxin has also been responsible for bird deaths on lakes supporting specialized cyanobacteria. The saxitoxins are notable in that they occur not only in strains of cyanobacteria but also in three distinct genera of dinoflagellates that regularly contaminate shellfish and cause a well-recognized manifestation in humans designated as ‘paralytic shellfish poisoning’. There are over 20 different variants of the saxitoxins, each with differing structures and physiological activity. Saxitoxins exhibit a relaxant action on vascular smooth muscle and depress cardiac muscle action. They are also known sodium-blocking agents and consequently, at high enough doses, can cause paralysis and death. The lipopolysaccharide endotoxins present in the bacterial cell walls cause gastrointestinal discomfort, whereas certain dermatotoxins induce skin irritation, rashes and blistering, while others have also been implicated in inflammation of oral and gastrointestinal tissues. Analysis of cyanobacterial blooms has demonstrated widespread production of the neurotoxic amino acid β-N-methylamino-l -alanine, originally identified in cycads in Guam, and implicated in amyotrophic lateral sclerosis/Parkinsonism dementia complex of Chamorro villagers consuming the cycad. Within mammalian cells, this amino acid binds to glutamate receptors and may be incorporated into proteins in place of l-serine and, in addition, can be converted to the d-isomer, showing toxicity at different receptors in the central nervous system. It is important to identify and evaluate the potential exposure routes in cyanobacterial poisoning. Higher environmental temperatures, especially during the summer season, can increase the frequency and number of outdoor recreation activities in rivers, lakes and beaches. This period may also coincide with the occurrence of cyanobacterial blooms. Cases of human dermatitis, eye irritation, diarrhoea and vomiting with allergic-like symptoms following contact with water have been linked to these blooms. In 2016, four Florida counties declared a state of emergency due to flu-like symptoms, respiratory issues, rashes, burning eyes and headaches in people exposed to the aerosols from algal blooms. Inhalation of cyanotoxins is emerging as a significant route of exposure and toxicity. Water contaminated with cyanobacterial toxins and used for direct consumption or for medical applications has also been linked with conditions such as vomiting, bloody diarrhoea, dehydration and even death in dialysis patients. These toxins may occur in food plants irrigated with cyanotoxin-contaminated water. Other sources of exposure include molluscs, fish and dietary supplements containing cyanobacteria. Management and mitigation strategies are important, as pollution and climate change combine to increase the frequency of algal blooms. However, the primary aim should be to reduce contamination of aquatic ecosystems with nitrogen, phosphorus, sewage and animal wastes.

2.3 Mycotoxins Secondary metabolism in certain fungi is characterized by the synthesis of a diverse and ubiquitous group of bioactive compounds. Those metabolites that

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are associated with pathological conditions in humans and other vertebrates are termed mycotoxins. Contamination of cereal grains, nuts, fruit and green coffee beans with mycotoxins represents a global food safety issue (D’Mello, 2003). When farm livestock are offered feeds containing mycotoxins, then associated residues and metabolites may appear in animal products. The mycotoxins of particular relevance in human health arise during the secondary metabolism of Claviceps, Aspergillus, Penicillium, Fusarium and Alternaria species. It is conventional to classify toxigenic fungi into plant-pathogenic (‘field’) and food-spoilage (‘saprophytic’ or ‘storage’) species. Claviceps, Fusarium and Alternaria are classical examples of toxigenic plant pathogens, while Aspergillus and Penicillium represent food-spoilage fungi, reflecting post-harvest ecology. Aspergillus fumigatus is a ubiquitous species, occurring in the soil, where it survives and proliferates on organic debris. However, the distinction between field and storage fungi is largely academic, as the inoculum for post-harvest spoilage in certain products frequently originates from field sources, including soil and plant debris. Mycotoxins are classified, and some named, according to fungal origin. The issue of mycotoxins is relevant here for several reasons. • Apart from enhancing overall knowledge of toxicology, the study of mycotoxins exemplifies how ecological and environmental factors converge to affect food safety and human health across the globe. • The impact of ambient temperature and humidity changes is well known, but emerging issues associated with UV radiation and drought conditions require elucidation. • There are also predictions about the likely impact of global climate change on mycotoxin contamination of foods, for example in maize grown in Europe. • In addition, the development of fungicide resistance among plant and human pathogens may, in some cases, increase mycotoxin production or exacerbate pre-existing health disorders. • Within the indoor environment, there is evidence of exposure to mycotoxins in water-damaged buildings, encapsulated in the term ‘sick buildings syndrome’. The mycotoxins most commonly associated with human health disorders arise from a diverse range of fungi and commonly occur as food contaminants. The major ergot alkaloids synthesized by Claviceps purpurea include the lysergic acid derivatives ergocristine and ergotamine. Aflatoxins B1, B2, G1 and G2 (AFB1, AFB2, AFG1 and AFG2, respectively) are synthesized by Aspergillus flavus and A. parasiticus. In addition, aflatoxin M1 may appear in the milk of dairy cows and women consuming and metabolizing AFB1 from contaminated diets. A. flavus only produces AFB1, but is also capable of synthesizing cyclopiazonic acid, a mycotoxin recently implicated as a co-contaminant in a batch of peanuts associated with mass mortality in turkey poults in 1960. A. parasiticus, however, regularly produces all four aflatoxins. The two Aspergillus species grow and synthesize aflatoxins when temperature and humidity/water activity conditions are favourable.

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Global aflatoxin monitoring of peanuts in relation to climatic conditions/ agroecology continues to be a major source of concern. However, it is now clear that diverse foods are contaminated with aflatoxin levels that exceed international statutory limits. An outstanding feature in recent surveillance has been the high level of AFB1 contamination of Indonesian maize, at 428 μg kg–1. Of much concern is the relatively high concentrations of total aflatoxins (up to 20 μg kg–1) in maize-based gruels used as weaning food for children in Nigeria. Following an outbreak of human aflatoxicosis in Kenya, 55% of maize products were found with aflatoxin levels exceeding the local regulatory directive of 20 μg kg–1, and 35% containing levels above 100 μg kg–1. The focus on aflatoxins in maize is likely to continue in view of predictions of contamination of home-grown sources in Europe due to global warming. In the UK, samples of peanut butter, imported pistachio nuts and dried figs have all come under scrutiny due to persistent and disturbing levels of contamination in global supplies. For example, in Haiti, total aflatoxin levels of up to 2720 μg kg–1 were reported for a batch of peanut butter. Although AFB1 levels in Iranian pistachio nuts during 2009–2011 declined compared with earlier surveillance, it should be noted that contamination occurred in 23% of samples examined in the UK. Aspergillus fumigatus synthesizes three major mycotoxins, including fumitoxin, fumigatin and gliotoxin. Aspergillus ochraceus and two important Penicillium species produce ochratoxin A and ochratoxin B, with the former being more common, occurring with citrinin in cereal grains, dried vine fruits and green coffee. Relatively high values of ochratoxin A in Bulgarian cereals (up to 140 μg kg–1) were associated with grain samples taken from villages with the incidence of Balkan endemic nephropathy. In the UK, ochratoxin A levels in imported dried vine fruit indicated that 88% were contaminated with concentrations up to 54 μg kg–1. A number of Penicillium species synthesize patulin and P. expansum is of particular significance due to its association with storage rot of apples and other fruits. The presence of patulin in apple juice, attributed to the use of mouldy fruit during processing, has been a cause of concern warranting extensive surveillance in the UK and elsewhere. For example, it has recently been concluded that patulin is a problem in fruit juices available in Tunisia, with 22% of samples exceeding the European Union (EU) limit. The principal Fusarium mycotoxins of regular concern include the trichothecenes, zearalenone and fumonisins. Ecological diversity in this group is exemplified by the general association of trichothecenes with cereal grains in temperate latitudes, whereas the fumonisins are common contaminants of maize kernels originating from tropical regions. The trichothecenes include T-2 toxin, HT-2 toxin, diacetoxyscirpenol, deoxynivalenol and nivalenol. Widespread contamination of cereal grains with the trichothecenes and zearalenone has been reported, with some samples exceeding the US advisory limits for deoxynivalenol. The acute deleterious effects of mycotoxins may be gauged by ample observations of LD50 data published in the literature. Although acute toxicity outcomes are often viewed as academic assessments, in at least two cases, human aflatoxicosis has been associated with high mortality, preceded by hepatitis. However, a more realistic measure of toxicity is provided by an analysis of the considerable body of epidemiological evidence exemplified in case studies

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and associated with mycotoxin contamination of staple foods. One of the ancient episodes of mycotoxicosis relates to ergotism (St Anthony’s Fire), caused by the bioactive alkaloids produced in the sclerotia of Claviceps purpurea. These mycotoxins cause constriction of the peripheral blood capillaries leading to oxygen depletion and gangrene of the limbs. However, the striking example of deleterious effects in humans relates to recurring episodes of aflatoxicosis in the tropics (see Case Study 2.2). Aspergillus fumigatus is, arguably, the most prevalent airborne fungal pathogen, inducing severe and generally fatal intrusive infections in patients already compromised by immune competence. The conditions are classified as ‘aspergillosis’ and include three primary forms, namely allergic bronchopulmonary aspergillosis, aspergilloma and invasive aspergillosis. The role of azole fungicides used in agriculture in facilitating the development of resistance in

Case Study 2.2.  Acute aflatoxicosis in the Tropics but Europeans should be concerned Aflatoxicosis is a condition associated with specific mycotoxins produced by tropical storage fungi, namely Aspergillus flavus and Aspergillus parasiticus. Moist and warm conditions favour the proliferation of these organisms in primary foods such as peanuts, tree nuts and maize. Initial infection may occur in the field, but further development of the fungi occurs during inappropriate storage or transport of harvested nuts and grain. These mycotoxins are collectively known as the aflatoxins. The major public health issue, as with other mycotoxins, is the association with carcinogenesis in populations that rely on staples such as peanuts and maize for their nutritional needs. In particular, there is good epidemiological and molecular evidence linking aflatoxin exposure in food with the incidence of liver cancer. In addition, there is concern that endemic factors such as chronic malnutrition and disease may contribute to or exacerbate the development of hepatocellular cancer. The enduring example of adverse effects is represented by episodes of aflatoxicosis in the tropics. For example, in 1974, an outbreak of liver disease in India was attributed to the consumption of mouldy grain contaminated with aflatoxins. Principal pathological lesions in hepatic tissues included destruction of centrilobular zones, thickening of central veins and cirrhosis. An outbreak of acute hepatitis in Kenya in 1981 was also linked with aflatoxin poisoning associated with contaminated sources of commercial maize. The long-term risk associated with carcinogenesis has resulted in the development of regulations designed to minimize contamination of primary foods produced in the tropics for local consumption or for export to Europe and other parts of the world. Consequently, global aflatoxin monitoring of peanuts, maize and pistachio nuts is an active area of investigation and will continue indefinitely, not only for these primary foods but also for processed products such as peanut butter. In particular, the focus on maize is likely to be enhanced in the light of recent predictions of aflatoxin contamination of home-grown sources in Europe due to climate change. • What factors are likely to affect aflatoxin contamination of foods in Europe in the future? • With predicted changes in climate, what are the risks of co-contaminants in food in Europe?

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A. fumigatus needs to be addressed for more effective therapeutic management of aspergillosis in humans. In the case of ochratoxin A, there have been consistent links with Balkan endemic nephropathy, a chronic disorder occurring among rural populations of Bulgaria, Romania and the former state of Yugoslavia. In affected individuals, the kidneys are markedly reduced in size and, histological examination indicates tubular degeneration and dysfunction, interstitial ­fibrosis and glomerular defects. However, the co-occurrence of ochratoxin A with citrinin in cereals consumed locally implies an interaction between the two mycotoxins in the aetiology of the disease. A possible endemic ochratoxin-­ related nephropathy has also been reported in Tunisia. The most significant public health issue is, arguably, the association of mycotoxins with carcinogenesis. In particular, there are good epidemiological and mechanistic models linking aflatoxin exposure with the incidence of liver cancer. However, other factors, including chronic malnutrition and disease, may contribute to the manifestation of hepatocellular cancer. In addition, aflatoxin exposure may enhance the carcinogenic potential of hepatitis B virus. In toxicological classification (IARC), AFB1 has been designated as a Group 1 carcinogen (i.e. sufficient evidence in humans for carcinogenicity), whereas its product in milk (AFM1) is placed in the Group 2B category (i.e. probable human carcinogen). Epidemiological evidence also links aflatoxin exposure with other forms of cancer, for example gallbladder malignancy observed in Chile, Bolivia and Peru. Contemporary approaches are focused on probing the underlying biochemical and molecular mechanisms in aflatoxin-induced disorders. These investigations include an understanding of nucleotide excision repair processes, role of AFB1-DNA adducts, gene expression, mutational spectra and genetic interactions, miRNA expression and anti-cancer response pathways. The search for biomarkers is emerging as a consistent underlying objective to enable early detection of aflatoxin exposure and carcinogenesis. Other epidemiological evidence indicates a link between dietary fumonisin exposure and human oesophageal cancer incidence in South Africa, China and Iran. Fumonisin B1 is classified as a Group 2B carcinogen and it has been suggested that it stimulates proliferation of oesophageal cells by modulating the cell cycle and apoptosis. In China, it is suggested that fumonisins may promote liver cancer initiated by AFB1 and/or hepatitis B virus. Emerging observations point to the carcinogenic potential of ochratoxin A in the liver as well as in the kidney and there may again be interactions with AFB1. A persistent theme in environmental toxicology concerns the identification and characterization of endocrine disruptors. Whereas zearalenone has long been linked with reproductive disorders in experimental models, emphasis is now turning towards the potential of AFB1 as an antagonist of the androgen biosynthetic pathway. Furthermore, the effects of mycotoxins in immunocompromised patients and resistance to bacterial and viral diseases require elucidation. Analysis of foods provides a valuable insight into potential risks from mycotoxin contamination (D’Mello, 2003). However, analyses of blood, breast milk, organ tissue, urine and stools give a more useful picture of exposure. The results give cause for concern, particularly as there may be interactions with other disorders. For example, analysis of urine and stools in Kenya indicated that,

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following feeding of an aflatoxin-free diet, children with kwashiorkor continued to excrete aflatoxins in urine for 2 days, whereas those with marasmus excreted aflatoxins for up to 4 days. Differences were also seen in the type of aflatoxin discharged in faeces. Of additional concern is the widespread in utero exposure of the fetus to aflatoxins following analysis of cord and maternal blood samples. Analysis of physiological fluids indicates that human exposure to ochratoxin A is also widespread, with geographical and regional differences in risk. In Croatia, for example, highest blood ochratoxin A levels were observed in subjects living in areas known for the incidence of endemic nephropathy. It is clear now that, despite enhanced awareness and the promulgation of advisory and statutory directives, human exposure to mycotoxins continues and not just in developing countries. Mitigation of risk associated with mycotoxins is only effective through measures to control food contamination, as corrective methods are of limited efficacy. In theory, effective use of fungicides against fungal pathogens of cereal and legume crops should result in reduced mycotoxin contamination of harvested products. However, it is generally accepted that fungicide control is only partially effective and there may be potential risks associated with the development of fungicide resistance in plant pathogens. Consequently, there is now growing interest in using plant selection and breeding as environmentally friendly alternatives to fungicide use. Adequate storage of harvested grain, nuts and fruit constitutes a crucial element in the prevention of mycotoxin adulteration, particularly from spoilage fungi. Grain moisture content and environmental temperature are critical factors during storage and transport. In addition, insect and rodent invasion may affect the microclimate within grain silos and also act as significant vectors in transmission of fungal inoculum. In the case of moist grain destined for animal feeds, addition of organic acids appears to be an effective treatment for inhibiting fungal growth and mycotoxin production.

2.4 Phytotoxins A diverse range of toxic compounds occurs in higher plants as a consequence of endogenous synthesis, involving intricate and extensive pathways of metabolism. These products differ widely in terms of molecular mass, structure and biological activity, evoking responses independently of each other or in synergy with other molecules. Although these substances are considered to be constitutive in origin, there are also significant mechanisms for induced synthesis in response to biotic and environmental stressors. In general, phytotoxins are of low to medium molecular weights, but more complex compounds regularly occur, particularly in the seeds and certain roots. Toxicity is directed towards, and readily expressed in, a wide range of organisms irrespective of taxonomic status, implying a proposed mechanism of defence in higher plants. Consequently, other plant genera may develop adverse effects just as well as microbes, insect herbivores and vertebrate animals. The study of phytotoxins is relevant here for several reasons: it highlights issues in chemical toxicology, particularly regarding differences between temperate and tropical plants and

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the interaction with biotic and environmental pressures, thus shedding light on niche biodiversity. An emerging issue is the putative role of phytotoxins in the elucidation of host–pathogen and host–parasite interactions and the expression of innate immunity and defence in plants (see also Case Study 2.3). A logical progression is the development of biopesticides as environmentally friendly alternatives to synthetic chemical protectants currently in use. In addition, several phytotoxins may potentially serve as novel pharmaceuticals and contribute to alleviation of drug pollution.

Case Study 2.3.  Grasping the nettle, but will Hazel and Vera come to the rescue? The natural ecology of plants has evolved in response to both intrinsic factors and environmental pressures. Important extrinsic factors are fungal invasion and predation by different species of animals. Plants contain a wide array of physical and chemical deterrents as a defence strategy against such attacks from, for example, pathogenic fungi, molluscs, insects and higher animals. The development of thorns in some shrubs and trees is an obvious example of deterrence, but potential and serious risks to predators occur neatly concealed in the chemistry of plants. This is why grasping a stinging nettle can be an uncomfortable experience. The plant is characterized by the presence of needle-like trichomes capable of piercing the skin and delivering an array of irritants, including histamine, serotonin and choline. Whether the supposed soothing, moisturizing and healing properties of secondary compounds in witch hazel or Aloe vera might help is an open question. An intriguing feature is the existence of certain phytotoxins that act only after binary action. The two components in such reactions are stored in separate compartments within the cell and only released upon attack by a predator or pathogenic fungus. The giant hogweed is a dangerous and invasive weed that has altered the ecology of urban areas in Western Europe, the USA and Canada, although it was initially introduced as an ornamental plant. The sap contains compounds that cause phytophotodermatitis in humans, resulting in blisters and scars when the skin is exposed to sunlight. This is another example of a binary reaction involving photoactivation of the toxic component. This plant is now designated a noxious weed in many countries. A number of phytotoxins occur exclusively in tropical plants while others are more universally distributed but with particular relevance to temperate environments. In many instances these compounds are more concentrated in the seeds compared with foliage. The toxicology in mammals ranges from digestive dysfunction to cognition defects, goitrogenic effects, reproductive abnormalities and even carcinogenesis. Lower organisms possess variable mechanisms for neutralizing several of these phytotoxins. A number of these compounds can be readily detoxified by heat, as in normal cooking. The challenge for the future is to exploit the wide array of phytotoxins as environmentally friendly protectants for food crops. Structure-activity and other functional attributes have been established for a limited number of phytotoxins, thus improving the prospects for the development of effective and safe biopesticides. Further impetus has emerged as a result of EU pesticide regulations favouring the use of reduced-risk substitutes in integrated pest management protocols. • Can you name a synthetic poison which acts in a binary mode? • What are ‘guard crops’ and how can they be used in arable farming?

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The phytotoxins of particular significance are classified within well-defined groups, including: • • • • •

glycosides; non-protein amino acids; phenolic compounds and derivatives; alkaloids; and proteins.

It is instructive to first consider the toxic glycosides, due to the diverse range of molecular complexity and mode of deployment of the active principle. These glycosides include cyanogens, glycoalkaloids, glucosinolates, saponins, pyrimidine glycosides, flavones and ptaquiloside. The adverse effects of these glycosides are only expressed after completion of an enzyme-dependent reaction releasing the deleterious component from its precursor. This enzyme reaction is triggered by tissue damage to the plant, as for example after insect herbivory or fungal penetration and infection. Cyanogens exist as a distinctive class of glycosides in the foliage and seeds of different plant species. The classical example is amygdalin, present in bitter almonds, while another wellknown cyanogen, linamarin, occurs in cassava. Following tissue damage and enzyme activation, HCN is released from the cyanogen, causing dose-related toxicity and lethality to insect herbivores and vertebrate animals. Extensive human health issues continue to be recorded in sub-Saharan communities dependent upon cyanogenic cassava even to the present time. Sub-lethal blood HCN concentrations are regularly observed, leading to symptoms of acute toxicity, including manifestations such as irreversible spastic paralysis, known locally as ‘Konzo’, and cognition deficits. However, age, gender and protein and micronutrient deficiencies may complicate diagnosis of this condition. Potato glycoalkaloids are consumed by significant numbers of the global population over their lifespans and when instances of poisoning have occurred, manifestations have consisted of headache, vomiting, diarrhoea, abdominal pain and neurological disorders. The pyrimidine glycosides cause favism in humans with a genetic deficiency of glucose-6-phosphate dehydrogenase in erythrocytes. Ingestion of the major toxins in bracken fern is positively linked with carcinogenesis through contact or inadvertent consumption. In contrast, glucosinolates and saponins, while associated with toxicity in animals via breakdown products, are attributed with beneficial properties as potential anti-cancer and hypocholesterolaemic agents, respectively. Non-protein amino acids induce a diverse array of toxic effects in mammals. For example, S-methylcysteine sulfoxide causes haemolytic anaemia in ruminants fed largely or exclusively on Brassica forage. The reactions involve metabolism of this amino acid by anaerobic rumen bacteria to dimethyl disulfide, a highly reactive metabolite. Mimosine, present in the tropical forage legume Leucaena leucocephala, causes disruption of reproductive processes, teratogenic effects and loss of hair and wool in cattle and sheep. However, toxicity of the legume is determined by geographical differences in rumen ecology. Other non-protein amino acids, including canavanine and the seleno-amino acids, act as antagonists towards arginine and the sulfur amino acids, respectively.

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The linear furanocoumarins, distributed in at least 15 plant families, are associated with phytophotodermatitis, mutagenesis and carcinogenesis. These furanocoumarins are photoactivated by ultraviolet A radiation. The epidermal manifestations include bullous eruptions, pigmentation, erythema and potential vesicle formation appearing at points of contact with plants containing furanocoumarins, or over the entire body if exposure occurs via ingestion. With condensed tannins, present in a wide range of legumes, the primary manifestations relate to anti-nutritional effects in farm animals, including reduced food intake and digestibility of nutrients. However, these effects may vary according to the ability of certain species to produce salivary proline-rich proteins. It is envisaged that these proteins form the first line of defence against ingested tannins and that deer and possibly goats produce copious quantities of proline-rich proteins, whereas they are absent in the salivary secretion of cattle and sheep. The protein phytotoxins exert moderate to powerful anti-nutritional effects in vertebrate animals. Proteinase inhibitors depress food protein digestibility in a wide range of animal species. In contrast, lectins are associated with rapid and wasteful growth of the small intestine, causing damage to the absorptive epithelium and reduced nutrient availability for essential metabolic processes in peripheral organs and tissues. The role of phytotoxins as plant defence compounds has been a major focal point, with the long-term objective of developing biopesticides to replace synthetic chemical protectants (Alves et al., 2016). Several phytotoxins exert defence functions towards predatory insects by reducing feeding activity. These include glycoalkaloids, saponins, furanocoumarins and condensed tannins. On the basis of mammalian toxicity, it would be expected that cyanogens might serve as highly effective defence compounds towards insect herbivores. However, the widespread herbivory of cyanogen-containing plants argues against any protective attributes. Nevertheless, it is possible that cyanogens may serve as deterrents in feeding rather than as lethal agents. Similarly, other glycosides, including glycoalkaloids and glucosinolates, are readily detoxified by insects by complex biochemical strategies, thus limiting exploitation of these compounds as potential biopesticides. In contrast, protein phytotoxins may contribute towards a more robust system of defence against insect pests. For example, proteinase inhibitors confer protection to various parts of the plant following wounding by larvae or adult insect pests. In addition, a working model involving the activity of a plant enzyme, threonine dehydratase, in response to insect herbivory illustrated novel aspects of molecular processes in defence. Following insect-provoked damage to plants, specific signal transduction induces synthesis of defence in the form of threonine dehydratase, which causes depletion of threonine in the insect gut, thereby depriving the herbivore of this essential amino acid. Proteinase inhibitors may also confer resistance to plant parasitic nematodes. Following fungal infection, plants generally exhibit ‘systemic-acquired resistance’ in a complex sequence of signal transduction and biosynthesis of pathogenesis-related proteins, phytoalexins and phytotoxins. Translation of these developments into an overarching model in plant immunity will take time.

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Pharmaceutical pollution represents an emerging risk factor for the environment, affecting water quality and ecotoxicity. It is possible that mitigation of potential risks may be achieved by the use of biodegradable phytochemicals with relatively short half-lives. The anti-cancer properties of secondary compounds in Brassica vegetables are noteworthy, particularly with respect to glucosinolates and certain non-protein amino acids. In addition, gossypol has been attributed with a wide range of therapeutic properties, including anti-fertility, antioxidant, anti-microbial and anti-cancer activities.

2.5  Key Issues Climate change will affect growth of algal blooms (Paerl et al., 2019) and toxigenic fungi and as such there will continue to be a watching brief for cyanobacterial toxins and mycotoxins. Interest in phytotoxins will be driven by the need to unravel the complexities of plant immunity and thus reduce dependence on harmful synthetic pesticides.

2.6 References Alves, G.C.S., Ferri, P.H., Seraphin, J.C., Fortes, G.A.C., Rocha, M.R. and Santos, S.C. (2016) Principal response curves analysis of polyphenol variation in resistant and susceptible cotton after infection by a root-knot nematode (RKN). Physiological and Molecular Plant Pathology 96, 19–28. D’Mello, J.P.F. (2003) Mycotoxins in cereal grains, nuts and other plant products. In: D’Mello, J.P.F. (ed.) Food Safety: Contaminants and Toxins. CABI, Wallingford, UK, pp. 65–90. Paerl, H.W., Havens, K.E., Hall, N.S., Otten, T.G. and Qin, B. (2019) Mitigating a global expansion of toxic cyanobacterial blooms: confounding effects and challenges posed by climate change. Marine and Freshwater Research 71(5), 579–592. doi: 10.1071/MF18392.

2.7 Exercises (i) Using specific examples, explain how climate change might affect food safety in the future. (ii)  What are the limitations to using plant secondary compounds as biopesticides? (iii)  Discuss the prospects of using biological compounds as replacements for pharmaceutical products in efforts to reduce medicinal pollution.

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Ambient Gases and Particulates

3.1 Overview Ambient gases of relevance in environmental toxicology include ozone, ­nitrogen dioxide and sulfur dioxide (Table 3.1). Interactions with particulates are also of significance in human morbidity and the detrimental effects may be underestimated. The lungs (Fig. 3.1) and heart are the principal target organs, although the central nervous system is increasingly implicated in the toxicology of these pollutants. In this chapter, the toxicology of ambient gases and particulates in human morbidity is reviewed in relation to a number of interrelated issues, including: • epidemiology; • susceptibility of individuals; • physiology; • pulmonary disorders; • cardiovascular disease; • neurological dysfunction; • carcinogenesis; and • corroboration using bioassay models. Over several decades, air pollution has emerged as the single largest environmental health hazard, causing about 7 million deaths per year worldwide. Exposure to these pollutants has been strongly associated with increased mortality from cardiovascular and pulmonary disease (Landrigan, 2017). Epidemiological investigations have shown that the onset and clinical course of lung diseases are markedly determined by poor air quality. This represents a significant healthcare and economic burden, particularly for low-income and deprived communities residing in polluted areas. Assessing the efficacy

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Table 3.1.  Adverse effects of ambient gases and particulates. The impact of interactions is emphasized in the text. Ambient gases and particulates Adverse effects Ozone Nitrogen dioxide Sulfur dioxide

Particulate matter

Increased mortality due to respiratory disorders; cardiovascular impairments in COPD patients Respiratory diseases, with increased risks for COPD and asthmatic individuals Exacerbation of cardiopulmonary disorders; associated with mortality in the London smog of 1952 Increased incidence of respiratory and cardiovascular disease; premature mortality in asthmatics and COPD patients

Fig. 3.1.  The pulmonary system is the target of several major pollutants present in vehicular exhaust emissions. The incidence and severity of conditions such as cystic fibrosis, asthma, emphysema and COPD are increased in polluted inner cities around the world. (Illustration ‘anatomi’ is licensed under CC0 1.0.)

of current control measures on health outcomes remains an intractable issue (Boogaard and van Erp, 2019). In addition, acid rain, containing products derived directly from sulfur dioxide and nitrogen dioxide, causes devastating effects on survival and ecology of plants.

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3.2 Ozone Ozone present in the upper atmospheric layer is associated with important protective properties. However, at ground level (i.e. troposphere), ozone is a highly reactive oxidant gas formed by the photochemical reactions of carbon monoxide, nitrogen dioxide and volatile organic compounds found in significant concentrations in major cities. The current WHO guidelines indicate that any 8-hour period should not exceed a mean ozone concentration of 100 μg m–3. In urban environments, ozone together with particulate matter represent the two dominant air pollutants worldwide. The American Lung Association recently claimed that almost 40% of Americans reside in areas with potentially harmful levels of ozone. On its own or in combination with particulate matter, ozone increases risk of mortality from respiratory diseases, and correlates with reduced life expectancy. In addition, extensive epidemiological statistics have demonstrated age, gender and inter-individual differences in the susceptibility to environmental exposures, with specific genetic polymorphisms associated with negative health effects. Thus, the adverse effects of ozone are markedly higher in women than in men, associated with relatively higher fat mass in women. This comparatively larger distribution volume makes women more susceptible to lipophilic contaminants in the environment. Furthermore, these compounds are also metabolized more rapidly in women, resulting in higher toxicity. Pre-existing diseases, duration and concentration of exposure, respiratory rate (e.g. during exercise) as well as other anatomical and physiological factors affect the deleterious response to ozone inhalation. Following inhalation, ozone damages the nasal and upper respiratory tracts as it travels to the alveoli, the primary sites of adverse effects. Ozone that permeates into the alveoli will initially encounter the fluid lining these tissues, known as lung surfactant. This fluid consists of a layer of molecules at the air– water interface, with the hydrophobic portion of the molecules in contact with the air and the hydrophilic portion embedded in the water surface where it disrupts the hydrogen bonding between the water molecules. Lung surfactant is critically important for proper pulmonary function, providing a barrier against infection and reducing the surface tension of the air–water interface, thereby reducing the effort required during the breathing cycle. In chemical terms, lung surfactant is a complex mixture of lipids and proteins. A wide range of lipids is present, but most are phospholipids. It has been demonstrated that a number of constituents of lung surfactant can react with ozone and although some oxidation products will leave the interfacial film, other types such as damaged lipids and surfactant proteins with oxidized amino acid residues may remain in the lung surfactant, thus impairing its ability to function. In addition to biophysical damage to the surfactant monolayer, ozone activates the alveolar macrophages and epithelial cells to produce inflammatory cytokines. Short-term exposures cause reduced pulmonary function, airway inflammation and increased bronchial reactivity, which are often reversible. Longer exposures generally result in permanent changes to lung architecture via airway remodelling and instigation of oxidative stress, resulting in systemic

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inflammation and extra-pulmonary lesions. Furthermore, high ozone exposures are associated with increased hospital admissions for lung disease, including pneumonia, asthma, allergic rhinitis and lung infections as well as premature mortality. Children and older adults are particularly vulnerable to the adverse effects of ambient ozone exposure, with pre-existing conditions, reduced immunocompetence and genetic factors adding to the risks. For example, asthmatic patients show greater bronchoconstriction on brief exposure to ozone at 400 ppb. In respiratory diseases disproportionately affecting women (e.g. asthma and COPD), sufferers appear to be more susceptible to the damaging effects of ozone than men. There may also be increased risk of stillborn births associated with ozone pollution. In patients with asthma, ozone exposure exacerbates symptoms such as coughing, wheezing and shortness of breath as well as the incidence of asthma attacks, with effects being more pronounced in summer, coinciding with peak ozone formation. Ozone exposure in COPD patients can induce an increase in cardiovascular rather than respiratory events via mechanisms involving increased myocardial energetics and impairment of pulmonary gas exchange. In addition, long-term inhalation of ozone has been associated with systemic oxidative stress, leading to endothelial cell activation and pro-coagulation effects, stimulating thrombosis and triggering myocardial infarction, stroke and cardiac arrhythmias. Thrombotic episodes may also occur in healthy individuals exposed to ozone concentrations as low as 0.03 ppm, as demonstrated by vascular markers of thrombosis in blood as well as increased levels of inflammatory indicators such as interleukins and tumour necrosis factor. Vascular changes caused by ozone include vasoconstriction of brachial artery diameter and increased risk of coronary episodes. Predictably, ozone inhalation also reduces life expectancy, especially in patients with pre-existing illnesses or those from vulnerable communities. Other evidence indicates that exposure to air pollutants, specifically ozone, can affect metabolic and endocrine responses. For example, healthy children in Mexico City exposed to high levels of ozone and particulates during their prenatal life showed increased serum levels of circulating leptin (a hormone linked with appetite regulation) and proinflammatory adipokine, which exerts important roles in brain development, diabetes, obesity, cardiovascular disease and insulin resistance. These children also showed alterations in other hormones such as glucagon-like peptide, glucagon and ghrelin, which act as regulators of feeding behaviour. On the basis of these and other observations, it has been concluded that ambient ozone modulates both glucocorticoid-dependent and independent pathways in combination with oxidative stress mechanisms to evoke adverse metabolic effects. Concerns over the negative impact of ambient ozone have also been extended to neurological disorders, including stroke, Alzheimer’s disease, Parkinson’s disease and neurodevelopmental abnormalities. Associations of ozone exposure with cognitive impairments in patients with Alzheimer’s disease have been linked to oxidative stress and brain lipid peroxidation, compromising memory and neural functions. In patients with Parkinson’s disease,

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alteration of dopaminergic neurons has also been associated with ozone inhalation. In addition, emergency admissions for psychiatric causes have been linked to increased ozone exposure in warmer seasons, when pollution risks are higher. Guidelines issued by the American Lung Association indicate that anyone spending time outdoors when ozone pollution is high is at risk for its negative effects. Five groups have been identified as particularly vulnerable to the adverse effects of ambient ozone, including children and teenagers, elderly individuals, those working or exercising outdoors, people with existing inflammatory lung disease and those with existing cardiovascular disease. Ozone may also affect other groups, for example obese individuals and those with allergies. Low-income populations as well as some minority groups are at risk due partly to limited affordability for healthcare resources. Additionally, these individuals may reside in deprived inner-city locations with higher levels of ozone and associated pollutants. It is significant that a number of the disease syndromes linked with ozone pollution can be replicated in animal models. This evidence is important if credibility of epidemiological data is to be established among the different stakeholders involved in environmental protection, including the legislature and compliance agencies. For example, it is gradually emerging that genetic factors may predispose individuals to pollution-related morbidity and animal studies show that ozone toxicity is species and strain dependent. Animal models resistant to ozone may assist in understanding the genetic mechanisms involved in manifestations such as acute inflammatory responses and pulmonary dysfunction. The interaction between ozone and allergens can be modelled in animal investigations as well as the complications induced by bacterial infections. Rodent models have also been used to study the effects of ozone on cardiovascular dysfunction and central nervous system disorders such as Alzheimer’s disease. Despite recent advances, much more needs to be accomplished in terms of preventive measures and treatment methodologies for the diverse conditions associated with ozone exposure. Furthermore, interactions with other urban pollutants have yet to be elucidated in a mechanistic model.

3.3  Nitrogen Dioxide Nitrogen dioxide is one of several nitrogen oxides occurring in gaseous forms at room temperature. It is a pungent gas with an acrid odour arising naturally in volcanic eruptions, bacterial metabolism, forest fires and lightning. The major source, however, is via anthropogenic activity, including fossil fuel combustion from both stationary installations, such as power generation, and motor vehicles. In urban environments, nitrogen dioxide is often used as measure of air pollution, which is a complex mixture of ozone, volatile organic compounds and particulate matter. Alarming increases in ambient nitrogen dioxides have been observed in major cities worldwide, often exceeding local legal limits and for protracted periods when traffic congestion is severe.

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Nitrogen dioxide is characterized by its properties to initiate free-radical reactions, to react with unsaturated fatty acids in specific organs and to induce auto-oxidation of organic constituents of tissues. Most of the toxic effects of nitrogen dioxide are associated with its oxidative properties. As it has limited solubility in water, uptake and physiological fate of inhaled nitrogen dioxide are determined by reactions with components of pulmonary surfactant rather than dissolution of the gas itself. In comparison with ozone, nitrogen dioxide is only a moderately potent oxidant. Consequently, whereas the former is able to react in the upper respiratory tract, nitrogen dioxide will act at the level of gaseous exchange in the alveoli. This is where typical nitrogen dioxide-induced lesions have been observed in several species following high levels of exposure. It is further established that this gas can reside in the lung for protracted periods. Once absorbed in lung fluids, nitrogen dioxide dissolves to form nitrous and nitric acids and both nitrite and nitrate anions are translocated via the bloodstream. The oxidant properties of nitrogen dioxide also induce the peroxide detoxification pathway of glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase. These free-radical-mediated reactions represent the mechanism by which nitrogen dioxide exerts direct toxicity in lung cells. Phospholipid peroxidation plays a key role in the pulmonary epithelial toxicity of this gas, resulting in damage to the pulmonary surfactant and membrane function. This peroxidation of surfactant phospholipids occurs at relatively low levels of exposures and impairs their adsorption to the air–liquid interface. In addition, oxidative degradation of surfactant results in reduced pulmonary clearance rates and increased retention of inhaled particles. Acute exposure to nitrogen dioxide is associated with lung inflammation characterized by infiltration of serum inflammatory cells and hyperplasia of type-2 respiratory cells. Transcription and release of pro-inflammatory cytokines and tumour necrosis factor occur, with consequent activation of pulmonary macrophages and lymphocyte proliferation. However, most of these changes have been observed with nitrogen dioxide concentrations exceeding those present in ambient air. In healthy human subjects, short-term exposure to nitrogen dioxide causes elevated levels of natural killer cells, neutrophils and pro-inflammatory mediators. Overall, the responses are more consistent in healthy volunteers exposed to concentrations up to 2 ppm compared with levels below 1 ppm. With regard to physical host defences, nitrogen dioxide can cause loss of cilia and ciliated epithelial cells. Inhalation of this gas leads to hypersecretion and altered composition of mucus, affecting lung clearance and respiration. Nitrogen dioxide also increases susceptibility to bacterial and viral pulmonary infections. Furthermore, respiratory mechanics may be affected by nitrogen dioxide inhalation, including decrements in lung function, particularly increased airway resistance in 2-hour exposure at concentrations as low as 2.5 ppm in healthy subjects. In asthmatics, nitrogen dioxide is associated with increased airway responsiveness to a variety of provocative mediators, including cholinergic and histaminergic compounds, sulfur dioxide and cold air. Exposure to nitrogen dioxide concentrations greater than 0.5 ppm increases the asthmatic response to a range of allergens. Effects are evident on both

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i­mmediate and delayed reactions to allergen exposure. Moderate increases in airway resistance may also occur in COPD patients following brief exposure to nitrogen dioxide concentrations as low as 1.5 ppm, and decrements in spirometric measures of lung function may become evident with longer exposures to concentrations as low as 0.3 ppm. Of potentially greater significance is the interaction of ambient nitrogen dioxide with pollution caused by ozone, sulfur dioxide and particulates in subjects already compromised by existing pulmonary and cardiovascular diseases.

3.4  Sulfur Dioxide Relatively substantial quantities of sulfur dioxide are released into the atmosphere during the combustion of fossil fuels in power generation plants and industrial facilities that utilize it in the manufacture of chemicals such as sulfuric acid, pesticides, preservatives and wine and other beverages. The principal contributors to global sulfur dioxide contamination are China and India, where it is produced through the combustion of coal in electricity generation. Although China has taken strong measures to reduce emission, India has increased it by a significant amount. In the presence of oxygen, water and other commonly occurring compounds in the atmosphere, sulfur dioxide reacts to form sulfuric acid, thus contributing to acidification of aquatic ecosystems and soil, causing serious damage to vegetation, including trees. Exposure to atmospheric pollutants such as sulfur dioxide causes disease and disability, while control of this gas together with particulate emissions reduces mortality, provides significant health benefits and reduces air quality management costs. The worst air pollution example in European history occurred in the 1952 London smog event, attributed to sulfates and sulfuric acid produced from sulfur dioxide following the widespread burning of coal for heating and industrial purposes. A Clean Air Act was passed by the UK parliament in 1956 to regulate sulfur dioxide and other pollutants, but poor air quality remains an important issue in London and other major cities worldwide. Although epidemiological evidence clearly demonstrates a link between sulfur dioxide pollution and morbidity in humans, the underlying mechanisms remain largely elusive. It has been suggested that inhaled sulfur dioxide reacts with moist airway epithelium to form sulfuric acid, which together with its bisulfite and sulfite derivatives is readily absorbed into the bloodstream, causing toxicity. Overall, sulfur dioxide inhalation causes irritation to the nose, throat and the lungs. Typical manifestations include sore throat, runny nose, cough and difficulty in breathing; reactive airway dysfunction syndrome, non-specific bronchial hyperreactivity and pulmonary oedema can follow. Individuals with asthma and COPD may experience bronchospasms upon sulfur dioxide inhalation. Accidental or occupational exposure to this gas can be fatal. For example, two of five previously healthy papermill workers died from accidental exposure to sulfur dioxide. At autopsy, extensive sloughing of the airways and haemorrhagic alveolar oedema were observed. Incidence of increased mortality in

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episodes such as the London smog of 1952 have focused attention on the role of sulfur dioxide in causing severe health effects, especially in patients with underlying cardiopulmonary conditions. The industrial threshold limit values may not be tolerated by individuals with existing pulmonary disorders such as asthma and COPD. There is consistent evidence that levels of ambient sulfur dioxide normally tolerated by healthy individuals can cause severe broncho­ constriction in asthmatics. Furthermore, sulfur dioxide in the presence of other pollutants such as nitrogen dioxide may enhance sensitivity to subsequent allergen challenge in these patients. Synergism between sulfur dioxide and cigarette smoking has been established, indicating that the detrimental effects of sulfur dioxide may be increased by other ambient contaminants, including particulates and nitrogen dioxide. Elucidation of the signalling mechanisms underlying the pathophysiological effects of sulfur dioxide is emerging in studies with animal models; for example, acute inflammation with neutrophils and macrophages in the airways were observed following a 5-hour exposure, and helper cell activation and pro-fibrotic cytokine were detected in airways within 24 hours. It is also clear that sulfite oxidase exerts an important role in protection against sulfur dioxide-mediated organ damage, with more extensive injuries occurring in deficiency of this enzyme. At the subcellular level, sulfur dioxide inhalation compromises pulmonary mitochondrial cytochrome c oxidase activity and expression of regulatory factors, implying general dysfunction in this organelle. Sulfur dioxide is also associated with detrimental cardiovascular episodes such as heart failure, ischaemic heart disease and cardiac arrhythmia. Increased susceptibility of the heart to oxidative stress due to depleted levels of antioxidants may play a role, as well as elevated levels of reactive oxygen species produced due to the high metabolic rate of cardiac muscle. Consistent with this aspect is an increased level of lipid peroxidation and reduced cardiac status of antioxidants and associated enzymes in animal models. Adverse effects of sulfur dioxide on skin, eyes and brain have also been observed. For example, the severe irritant impact of sulfur dioxide vapours is associated with redness and blistering of the skin and burns on the cornea. Sulfur dioxide-containing fog causes a variety of ocular derangements, including itching, tearing, burning and foreign body sensation, while in other cases there will be eyelid swelling, oedema and mucous discharge. Loss of parasympathetic control of brainstem in animal models exposed to sulfur dioxide and oxidative brain damage with extensive lipid peroxidation have been reported. Elevated lipid peroxidation and reduced antioxidants are also a feature of neurodegenerative diseases such as Alzheimer’s disease, and it is pertinent to consider environmental pollutants in the aetiology and progression of such diseases. It has also been implied that sulfur dioxide inhalation may induce brain damage similar to cerebral ischaemia and may contribute to the progression of ischaemic stroke. Carcinogenic potential represents a further aspect of sulfur dioxide toxicity, particularly following occupational exposure during production or utilization of this gas. Although no evidence of lung cancer has been observed in workers

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e­xposed to sulfur dioxide in sulfuric acid-producing factories, significant ­increases in incidence of bladder cancer have been reported. Increased mortality due to lymphosarcoma, gastric, rectal and pancreatic cancer and Hodgkin disease has been observed in sulfite and sulfate process workers in the pulp and paper industries. In animal models, inhalation of sulfur dioxide on its own is not associated with malignancy but may potentiate the tumour-promoting effects of established carcinogens such as benzo[a]pyrene. However, there is evidence that endogenously produced sulfur dioxide may exert a tumour-­suppressing role. This observation is reminiscent of the opposing effects of nitric oxide as a toxicant and neurotransmitter in higher animals, including humans.

3.5  Particulate Matter It is relevant to consider the effects of particulate matter here due to interactions with gaseous pollutants in the induction of human morbidity in urban environments affected by vehicular traffic. In contrast to toxic combustion products such as carbon monoxide and polyaromatic hydrocarbons, which are well characterized in terms of chemical structure and physical properties, particulates are complex and variable in respect of chemical composition, surface properties, size and physical structure. In addition to direct toxicity in humans, combustion particulates are deposited on vegetation, soils and water, thereby resulting in uptake by and contamination of food resources. It is widely reported that the EU favours the use of wood as a renewable carbon-neutral source of energy. However, use of wood as fuel is associated with emissions of particulates and polycyclic aromatic hydrocarbons and contributes significantly to air pollution in developing countries, for example in populated regions of Chile. Smoke haze is a regular feature associated with fires set in forests and carbon-rich peatlands to clear land rapidly for agriculture, a practice seen in Indonesia and more recently in Brazil. Emission of particulates in these regions has been associated with significant premature mortality of local residents. Smoke inhalation in the 2019 fires in Brazil has been associated with increased incidence of respiratory illness among children. The emission of particulates in the smoke plumes caused by the apocalyptic bushfires in Australia during the 2019–2020 summer are likely to exacerbate pre-existing respiratory disorders among residents in affected locations. Particulates comprise condensed liquid droplets or solid particles, including water mists, hydrocarbon or organic condensates of specific compounds and carbon soot particles. These appear as approximately spherical particles in the nanoparticle size range (also known as ‘ultrafine’ particles) or in the lower end of the micro-particle range. Typically, in fires these coalesce into larger and more complex agglomerates in smoke plumes, mostly within the respirable range, but in some cases growing to millimetre-size particles. For particles small enough to remain in suspension in the atmosphere, a distinction is made between fine particles with a diameter less than 2.5 μm (PM2.5) and coarse particles with a diameter less than 10 μm (PM10). Of these PM2.5 is considered to be of greater significance for respiratory health disorders, since

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particles within this range penetrate more readily into the lower airways and alveolar regions of the lung. Deposition of airborne particles within the respiratory tract occurs by a number of processes, including impaction, interception, sedimentation, electrostatic attraction and diffusion. Particles can be classified into three fractions, depending on their main site of deposition. The inhalable fraction represents that part of the particulate cloud that can be breathed into the nasal passage and mouth; the thoracic fraction is that part that can penetrate the cranial airways and so enter the lungs; the respirable particulate fraction is that part of the inhaled airborne particles that can penetrate beyond the terminal bronchioles into the gas-exchange region of the lungs. Epidemiological evidence consistently demonstrates associations between the incidence of respiratory and cardiovascular disease, including deaths, and both short-term and long-term exposure to PM2.5 present in vehicle exhaust emissions (Mehta et al., 2013). Patients with underlying illnesses such as asthma and COPD are particularly vulnerable to the adverse effects of particulates. Diverse mechanisms are implicated in these aspects of particulate toxicology. For example, inflammation of the lungs may release inflammatory mediators (oxidants and cytokines) which enter the circulation, thereby promoting inflammatory reactions in the walls of blood vessels and endothelium. Another mechanism involves the direct transport of nanoparticles in the blood to the cardiovascular epithelium. Uptake of nanoparticles by cells of the immune system and the autonomic reflex pathways specifically affect cardiac functions, including heart rate variability. Of considerable significance is the recent observation that air pollution nanoparticles have been detected on the fetal side of placentas, presenting greater risks for pregnant women living near congested roads.

3.6  Key Issues Urban air comprises a complex mixture of toxic gases and particulates arising from vehicular emissions. Ambient concentrations of these contaminants regularly exceed local legal limits in congested cities like London, Los Angeles, Tokyo and several other major cities. In the UK, for example, almost 2000 ‘toxic hotspots’ were identified in a recent survey. Although the risks associated with each pollutant have been evaluated, the extent to which ozone, nitrogen dioxide, sulfur dioxide and particulates interact to cause morbidity is distinctly more difficult to quantify. Whether the effects on pulmonary and cardiovascular diseases are the consequence of additive or synergistic interactions remains an intractable problem for the future. Meanwhile the complexity of establishing cause-and-effect issues in individuals affected by pollution is increasingly being resolved in the courts rather than pathological or research laboratories, as illustrated in Case Study 3.1 relating to asthma. It is important that environmental protection agencies and local government authorities charged with ensuring the health of their communities by reducing pollution take appropriate and effective action, while evaluating the efficacy of current measures (Boogaard and van Erp, 2019).

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Case Study 3.1.  Landmark judgement on urban pollution and asthma The historical role of the courts in delivering environmental justice stretches over several decades, highlighted recently in the aftermath of the Deepwater Horizon oil spill and the punitive compensation for a terminally-ill individual exposed to a well-known herbicide in the USA. However, a radical decision in the UK by the Attorney-General constitutes a landmark development in environmental health. This intervention granted permission for an application to the High Court in London for a new inquest in the case of a child who died in 2013, following a series of seizures and over 25 hospital emergencies for asthma attacks. The original inquest relating to this case implicated ‘acute respiratory failure’ precipitated by the asthma attacks as the cause of mortality. A subsequent report by a specialist maintained that there was a marked association between the hospital admissions and illegal increases in ambient nitrogen dioxide and PM10 levels in the vicinity of the child’s home situated near one of London’s most polluted streets. The expert concluded that this pollution contributed directly to the fatal asthma attack. The campaign for a new inquest was supported by over 150,000 members of the public. Campaigners for environmental justice will be emboldened by the Attorney-General’s decision. This case should not be viewed in isolation but in conjunction with current developments in enabling biotechnologies. For example, the Human Genome Project is now gaining momentum and should provide critical elements for the prognosis of human disease in relation to intrinsic as well as environmental factors. This work should resolve cause-and-effect issues for a wide range of pollutants similar to that existing for identifying and specifying the carcinogenic properties of the aflatoxins (see Chapter 2). It is envisaged that the characterization of particular signature molecules at genomic, transcriptomic, proteomic or metabolomic levels of expression will assist in identifying interactions of pollutants with specific mechanisms. Any advances in the use of cellular biomarkers should be advantageous for diagnosis and treatment of pollutant-related morbidity. In addition, these developments might equally embolden patients and others exposed to noxious emissions to instigate class actions against public health authorities to legally enforce a remediation programme in their local environment. Consequently, a mechanistic approach would be employed to reinforce or replace the existing statistical inference methodology in correlating specific pollutants with particular disease conditions. • How can the courts help in instances of human health disorders caused by industrial pollution? • Compare the health outcomes in the above case with those reported for the London smog of 1952.

3.7 References Boogaard, H. and van Erp, A.M. (2019) Assessing health effects of air quality actions: what’s next? The Lancet Public Health 4(1), e4–e5. Landrigan, P.J. (2017) Air pollution and health. The Lancet Public Health 2(1), e4–e5.

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Mehta, S., Shin, H., Burnett, R., North, T. and Cohen, A.J. (2013) Ambient particulate air pollution and acute lower respiratory infections: a systematic review and implications for estimating the global burden of disease. Air Quality, Atmosphere & Health 6, 69–83.

3.8 Exercises (i)  Summarize the effects of vehicle exhaust pollutants on human health. (ii)  Draw up proposals that you might put forward to your local authority to curb vehicle emissions. (iii)  What objections would you anticipate from (a) local residents and (b) local authority officials for your proposals to reduce pollution in your town/city? (iv)  Inner-city air pollution is conventionally assessed by determining ambient concentrations of nitrogen dioxide and particulates. Should we also include ozone and sulfur dioxide in these determinations?

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Persistent Organic Pollutants

4.1 Overview Conventionally, the term ‘persistent organic pollutants’ (POPs) is restricted to polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), dioxins, organochlorine and organophosphate pesticides, fungicides and herbicides (Table 4.1). These contaminants are distinct from another group of commonly occurring pollutants known as volatile organic compounds (VOCs). An overriding feature of POPs is their resistance to breakdown by natural processes in different ecosystems and their lipophilic properties, thus favouring accumulation in animal tissues and human milk, and consequently presenting risks for breast-fed infants (Tsygankov et al., 2019). As a result, the environmental and health hazards associated with POPs are likely to remain with us for some considerable time. Although classified together, POPs are known to elicit widely different toxicities in humans and other animals, potentially threatening the very existence of some species. The principal objectives in this chapter are as follows. • To review the impact of POPs on human health and aquatic/marine ecosystems. • To evaluate structure–activity relationships among selected POPs. • To emphasize that endocrine disruption is now recognized as a common underlying expression of the activity of several pollutants, particularly specific POPs. • To exemplify the concept of biomagnification of selected POPs and the implications for predators. • To note that risks are also associated with vehicle emissions of volatile organic compounds (VOCs), including benzene, toluene, ethylbenzene and xylene (BTEX group) and acetaldehyde. • To clarify that some or all of these VOCs may contribute to the carcinogenic potential of traffic-related air pollutants via unique mechanisms or in synergistic interactions. 42.

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Table 4.1.  Principal toxic effects of persistent organic pollutants (POPs). It should be noted that, in addition to other contaminants, a number of the following compounds are implicated in endocrine disruption. POPs

Effects/properties

Polycyclic aromatic compounds Polychlorinated biphenyls

Reproductive dysfunction; cancer Reproductive defects; chloracne; cancer; developmental neurotoxicity Liver damage; immune suppression; cancer Neurological disorders Neurotoxic; lethality Implicated in neurodegenerative disorders Implicated in neurodegenerative disorders and cancer

Dioxins and furans Organochlorine insecticides Organophosphate insecticides Fungicides (as specified in text) Herbicides (as specified in text)

4.2  Polycyclic Aromatic Hydrocarbons PAHs constitute a group of numerous structurally-related compounds formed by fused aromatic rings, the simplest of which is naphthalene, containing two fused rings. Anthracene is a 3-ringed compound, whereas pyrene, chrysene and naphthacene are composed of four rings in different structural arrangements. Five-ringed PAHs include benzo(a)pyrene, benzo(e)pyrene and perylene and, in addition, there are numerous 6-ringed compounds all with different structural configurations, including linear, cyclical, alternant, non-alternant, branched and non-branched conformations. PAHs occur in coal, asphaltic rocks and petroleum and are formed by the incomplete combustion of organic matter (pyrogenic PAHs). Following industrial and engine combustion of fossil fuel (source of petrogenic PAHs) and emissions into the environment, PAHs contaminate air, water and soil and are thus transferred into foods. Consequently, PAH contamination occurs in all ecosystems and the effects are magnified in accidental oil spills. Following oral consumption via contaminated foods, PAHs are absorbed in the gastrointestinal tract and distributed to other organs through enterohepatic circulation. Food components may affect the uptake of PAHs, either enhancing or reducing their absorption, resulting in potentiation or attenuation of toxicity. Exposure to PAHs is associated with diverse manifestations of toxicity in experimental models, including reproductive dysfunction, cardiovascular disorders, bone marrow abnormalities, immune suppression and hepatic lesions. In addition, teratogenic, mutagenic and carcinogenic properties have been attributed to PAHs. In general, the reproductive toxicity of benzo(a)pyrene, the best-documented PAH, includes resorption, malformation, stillbirths and decreased fertility of progeny in laboratory models. It is clear that active metabolites can cross the placenta and reach the fetuses of orally exposed animals. Immunotoxic effects are seen in the bone marrow, thymus, spleen and lymph nodes. Several PAHs elicit mutagenic responses in bacterial and mammalian cells in vitro.

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Of all toxic effects attributed to PAHs, its carcinogenic potential has attracted the greatest human health concern. It is known that PAHs undergo transformations in living organisms which determine the ultimate biochemical fate towards excretion or malignancy. In the latter pathway, activated metabolites form covalent adducts with DNA, an initial step in chemical carcinogenesis. Biotransformation of PAHs commences with a cytochrome P450mediated epoxidation of these molecules, a reaction catalysed by the enzyme complex known as mixed-function oxidase. The next step involves hydroxylation with the formation of diols, catalysed by a hydrase, acting in harmony with the mixed-function oxidase complex. This system is generally referred to as an aryl-hydrocarbon hydroxylase. The resulting diols can undergo further conversion into highly reactive dihydrodiol epoxides, which can attack critical nucleophilic sites in DNA, either directly or through the mediation of other reactions. Nevertheless, the intermediate diols can also follow a detoxification pathway via conjugation with glucuronic acid or glutathione, leading to metabolites that can be excreted by renal or biliary routes. Ingested PAHs can be metabolized by gut microbes, intestinal mucosa or liver. The intestinal epithelium contains the complete metabolic system required for the processing of PAHs, although capacity is generally much lower than in the liver. In addition, the biological activity can be determined by compounds that can act as inducers, promoters or inhibitors of PAHs metabolism. Thus, some drugs, vegetables, PCBs and gastric hormones may affect carcinogenic potential of PAHs. Many PAHs are associated with carcinogenesis in animal models employing different routes of administration with resulting effects such as hepatomas, lung adenomas, squamous papillomas, forestomach papillomas and carcinomas as well as stomach tumours. However, a variety of factors affect the final outcome, including dose level, administration route, the vehicle containing the PAHs, the presence of other PAHs and the frequency of exposure; the biological factors include age, sex, genetics and nutritional status. Although there are exceptions, in general PAHs with fewer than four fused rings are non-carcinogenic, whereas those with six rings are mostly carcinogenic. The variation in carcinogenic potential can be explained on the basis that some characteristics are necessary in both the parent molecules and in their respective metabolites to form DNA adducts. In PAH topology, some regions and carbon atom positions determine biological activity. For example, the presence of the bay region in PAHs (Fig. 4.1) is generally considered to be a major prerequisite for carcinogenic activity (Ewa and Danuta, 2017). However, Bay region M or distal bay region peri position

L region

K region

Fig. 4.1.  Regions associated with biological activity in PAHs.

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in spite of the role of PAH-DNA adducts in carcinogenesis, the formation of such adducts does not automatically imply the development of tumours, since the damaged template can be repaired before cell replication occurs. In addition, there are tumorigenic PAHs without bay regions or which are not activated via a bay region epoxide. Thus, it is clear that there are many other factors such as metabolic, stereochemical and conformational factors as well as the inherent reactivity of the metabolites which determine the marked differences in the tumorigenicity of different PAHs. As indicated in Chapter 1, the IARC classifies carcinogenicity of pollutants and other potentially deleterious compounds within four groups. With regard to PAHs, the evidence is based primarily on studies with animal models. Most PAHs are designated as Group 3, i.e. unclassifiable as to carcinogenicity in humans, whereas three, namely benz(a)anthracene, benzo(a)pyrene and dibenz(a,h)anthracene, are considered to be probable human carcinogens (Group 2A). A further nine PAHs appear in Group 2B as possible human carcinogens; for example, two of these include dibenzo(a,e)pyrene and dibenzo(a,h)pyrene. In view of the foregoing evidence, measures are in place to provide risk assessments for PAH exposure in human populations. The first approach is to evaluate the risk associated with ambient air and dietary exposure to PAHs. However, the analysis of these external sources does not take into account the assimilation, metabolism, distribution or excretion pathways for PAHs. Biomarkers can be used to measure internal exposure of individuals to these potential carcinogens. Biomarkers are indicators that can be determined quantitatively, semi-quantitatively or even qualitatively in body fluids, blood and other cells or tissues. In general biomarkers can be used to signify exposure, adverse effects or susceptibility of individuals to PAH contamination in ambient air or foods. It is generally accepted that PAHs cause adverse effects in aquatic organisms at all life stages and at different levels of organization. These effects, as indicated by extensive bioassays, include growth depression, DNA damage, cytotoxicity, endocrine disruption and malformations of embryos and larvae. For example, embryonic exposure can cause sub-lethal effects, including yolk sac and pericardial oedema, disruption of cardiac function, cardiac deformities and impaired swimming in fish. Due to co-occurrence of multiple environmental stressors, there is a need to evaluate the effects of complex mixtures. For example, the deleterious effects of plastic debris in aquatic ecosystems may be affected by its role as a vector/transporter of PAHs, thus determining the environmental fate of both contaminants. There is currently a call for the development of technologies to enable fingerprinting of PAHs to assist efforts in environmental risk assessment and management.

4.3  Polychlorinated Biphenyls Polychlorinated biphenyls (PCBs) exemplify the meaning of POPs in the clearest sense of the term. PCBs are a structurally-related group of synthetic compounds defined chemically as biphenyls with variable chlorine substitutions

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for the hydrogen atoms in the benzene rings. There are 209 possible PCBs, each of which is referred to as a congener. These variants are classified into two categories: dioxin-like and non-dioxin-like, based on structural differentiation. Recent data suggest that non-dioxin-like PCBs predominate in diverse matrices, including human tissues. PCBs have ideal heat-dissipating and flame-retardant properties which have formed the basis of large-scale commercial production on a global scale. Due to the low flammability, chemical stability and electrical insulating properties, PCB mixtures were widely used as coolants and lubricants in electrical transformers, capacitors and hydraulic equipment. The same physicochemical properties that conferred desirable industrial and commercial applications ensured that PCBs would be highly resistant to degradation in the environment. In addition, PCBs are highly lipophilic and thus bioaccumulate up the trophic system, concentrating in fatty tissues. Recognition that PCBs were pervasive pollutants in the 1960s and growing concerns over the human health implications resulted in a worldwide ban on their production. Although environmental PCB contamination declined initially, levels may be rising again due to legacy sources released during ageing of materials containing these compounds. Metabolism of PCBs is essentially a detoxification process, with the retention or accumulation of congeners being correlated with biological stability. Generally, the presence of fewer Cl atoms on the biphenyl rings coupled with the absence of one or more Cl atoms at the para position, appears to facilitate metabolism and excretion. The elimination of PCBs is largely dependent upon metabolism to more polar metabolites following Phase I and Phase II reactions. Elimination of these products occurs primarily via the bile and faeces but some of the lower chlorinated congeners may be excreted in the urine, depending upon species under consideration. Human exposure to PCBs occurs primarily through intake of contaminated food and inhalation. Following entry into the human body, PCBs accumulate in lipid fractions of adipose, liver and brain tissues, but are also present in quantifiable levels in blood. Until recently, most adverse human health effects have been associated with dioxin-like PCBs. Apart from structural resemblance to dioxins, these classes of PCBs, like dioxins, bind to the arylhydrocarbon receptor. Consequently, the toxicity profiles of dioxin-like PCBs are similar to those of dioxins. Thus, exposure to high levels of dioxin or dioxin-like PCBs can precipitate chloracne and liver damage, while chronic exposure to lower levels may compromise immune function or cause cancer. In contrast, the non-dioxin-like PCB congeners have negligible arylhydrocarbon-binding activity. Consequently, it was long assumed that these class of PCBs were toxicologically benign. However, subsequent work demonstrated that certain non-dioxin-like PCBs, but not dioxin-like PCBs, interfered with dopamine signalling and altered Ca-dependent signalling in neurons in vitro. These observations corroborated earlier epidemiological and preclinical studies with animal models indicating the neurotoxic nature of at least some PCBs and that the developing nervous system is considerably more sensitive than that of adults with mature networks. These initial developments were given added significance following data from

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the United States Centers for Disease Control confirming widespread exposure to PCBs among women of childbearing age living in the USA as well as experimental evidence demonstrating that PCBs can cross the placenta and also accumulate in breast milk. An analysis of breast milk samples in Canada during the early 1970s indicated contamination with PCBs in almost all samples. It is instructive to summarize the diverse toxicology of PCBs as determined with animal models and in epidemiological studies (Sethi and Lein, 2019). Any interpretation of data tends to be confounded by the fact that PCBs are a mixture of congeners with differing or relatively sparsely known mechanisms of action for each component. In addition, commercial mixtures of PCBs may also contain varying quantities of contaminants. Work with animal models demonstrates that PCBs are associated with a diverse range of adverse effects, as summarized below. • For example, reproductive effects include depressed conception rates, increased fetal mortality and reduced birthweights of progeny. • Although not comprehensively studied, teratogenic effects have also been observed in mammalian and avian bioassays. • Several commercial PCB mixtures are associated with oestrogenic properties. Congeners with the strongest bonding to the oestrogen receptor have at least two ortho Cl atoms in the PCB structure, but hydroxylated congeners also exert oestrogenic activity. • Commercial mixtures of PCBs are known to reduce plasma thyroxine concentrations, increase circulating thyroid-stimulating hormone and alter features of thyroid histology. • In rodent models, commercial PCB mixtures are linked with impaired neurological development causing behavioural abnormalities following exposure in utero, but not post-natally. Manifestations in rhesus monkeys after maternal exposure include hyperactivity, retarded learning ability and significant alterations in cognitive behaviour in offspring. However, post-natal exposure can also result in similar behavioural alterations and it is now believed that type of PCBs and age at exposure may also be contributory factors in neurotoxicity. • Available evidence with animal models suggests that immunocompetence may also be compromised following exposure to PCBs. In particular, the findings with non-human primates tend to be emphasized due to biological and phylogenetic similarities to humans. These data indicate changes in the immune function of adult female rhesus monkeys and their offspring following exposure to low levels of the PCB, Aroclor 1254. • A significant feature of the toxicity of PCBs is associated with carcinogenic potential and there is ample evidence to demonstrate development of tumours but the effects may be determined by composition of PCBs, sex and even the strain of animals used in bioassays. It is also suggested that PCB mixtures are not complete carcinogens but may act as tumour promoters. Epidemiological evidence of human PCB toxicity can be divided into non-cancerous and cancerous categories. Substantial data has accumulated

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following the accidental exposure of people in Japan and Taiwan following ingestion of rice oil inadvertently contaminated with PCBs. Subsequent to these incidents, affected individuals developed chloracne and hyperpigmentation of the skin, gingiva and nails, with partial recovery over time, although symptoms were still present 10–14 years later. Ocular lesions, including hypersecretion and swelling of the sebaceous glands of the eyelids, are also common with PCB intoxication. Other findings indicate that women in a number of high-exposure environments, such as industrial or accidental, have given birth to offspring with lower birthweights or shorter body lengths and/or smaller head circumferences. However, methodological issues and the presence of co-contaminants need to be addressed before definitive conclusions can be drawn on the reproductive effects. In addition, PCBs have not been found to affect the incidence of spontaneous abortions or stillbirths. The neurological implications of exposure to PCBs have been assessed in mothers who ingested contaminated rice oil in Japan and Taiwan. It was considered that prenatal exposure to PCBs and other POPs may adversely affect the neurological development of children born to these mothers. The evidence showed that infants of the exposed mothers exhibited a range of neuropsychological deficits that persisted for several years, but the effects of other POPs present as co-contaminants could not be excluded in this analysis. In addition, there is a need to determine the effects of the number and type of congeners on developmental neurotoxicity in children in the Taiwan and Japanese cohorts compared with other populations reliant on PCBcontaminated sources such as marine mammals. An additional requirement is to distinguish between the roles of dioxin-like and non-dioxin-like PCBs in neurological development. Nevertheless, there are possible mechanisms whereby PCBs may affect neurodevelopment, including disruption of thyroid hormone signalling, altered neurotransmitter signalling, perturbation of calcium homeostasis and oxidative stress. The Taiwan incident also suggested other toxicological effects in victims, including: substantial elevation in mortality rates due to cirrhosis and chronic liver disease; an increased incidence of goitre in both men and women; immunological defects; and occurrence of bronchitis-like syndromes, marked by a large quantity of expectorant during the initial phase of exposure. The carcinogenic potential of PCBs has been a cause of considerable concern, as with other POPs. Following the Japanese poisoning episode, a significant increase in the incidence of mortality attributable to cancer of the liver and respiratory system occurred in men but not in women. Thirteen years after the Taiwan contamination, a substantial increase in mortality due to chronic liver disease and cirrhosis was evident, but deaths associated with malignancy were not significantly increased. Nevertheless, based on extensive animal studies and epidemiological observations, IARC has classified PCBs as Group 1 human carcinogens. In summary, PCBs are associated with a wide array of adverse effects in humans, reflecting the complex range in structure and degree of chlorination. Although the primary concern in human health is carcinogenesis, effects on developmental neurotoxicity need further consideration.

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4.4  Dioxins and Furans The terms dioxins and furans are abbreviated from polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs), respectively, and represent two groups of planar, tricyclic compounds which can accommodate up to eight Cl atoms attached to specific carbon atoms. In total, there are 75 possible PCDD congeners and 135 possible PCDF analogues. Like PCBs, dioxins and furans are lipophilic, resistant to biodegradation and, therefore, persistent in the environment. These compounds are undesirable by-products of many chemical industrial processes and of all combustion processes. Historically, the production of organochlorine chemicals has been identified as the major source of PCDDs/PCDFs, but in modern situations sources include incineration of municipal and hospital wastes, the production of iron and steel and all types of uncontrolled burning of organic matter. As a consequence, PCDDs/PCDFs are present in all ecosystems and accumulate in fatty tissues of humans and both prey animals and associated predators. For humans and other animals, the main exposure route is via ingestion of contaminated food (Tuomisto and Viluksela, 2020). Metabolism is almost negligible and estimation of body compartmentation and turnover as well as protection of the fetus are of particular concern when precautionary measures are considered. In most vertebrates, the 2,3,7,8-substituted congeners of PCDDs/ PCDFs are predominantly retained, meaning that biotransformation rate of these compounds is markedly reduced, resulting in significant bioaccumulation. In most species, the liver and adipose tissue are the major storage sites. The half-life especially of the PCDFs in humans is considerably longer than that in animal models. The marked potency of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related PCDDs/PCDFs has been demonstrated in several animal models, with effects as listed below: • liver damage; • immune suppression; • carcinogenesis; • abnormalities in fetal development; • skin defects; and • endocrine disruption. It is generally believed that these types of substituted PCDDs/PCDFs elicit similar patterns of toxicity. The toxic responses are initiated at the cellular level by the binding of these compounds to the specific protein in the cytoplasm of cells, the aryl hydrocarbon receptor (AhR) and induction of cytochrome P450 gene expression. With increasing degree of chlorination, receptor-binding affinity decreases. 2,3,7,8-TCDD is a multi-site carcinogen in animal models and in humans. TCDD induces liver tumours in animals at lower concentrations than any other anthropogenic chemical. Dioxins are not genotoxic (i.e. do not initiate cancer development) but 2,3,7,8-TCDD and other dioxins and furans are strong promoters of tumorigenesis.

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In humans, effects attributable to dioxins are observed mainly with accidental and occupational exposures. In children, in utero exposure to dioxins and/or PCBs at or near background levels has been linked with effects on neurodevelopment, behaviour and thyroid hormone status. At higher levels, children exposed transplacentally to these contaminants exhibit skin abnormalities such as chloracne in both children and adults, developmental delays, low birthweight, behavioural disorders, reduced height among girls at puberty and hearing loss. It is not fully known whether these effects are caused by dioxins and related chemicals or other contaminants in the environment, but there is a general consensus that subtle effects might already be occurring in the general population at current background levels of exposure to these contaminants. There are a number of cohorts with high exposure to PCDDs/PCDFs (including PCBs and additional contaminants) associated with the Vietnam conflict (1961–1971) and the Seveso chemical plant explosion in Italy in 1976 or in occupational circumstances. In one such population highly exposed for more than a year and with a 20-year latency period, there was an increase in all cancers. The Vietnam investigation showed higher incidence of diabetes correlating with increasing dioxin levels, but no other effects. In the Seveso survey, residents had elevated dioxin levels and there were significantly more girls born than boys, indicating a change in normal sex ratio in that population. Four epidemiological studies of high-exposure industrial cohorts in Germany, The Netherlands and the USA indicated higher overall cancer mortality rates. In general, the strongest evidence for the carcinogenicity of 2,3,7,8TCDD is for all cancers combined, rather than for any specific type. In these cohorts, blood lipid levels of this dioxin were markedly elevated compared with values for populations exposed to background levels. In the IARC classification, 2,3,7,8-TCDD is designated as carcinogenic to humans. This conclusion was based on a number of factors, including the observation that 2,3,7,8-TCDD is a multi-site carcinogen in animal models, involving the aryl hydrocarbon receptor, and that this receptor is highly conserved in an evolutionary and functional context in humans and animal models; furthermore, tissue concentrations of this dioxin were comparable in humans and a rat model. Other PCDDs and non-chlorinated congeners are not classifiable as to their carcinogenicity in humans. In addition, the IARC concluded that there was inadequate evidence for the carcinogenicity of PCDFs in humans, although there is limited evidence for carcinogenicity of certain congeners in animal models. The US Environmental Protection Agency (EPA) confirmed the IARC classification for TCDD as a ‘human carcinogen’ and thus satisfying the stringent criteria required to accept a causal relationship between TCDD exposure and cancer risk. Historically, risk assessments were only performed with the most toxic congener, 2,3,7,8-TCDD, but a much greater number of dioxins are highly toxic and may contribute significantly to the overall toxicity of complex dioxin and furan mixtures. The extent to which these mixtures act additively or synergistically in the development of cancer remains an intriguing question that is difficult to resolve. Nevertheless, there can be no doubt as to the carcinogenic potential of dioxins individually or as a group or in combination with PCBs, in view of the incidence of mortality and malignancy following high-exposure

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a­ ccidents in industrial environments. Furthermore, a combination of chlorinated solvents and dioxins/furans, from industrial sources, has been implicated in the incidence of thyroid cancer for the general population. Although the main focus in the toxicology of dioxins and furans has, justifiably, been on carcinogenic potential, the relationship of these compounds to diabetes and associated nephropathy is emerging as an additional feature of risk in humans. These associations have been inferred from meta-analyses which indicate that repeated exposure to TCDD appears to be important when considering associations with diabetes. Of eight dioxin-like compounds, six were linked with diabetes, five with diabetes without nephropathy and seven with diabetic nephropathy. The underlying mechanisms of these associations have yet to be established.

4.5  Organochlorine Insecticides Chlorinated insecticides belong to a heterogeneous group of compounds comprising three different chemical classes: the diphenylethanes, the cyclodienes and the cyclohexanes. The diphenylethanes include dichlorodiphenyltrichloroethane (DDT), dicofol and methoxychlor. These and other classes of insecticides were designed to be used for the control of insect-borne diseases and agricultural pests. DDT and its major metabolites are lipophilic compounds and tend to accumulate in body fats. DDT degrades very slowly in the environment, with a half-life estimated to be 4–5 years in soil and up to 15 years in seawater. Consequently, both humans and marine species are regularly exposed to DDT and other organochlorines. The utility of organochlorine insecticides was embodied in unique characteristics that rendered these compounds to be highly toxic to insects, coupled with a persistence and chemical stability that promoted long-lasting effects after application. However, these same properties that conferred such efficacy resulted in their eventual exclusion with the recognition of human health and environmental consequences of organochlorine insecticide applications. Over several decades, human health concerns and adverse effects on environmental biodiversity have been addressed in population-based, laboratory and field studies to determine risk. Human exposure to organochlorine insecticides occurs via different routes, including dermal, inhalational and oral. In general, dermal exposure to DDT is well tolerated and does not result in adverse effects. In contrast, acute oral exposures are most notably accompanied by hypersensitivity in the buccal cavity, followed by spontaneous motor movements, muscle hyperexcitability, tremors and cognitive aberrations. These neurological manifestations have been attributed to the well-defined mechanism of action of DDT specifically directed at the function of the sodium channels residing in neurons. The brain and other regions of the central nervous system are important target organs for the toxicity of organochlorine insecticides. As neuronal communication is regulated by the generation of electrical signals that travel along the axon, the highly coordinated movement of sodium ions through voltage-gated channels integrated within the neuronal membrane underlies the action potential. When

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these s­odium channels open, allowing an influx of the ion into the axon, a marked change in voltage across the membrane forces the sodium channels to close and an opposing opening of potassium channels to release potassium into the extracellular space, effectively restoring equilibrium in the neuronal environment. Exposure to DDT binds to sodium channels, increasing the time required for closure, which in turn prolongs the activation of the neurons, resulting in neuronal hyperexcitability. DDT also affects the movement of other ions in and out of the neuron through their interactions with associated ATPases. As these enzymes participate in the maintenance of ionic balance across the neuronal membrane, inhibition of these processes by DDT can contribute to neuronal excitation and toxicological cascades. DDT can also disrupt neurotransmitter signalling by affecting glutamate flux in the brain and altering the levels and functioning of serotonin, norepi­ nephrine and dopamine networks in different regions of the brain. In particular, DDT and its major metabolites induce significant deficits in dopamine handling and transport, causing pathological accumulation of dopamine in the cytosol of the dopamine neurons, resulting in oxidation to neurotoxic metabolites and cell death. This aspect is of considerable significance as DDT and DDE have been identified in post-mortem brain tissues and found to be associated with neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases. The chemical stability of DDT in the environment ensures continued human exposure to this insecticide. Consequently, while initial dosages may not be acutely toxic, body burdens can increase over time and thus chronic exposure becomes much more relevant. Additional risks are associated with the relative ease with which DDT is transported around the body, particularly from mother to the developing fetus and via breast milk. Although DDT levels are relatively low, fetal development represents a critical phase in neurological development and emphasizes the vulnerability of the fetus to neurotoxic agents such as DDT. Although the manufacture and use of DDT has been banned in North America for many years, neurodevelopmental defects have been associated with preand post-natal exposure to DDT. Effects include multiple neurological deficits, including abnormal reflexes, impairments in memory, executive functions and social and attentional processes. This indicates the existence of residual levels of this insecticide in the environment and in the food sources, reflecting a scenario of chronic or continual exposure to DDT. In many tropical countries, DDT is still used to control insect-borne diseases such as malaria. Under these circumstances, it is imperative to evaluate the risks of prenatal and post-natal DDT exposure to both mother and offspring. It is known that pregnant women in high-exposure situations, for example in Africa, carry a significant serum load of DDT and DDE in comparison with other pregnant women in the general population, but the neurodevelopmental risks for the fetus require elucidation. Other organochlorine insecticides of relevance, including cyclodienes and hexachlorocyclohexanes, are differentiated from DDT not only on the basis of chemical structure but also on the mechanisms of neurotoxicity and defined ecological risks. Both groups include well-known insecticides extensively used

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in rural and residential environments. Within the cyclodienes, the insecticides aldrin, endrin, dieldrin, chlordane, heptachlor, endosulfan and toxaphene represent the most prominent examples. The hexachlorocyclohexanes include a variety of isomers such as lindane and β-hexachlorocyclohexane. In several cases toxicity is equal to or greater than that of DDT, a feature contributing to the high efficacy of these insecticides for pest control. However, as seen in earlier examples, toxicity coupled with persistence in the environment and the ability to accumulate eventually culminated in the phasing out and banning of these organochlorines in the USA and elsewhere. Despite this action, and the passage of time, detectable levels of these residues still occur in human tissues and in a variety of ecosystems. Potential or actual contamination of foods represents another dimension of risk to consumers and residents in rural locations adjoining farms. As with DDT, cyclodienes and hexachlorocyclohexanes primarily act on the central and peripheral nervous systems, inducing a sustained neuronal hyperexcitation that results in a rapid onset of convulsions and seizures. The aforementioned effects are attributed to the ability of these insecticides to inhibit ion transport by specific ATPases, in addition to interfering with the signalling of the primary inhibitory neurotransmitter, gamma-aminobutyric acid, in the central and peripheral nervous systems. These insecticides block the activity of gamma-aminobutyric acid by inhibiting the influx of chloride through the specific receptor–ionophore complex, effectively removing the inhibitory signal essential for modulating neuronal activity, thus causing hyperexcitation. The neurological effects of the cyclodienes and hexachlorocyclohexanes centres on the association with specific neurodegenerative disorders such as Parkinson’s disease. In particular, efforts have focused on the effects of cyclodiene exposure on disruption of the dopamine system implicated in the pathogenesis of Parkinson’s disease. Other evidence points to the role of cyclodiene insecticides as risk factors for neurodevelopmental deficits, including autism spectrum disorder, but these findings await confirmation. The characteristic nature of organochlorine insecticides, including cyclodienes, is the ease with which these compounds can cross the placenta to induce in utero exposure to the fetus and impact on neurodevelopmental processes. Although Parkinson’s disease is perceived as an ageing condition, it is important to determine the potential role of prenatal exposure to organochlorine insecticides on the development and functioning of the dopamine pathways in the central nervous system. Dieldrin is also associated with neurotoxicity, inducing rapid onset of convulsions following acute administration. In addition, chronic exposure to lower concentrations causes headaches, dizziness, muscle twitching and hyperirritability, most likely due to disruption of ionic homeostasis and gamma-aminobutyric acid signalling. However, the effects of dieldrin on the dopaminergic system and the possible association with the development of Parkinson’s disease are worth noting. Several epidemiological investigations indicate a link between levels of dieldrin found in post-mortem brain samples and Parkinson’s disease. In particular, increased levels of dieldrin occurred in specific brain regions, including those uniquely damaged in this disease. It is envisaged that dieldrin induces a marked attenuation of antioxidant capacity and a concomitant increase in oxidative stress in dopaminergic regions of the brain. It is important to

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establish whether dieldrin, and indeed other POPs, causes additional damage to dopaminergic activity and so contribute to or exacerbate the pathogenesis of Parkinson’s disease. Similarly, other organochlorine insecticides, including heptachlor and endosulfan, have been associated with neurotoxicity and with disruption of dopaminergic pathways as the principal focus of attention. Of particular concern is the association with neurodevelopmental deficits in children following in utero exposure to endosulfan. Elevated levels of endosulfan have been found in cord blood and breast milk of pregnant mothers. There is added significance due to epidemiological evidence associating endosulfan exposure with Parkinson’s disease and incidence of autism spectrum disorder. It is abundantly clear from the foregoing review that, although the principal organochlorine insecticides have been banned, persistence in the environment and resistance of deposits in tissues to degradation will continue to impact on human and wildlife well-being for the foreseeable future. This outlook is compounded by emerging evidence of toxicity in pesticides currently recommended for use by farmers. For example, metam sodium, the widely used soil fumigant, has recently been associated with respiratory intoxications among farmers and their neighbours. In 2004, the US EPA designated this pesticide as a ‘probable human carcinogen’. In 2018, regulatory authorities in France imposed a ban on products containing metam sodium, arguing that these pesticides constitute a risk to human health and ecosystems.

4.6  Organophosphate Compounds The history of organophosphates (OPs) is deeply embedded in acute toxicity, associated with their development as chemical weapons in World War II. In 1944, the insecticidal activity of parathion was discovered, subsequently culminating in its use as a pesticide, and marketed on the basis of high efficacy, wide range of action and rapid degradation in the environment. Its high toxicity was perceived as an advantage, not a deterrent, presumably at a time when regulatory authorities were still being established. As a result, the number of registered OPs increased rapidly over subsequent decades, representing nearly 40% of the pesticide market, and used extensively in developing countries where safety precautions are less stringent than those in more affluent economies. In developing and emerging countries, access to these potentially lethal agents is not well regulated and results in poisoning of agricultural workers, manufacturing personnel and children due to inappropriate storage, transport and inadequate provision of personal protective equipment. Consequently, OP exposure may occur mainly via cutaneous absorption or inhalation during preparation and distribution of the insecticide formulation. In normal situations, food may also be contaminated with OPs. Recent cases of OP toxicity include the poisoning of five individuals in Salisbury (England) involving the deployment of Novichok (see Chapter 1), which followed the use of sarin during the civil war in Syria, causing the deaths of over 1000 civilians. OP pesticides are categorized in three major hazard

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classes, according to the WHO classification, including ‘extremely toxic’ (e.g. parathion; Class Ia) to ‘slightly toxic’ (e.g. malathion; Class III). The fate of OPs within an organism is determined by the dynamics of absorption, internal transport, metabolism, bioaccumulation and excretion. OP compounds rapidly distribute within the body compartments and can even cross the blood–brain barrier. Due to their lipophilic properties, OPs accumulate in fatty tissues and in the major organs, including the kidney, liver, lungs and brain. The differentiation of OP pesticides into phosphorothioates (P=S) and phosphates (P=O) confers important toxicokinetic properties. The former compounds are more lipophilic than their respective phosphate/oxon metabolites. For parathion, this results in considerably higher affinity to fat compared with paraoxon, leading to an extensive accumulation of phosphorothioates in fatty depots with prolonged release and repetitive clinical relapses. In addition to lipophilic properties, OP pesticides show a strong binding affinity towards plasma and tissue proteins. OP pesticides are subject to extensive metabolism, modulating toxicity in both directions through bioactivation and detoxification. A significant reaction in bioactivation involves the oxidative desulfuration of phosphorothioates to yield the respective oxon analogues. This pathway requires the intervention of the most important class of xenobiotic-metabolizing enzymes in the form of the cytochrome P450 enzyme family. These monooxygenases catalyse the addition of oxygen with electrons transferred from NADPH, thereby releasing the sulfur atom. Additional metabolizing enzymes include the flavin-containing monooxygenases and paraoxonase. The latter is produced in the liver, attached to high-density lipoproteins; its affinity to OP pesticides varies, with preference for the oxon analogues of parathion and chlorpyrifos. OPs exert their toxic effects by irreversibly binding to the pivotal enzyme, acetylcholine esterase. The failure of this esterase to hydrolyse acetyl choline results in an endogenous overflow at muscarinic and nicotinic synapses in the central nervous system and at the neuromuscular junctions in the peripheral nervous network. Initially, the nicotinic acetylcholine receptors in the sympathetic gangliae are stimulated, resulting in release of catecholamines and subsequent tachycardia and an increase in blood pressure. Thereafter, the muscarinic overstimulation assumes precedence, resulting in parasympathetic signs at the target organs. This process eventually leads to a cholinergic crisis, with hypersecretion of glands (salivation, lacrimation) and smooth muscle contraction (bronchoconstriction, urination, diarrhoea, abdominal cramps and emesis). Finally, cardiovascular aberrations, including bradycardia, arrhythmia and hypotension, become apparent. Overstimulation of the perspiratory glands is mediated via the sympathetic nervous system and often observed in OP intoxication. Nicotinic stimulation results in muscle fasciculations, twitching, cramps and severe muscle dysfunction. Respiratory failure and finally death may occur due to profuse secretions in the respiratory system and paralysis of the diaphragm and intercostal muscles. The onset of symptoms is dependent upon the dose and toxicity of the OP, route of exposure and metabolism within the body. Exposure of mucous membranes via droplets or volatile sources will result in a rapid manifestation of local effects followed by systemic toxicity. Percutaneous uptake delays onset

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of clinical symptoms. Nevertheless, the time interval between initial symptoms and acute respiratory distress might be short, as demonstrated in the Salisbury poisoning incident. First indications of toxicity occur at approximately 50% inhibition of the target enzyme, acetylcholine esterase, but life-threatening symptoms appear after over 80% inhibition of this enzyme. In view of the foregoing evidence, it is particularly noteworthy that in 2020 the largest manufacturer of chlorpyrifos announced discontinuation of production of this pesticide for commercial reasons. However, some earlier studies showed that low to moderate exposure to chlorpyrifos during pregnancy was associated with memory deficits and reduced IQ in children.

4.7 Fungicides The use of fungicides is associated primarily with the cultivation of cereals, vegetables and fruit, mostly in developed countries. The major classes of fungicides include inorganic salts, dithiocarbamates, benzimidazoles, dicarboximides, triazoles, anilinopyrimidines and strobilurines. Sulfur and copper salts are the predominant members of inorganic fungicides. For ecological reasons and also on the basis of efficacy, organic fungicides are the preferred compounds in current use. The site of action of compounds in the latter group varies with the chemical class of fungicides, with some acting by leaf contact and others after systemic transport to appropriate subcellular organelles. At the biochemical level, systemic fungicides act by diverse mechanisms including, for example, inhibition of ergosterol biosynthesis in fungal pathogens; safety is assumed on the basis that this pathway is absent in humans and other animals. One might deduce that fungicides are designed exclusively to act on fungal pathogens, without causing significant risks to human health or to biodiversity in soil and aquatic ecosystems. In part, this notion is supported by LD50 results for rats ranging from 800 to in excess of 15,000 mg kg–1 on oral exposure. However, first-generation fungicides such as hexachlorobenzene and a few organomercurial preparations caused such large-scale poisoning that they were banned by regulatory authorities. Nevertheless, there are now profound concerns regarding the long-term safety of certain fungicides for human health. As with several environmental contaminants, the association with neurodegenerative disorders is the predominant issue, particularly as genetic factors play a relatively minor role in the aetiology of such conditions, with the main focus now turning towards the possible role of environmental modulators. For example, although significant progress has been achieved in the understanding of the pathophysiology of Parkinson’s disease (PD), the factors contributing to the development of this disorder remain elusive. Current evidence implicates a role for α-synuclein, a protein in presynaptic terminals, in the pathogenesis of PD. This protein accumulates as a major constituent of Lewy bodies, the pathological characteristic of PD. Residential and occupational exposure to ziram has been associated with markedly increased risk for the development of PD and for early-onset cases. Furthermore, ziram is toxic to dopaminergic neurons and this effect is α-synuclein-dependent, as determined in bioassays

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with zebrafish embryos. Using the zebrafish model system, it has been demonstrated that azoxystrobin exposure induces hepatic pathology, oxidative stress, lipid peroxidation and genotoxicity, with excess reactive oxygen species (ROS) implicated in the DNA damage. It is, therefore, possible that fungicides in other chemical classes may also be associated with adverse effects in humans and non-target species in general and may interact with other pesticides such as herbicides, as explained below. A major concern among farmers and toxicologists alike is the development of fungicide resistance in plant pathogenic fungi, particularly in those organisms associated with mycotoxin production. In theory, effective use of fungicides against plant diseases such as Fusarium head blight of cereal crops should result in reduced mycotoxin contamination of harvested grain. However, it is generally accepted that fungicide control is only partially effective. In addition, the potential exists for the development of resistance to fungicides by certain phytopathogens which may possibly be linked with stimulation of mycotoxin production. Recent observations with Botrytis, Penicillium and Aspergillus pathogens serve to demonstrate the rising threat of fungicide resistance in plant pathogenic fungi and the risks for enhanced mycotoxin contamination in plant products. Five classes of fungicides have been proposed with respect to efficacy towards phytopathogens and mycotoxin inhibition, including: Class I (effective); Class IIA (partially effective, mycotoxin residues possible); Class IIB (partially effective, direct inhibition of mycotoxin synthesis but disease/infection/fungal growth possible); Class IIIA (ineffective); and Class IIIB (stimulatory and/or inducing fungicide resistance). It should be stressed that the relationship between fungicide resistance and mycotoxin production by phytopathogens remains to be established. Nevertheless, it has been apparent for some considerable time that new fungicides have to be devised on a regular basis and added to the growing mixture of POPs in the environment.

4.8 Herbicides The application of herbicides in intensive agriculture has increased markedly over the past few decades. Herbicides can be classified according to their chemical properties, but more generally on the basis of their selectivity, mode of action and timing of use in the crop production cycle. Of particular relevance here is the use of non-selective herbicides that act on weeds as well as plants used by beneficial insect pollinators such as bees and hoverflies. Two herbicides are of particular toxicological relevance: paraquat (a bipyridyl) and glyphosate (an amino acid derivative). As with other pesticides and strictly on the basis of semantics, we would not expect herbicides to cause adverse effects on human health or biodiversity in different ecosystems. LD50 values (determined with a rat assay) range from 157 to over 10,000 mg kg–1 for herbicides of current interest. It can be argued that since herbicides act on biochemical processes unique to plants (for example, photosynthesis) there should be minimal impacts on human health. However, this supposition is rapidly undergoing revision in view of specific

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developments regarding chronic human exposure to certain herbicides, and particularly in relation to paraquat and, separately, to ongoing legal issues with glyphosate-based herbicides (see Case Study 4.1 below). Exposure to paraquat extends the hypothesis for an environmental dimension in the aetiology of PD. Post-mortem PD brain samples are noted for astrocyte senescence, while cultured human astrocytes exposed to paraquat also become senescent. It is believed that paraquat and other environmental pollutants promote accumulation of senescent cells in the ageing brain which can result in dopaminergic neurodegeneration. In different animal models, regular doses of paraquat can induce several of the pathological characteristics of PD, including loss of dopaminergic neurons in the nigrostriatal dopamine network. Other evidence indicates the increased incidence of PD in rural communities exposed to farm applications of paraquat and among workers using the herbicide without adequate protection. Wide-ranging mechanisms exist to explain the development of paraquat-induced PD, including: • oxidative stress and inhibition of mitochondrial complex I enzyme activity; • activation of nitric oxide synthesis in the brain, forming the toxic peroxynitrite anion on reacting with oxygen; • activation of microglial NADPH oxidase with alteration of energy metabolism; • damage to the endothelial cells in the blood-brain barrier, following oxidative stress induction, allowing transport of paraquat into the brain; • increased glutamate-mediated excitotoxicity in the brain; promotion of dopamine catabolism via an oxidative pathway; • induction of α-synuclein aggregation; and • inactivation of rate-limiting enzyme synthesis of dopamine. Of greater concern are the synergistic effects associated with combinations of paraquat and other common pesticides, which in animal models replicate the full spectrum of clinical manifestations observed in PD patients. For example, paraquat with the fungicide maneb reduces dopamine synthesis and affects dopaminergic neurons as well as motor functions. Synergism is also evident among individuals living in close proximity to fields treated with this combination and, furthermore, risks for children are even greater than for adults. Although paraquat has been banned in the EU, it is permissible under restrictions in USA and extensively used in developing countries, thus the risks for the incidence of neurodegenerative disorders remain for the future. Other neurodegenerative disorders, particularly Alzheimer’s disease (AD) should also be considered in a multicomponent context, implicating paraquat and several insecticides operating additively or synergistically. AD is a common progressive neurological condition characterized clinically as loss of neurons and associated functions. Although evidence for the aetiology of AD remains elusive, it is generally agreed that the major risk factors include age, genetics and environmental contaminants, particularly pesticide exposure. Epidemiological data imply higher incidence of AD in rural locations compared with urban areas. Results from in vitro and animal models indicate that chronic low-dose pesticide exposure can cause neuronal loss in specific brain regions, eventually resulting in diagnostic features, including cognitive

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­ eficiency, d d ­ ecreased memory and attention and loss of motor functions. Most insecticides are designed to operate as neurotoxins against target invertebrate pests, so it is logical to implicate these compounds in the development of PD, AD and other disorders of the central nervous system in humans. The supposed involvement of paraquat in neurodegenerative disease adds another dimension to pesticide toxicology. However, it should be noted that the adverse effects of several pesticides are mediated through shared pathways, including the induction of oxidative stress, mitochondrial dysfunction and neuronal deficits. Glyphosate is the active ingredient in the pervasive herbicide, Roundup®. The global reach of this herbicide is undeniable, with usage rate increasing exponentially over the past two decades. Glyphosate is an analogue of the ubiquitous amino acid, glycine. It has been assumed that glyphosate would be relatively non-toxic to humans as its main action in weeds involves blockage in the shikimate pathway, which is essential for plant survival and growth but absent in humans and other vertebrates. However, glyphosate is associated with disruption of the balance of gut microbes, favouring proliferation of pathogenic microorganisms, thus potentially resulting in inflammatory bowel disease and leaky gut syndrome. At the metabolic level, it is also possible that glyphosate might excite certain receptors in neurons, potentially leading to neurotoxicity. In animal models, glyphosate is actively taken up by l-type amino acid transporters and translocated directly into the brain following intranasal administration. Under such conditions, animals exhibit neurological impairment, including memory deficits, increased anxiety and motor dysfunction. It has been tentatively suggested that the adverse effects of glyphosate may reside in its structural analogy with glycine. Structural antagonisms are well characterized, particularly in relation to amino acids, for example in interactions between canavanine and arginine, β-amino-l-alanine and serine, lysine and arginine and leucine, isoleucine and valine. Consistent with the canavanine– arginine and β-amino-l-alanine–serine antagonisms, it has therefore been proposed that glyphosate may erroneously be incorporated into tissue proteins during protein biosynthesis, in place of the coding amino acid, glycine, creating anomalous compounds and structural macromolecules. Although it may be argued that the resulting aberrant proteins will be degraded rapidly, with consequences merely in increased protein turnover, there is, nevertheless, the possibility of adverse effects. For example, β-amino-l-alanine, occurring naturally in false sago palm, has been linked with neurological damage, characterized as amyotrophic lateral sclerosis, or Guam dementia. It is implied that misincorporation of β-amino-l-alanine in place of serine leads to bioaccumulation within aberrant proteins which break down slowly, releasing the former amino acid as a neurotoxin and contributing to Guam dementia in individuals using the palm as a food resource. It has been proposed that aberrant proteins containing glyphosate may be recognized as foreign molecules by body defence systems, instigating an adverse immune response. The concept that immunocompetence might be compromised by pesticide exposure is widely recognized to occur via a myriad of mechanisms, including, for example, through perturbations in cytokine status. It is known that glycine substitutions can cause major defects in the way a protein folds, inducing transformation of

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structural proteins into a soluble form that remains in the cytoplasm. There is speculation, but no definitive proof, that corruption of certain specific proteins may account for a variety of human disorders that have increased in incidence with the rise in use of glyphosate. Questions are being addressed about the implications of developmental exposure to glyphosate and the association with depressive-like behaviour, glutamate excitotoxicity and oxidative stress, following results with experimental models. Other investigators claim that the autism epidemic in the USA initiated by acetaminophen is aggravated by oral antibiotic amoxicillin/ clavulanate and exponentially by glyphosate. Another hypothesis is based on the concept that environmental glyphosate levels may adversely modulate the gut–brain axis by stimulating the proliferation of Clostridium bacteria in autistic children. It is established that this herbicide is capable of altering the balance of microflora in the gut. In addition, it should be noted that glyphosate was classified as ‘probably carcinogenic to humans’ by IARC in 2015, a feature that has emerged under further scrutiny in the US courts (see Case Study 4.1 below). A ‘statement of concern’ has been issued by a group of experts to the effect that human exposure to glyphosate-based herbicides is rising worldwide and that regulatory estimates of tolerable daily intakes in the USA and EU are based on outdated evidence, while reiterating the IARC classification on carcinogenicity and emphasizing widespread contamination of drinking water, precipitation and air, particularly in agricultural regions. It was also noted that glyphosate-based herbicides were more toxic than glyphosate alone to non-­ target species, including mammals. These experts recommended, on the basis of animal and epidemiology studies, that there is a need for a further consideration of glyphosate safety.

4.9  POPs Associated with Endocrine Disruption Human health and reproduction are critically dependent on a functional endocrine system. Hormones are secreted from glands/organs and transported in the bloodstream to act as chemical messengers at distant target sites in order to coordinate and regulate physiological processes. It has long been known that certain plants and fungi naturally synthesize oestrogenic compounds with the ability to disrupt normal endocrine function. More recently, a number of POPs have been consistently linked with endocrine disruption in humans and other animals, particularly as a result of chronic exposure. The site of such activity varies according to the nature of the pollutant, age at exposure and sex of the individual, with effects even discernible at the population level. Endocrinedisrupting chemicals include: • PCBs; • dioxins; • pesticides; • flame retardants; • components of plastics;

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Case Study 4.1.  Can GBHs inflict gross bodily harm? Glyphosate-based herbicides (GBHs) are currently among the world’s most used formulations on the planet – a dubious achievement according to some observers. It has been postulated that the significant increase in the incidence of debilitating disorders such as autism, diabetes, inflammatory bowel disease and coeliac disease may be correlated with the exponential rise in global usage of GBHs. However, statistical associations and other quantitative methods, as sophisticated as they are and while serving as useful markers, must be validated by sound scientific evidence based on elucidation of the underlying biological mechanisms. GBHs were brought into sharp focus in 2018 when the company Monsanto was ordered to pay substantial damages at the conclusion of a glyphosate cancer trial in the USA. This award was in connection with an operative who reportedly developed non-Hodgkin’s lymphoma following regular exposure to a GBH formulation. According to online sources, many other individuals are expected to pursue the manufacturer and secure redress through the US courts. It is the duty of toxicologists to actively enquire why the US Environmental Protection Agency (EPA) sanctioned the use of this herbicide, given its classification in 2015 as ‘probably carcinogenic to humans’ by a World Health Organization (WHO) agency. This advice was revised in 2016 by a joint WHO/Food and Agriculture Organization (FAO) statement to the effect that there were no cancer risks associated with glyphosate residues in food. However, this declaration ignores other routes of exposure to GBHs. Future assessments of carcinogenic potential must also consider recent observations pointing to greater relative toxicity of GBH formulations compared with glyphosate alone for a number of end-points tested. The carcinogenic potential of the principal metabolite of the herbicide must also be considered. In addition, it is crucial that environmental protection agencies around the world adopt a ‘without fear or favour’ policy in determining the safety of this and other contaminants that may impact upon human health or habitat biodiversity. The ongoing safety questions prompted a respected group of experts to issue a ‘statement of concern’ regarding GBHs taking into account contamination of drinking water, precipitation and air (particularly in rural environments), the previously underestimated half-life of glyphosate in water and soil, presence in global soyabean resources, increasing human exposure (and wildlife too?), questionable estimates of tolerable daily intakes and the potential role as endocrine disruptors. The ecological impact of GBHs was also raised in that statement. In addition, recent observations question the potential impact on neuropathology during developmental exposure to GBHs. In summary, the question raised at the beginning of this case study cannot be definitively answered until further systematic studies have been conducted; so watch this space in future editions! • What is your opinion about the safety evaluation procedures for pesticides and how can these be more effective? • Can you recall the different routes of exposure to pollutants in living organisms?

• surfactants; • stain-resistance coatings; and • personal care products such as antimicrobials, antiperspirants, UV filters and fragrance compounds.

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The extent to which these compounds are retained in tissues and organs depends on the efficacy of detoxification mechanisms involving cytochrome P450 enzymes and the conjugation pathways. Some compounds such as the phytoestrogens, ubiquitous in higher plants and therefore consumed in relatively large quantities, are removed from the body within hours. Others, particularly POPs, which are usually taken into the body as a result of chronic low-level exposure, may accumulate in body fat and be deposited there for many years. However, POPs stored in body reserves may be recirculated during times of food shortages or during lactation. The US National Health and Nutrition Examination Survey has confirmed that the human population carries a significant burden of chemicals, including PCBs, DDT, PBDEs, phthalates, bisphenol A, personal care compounds and antimicrobials, with some existing as co-contaminants in the same individual. The mechanisms underlying adverse effects reflect the chemical diversity of the endocrine disruptors. Current hypotheses include: alteration of hormone biosynthesis in the endocrine gland by modulating the activity of key enzymes; alteration of hormone transport to the target site, by interfering with conjugation enzymes or with binding to carrier proteins; and altering receptor levels, activity and signalling pathways in the target cells. Many endocrine disruptors act by a common mechanism, which implies additive effects in mixtures of these compounds. Metabolism of some endocrine disruptors can affect their activity: for example, certain metabolites of DDT are associated with greater oestrogenic activity than the parent compound. The potency of some PCB congeners has been attributed to conversion to more reactive intermediates through hydroxylation or other processes. Conversely, endogenous metabolism may serve to reduce the endocrine-disrupting properties of some foreign compounds. Endogenous hormones are ultimately responsible not only for regulating major physiological processes in growth, development and reproduction but also for maintenance of all the organs and tissues of the body and for enabling adaptations to environmental pressures. Consequently, endocrine disruptors exert wide-ranging deleterious effects on human health. Much of the disruption is, therefore, directed towards the action of oestrogens and androgens as regulators of reproductive functions. In addition, endocrine disruptors also affect thyroid function, with profound implications for metabolic regulation in all organs and tissues as well as for energy metabolism. Furthermore, immunocompetence may be compromised during such exposures. The strongest evidence for adverse effects on female reproduction following exposure to an endocrine disruptor has emerged from examination of the impact on women prescribed diethylstilboestrol to prevent miscarriage during the first trimester of pregnancy during the period 1940–1971. Daughters born to these women developed a rare vaginal cancer attributed to in utero exposure to this synthetic non-steroidal oestrogen. Further prescription ceased, but subsequent observations of these daughters indicated the development of numerous adverse reproductive health outcomes. Animal studies have confirmed that diethylstilboestrol causes tumours in oestrogen-responsive tissues. Puberty is the stage during late childhood when secondary sexual characteristics emerge and reproductive capacity is attained. These changes are endocrine-regulated and thus vulnerable to the effects of endocrine disruptors. Chemicals implicated

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i­ nclude oestrogenic components of personal care products contributing to early development of puberty. It is generally acknowledged that puberty is occurring at an earlier age in girls today, particularly in the western world, and environmental contaminants such as POPs may be contributing to this phenomenon. Other evidence indicates that ziram can disrupt Leydig cell development during puberty, possibly by down-regulation of the steroidogenic factor 1. The ovary is another critical organ as it not only produces steroid hormones but is also affected by xenobiotic endocrine-disrupting chemicals, for example parabens, methoxychlor and bisphenol A. Defects include anovulation, infertility, oestrogen deficiency, premature ovarian failure and ovarian cyst development, with some of these effects reproducible in animal models. The uterus is a major hormone-sensitive organ and endocrine-disrupting compounds have been implicated in a number of benign disorders such as uterine fibroids and endometriosis. Elevated levels of some PCB congeners have been found in the abdominal fat of women with fibroids. Although there are genetic determinants, incidence of endometriosis may be linked to organochlorine pollutants, while data obtained with animal models implicate PCBs, dioxins, dibenzofurans and bisphenol A in the aetiology of this condition. An important focal point for the action of POPs as endocrine disruptors is the mammalian placenta, responsible for the production of progesterone and oestradiol for the maintenance of pregnancy. The enzyme responsible for the synthesis of oestradiol known as aromatase is inhibited by the fungicide ziram which combines with its steroid-binding site, thereby reducing production of oestradiol. The mammary gland is also a potential site for the activity of endocrine disruptors as its development is under hormonal control. Benign breast abnormalities such as cysts and fibroadenomas have been attributed to endocrine disruptors present in underarm personal care products. Male reproductive development is regulated by hormonal activity and is, therefore, affected by endocrine disruptors at all stages from the early embryo to adulthood. The androgen-to-oestrogen ratio is pivotal in male sexual development, which implies that endocrine disruptors with oestrogenic or anti-­ androgenic activities are particularly critical. Animal and human epidemiological studies have implicated several contaminants, including PCBs, dioxins and some pesticides, in modulating the timing of onset and attainment of pubertal milestones. Increasing incidence of urinogenital malformations, abnormalities in spermatogenesis and testicular cancer, particularly in westernized cultures, indicates that environmental rather than genetic factors are the predisposing conditions and that the role of POPs should be considered. Epidemiological observations show that living near hazardous waste landfill sites or in close proximity to intensive farms where pesticides are used may predispose to malformations of the urinogenital system. An emerging feature is the consistent roles of fungicides as endocrine disruptors and teratogenic effects in animal models. For example, azoxystrobin has been linked with reproductive toxicity in a zebrafish bioassay, with males being more sensitive than females. Manifestations included reduce egg production and fertility, with alterations in sex steroid production and gonadal pathology. In addition, azoxy­ strobin adversely affects the genes involved in the endocrine system of zebra­ fish embryos, particularly after parental exposure to the fungicide.

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Thyroid functions may also be affected by endocrine disruptors, taking into account the rising incidence of goitre even in regions where there is no natural deficiency of iodine, a critical component of thyroxine and triiodothyronine. There is evidence that exposures to PCBs, phthalates, brominated flame retardants and perfluorinated chemicals are associated with thyroid-disrupting effects. Recent observations consistently point to effects of gaseous pollutants on insulin resistance mechanisms, with adverse implications for blood pressure, while exposure to fine particulates is linked with vascular insulin resistance by inducing pulmonary oxidative stress. Similarly, air pollution may activate the hypothalamic–pituitary–adrenal and sympathetic–adrenal–medullary axes, culminating in the release of stress hormones from the adrenal gland into the peripheral blood circulation to instigate compensatory physiological mechanisms. Noise pollution, as an environmental stressor, is also associated with increased circulating levels of stress hormones and endothelial dysfunction. With regard to POPs, prenatal exposure to the pesticide, lindane, may predispose girls to subsequent development of metabolic syndromes by affecting insulin status. Separately, it has been established that lindane may impart insulin resistance in muscles by impairing hormonal signalling. It is therefore clear that environmental contaminants in general, and POPs in particular, are consistently associated with endocrine-disrupting effects and that there is sufficient evidence to warrant action to safeguard human health and reproductive capacity.

4.10  Assessment and Management of Risk Risk assessment is an estimate of the likelihood of harmful effects on the health of a population as a result of exposure to a compound with potential or established toxicity. This process is also employed to estimate potential or real harm to different ecosystems. The approach for POPs in general is exemplified by risk data for dioxins. In general risk assessment of dioxins and dioxin-like compounds, protocols based on toxicity equivalency factors (TEFs) have been developed to establish some uniformity of expression of toxic potential. TEFs are based on acute toxicity values obtained in laboratory bioassays. The theory assumes that there is a common receptor-mediated mechanism underlying the toxicity of these compounds. Although the scientific basis of this system cannot be fully justified, the TEF approach has been widely used in risk assessment by international agencies. TEFs assess the relative potency of various polyhalogenated aromatic hydrocarbons against that of 2,3,7,8-TCDD, the most toxic of all congeners in this group. TEFs can be established by any in vivo or in vitro test, but the relative rankings within or between assays are affected by factors such as species, pharmacokinetics and exposure duration. It should be emphasized that TEFs are only estimates of the toxicity of the different congeners. The universal adoption of the TEF system has been attributed to the observation that values based on receptor-mediated responses are additive. However, there are major limitations of this system arising from non-additive interactions involving mixtures of dioxin-like and non-dioxin-like congeners, species differences and

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discrepancies in the shapes of dose–response curves among receptor agonists. Different international expert agencies have established health risk assessment of dioxins and related compounds. A Nordic group proposed a tolerable daily intake (TDI) for 2,3,7,8-TCDD and structurally similar chlorinated PCDDs and PCDFs of 5 pg kg–1 body weight, based on evidence for cancer, reproduction and immunotoxicity. A WHO group of experts proposed a TDI of 10 pg kg–1 body weight for 2,3,7,8-TCDD, based on liver toxicity, reproductive effects and compromised immune function. With organophosphate poisoning, identification of early markers or physiological changes prior to the onset of toxic symptoms to promptly detect and treat cases of OP poisoning before overt clinical manifestations appear is essential for individual and public safety. For both clinical and on-site applications, testing of blood samples for acetylcholinesterase and butyrylcholinesterase activities is recommended to support clinical diagnosis, to provide evidence of atypical symptoms, to exclude exposure to OP pesticides or nerve agents and finally to optimize implementation of appropriate treatment procedures. This indirect detection of OP exposure is markedly more rapid than direct determination of free OP, its blood metabolites or the phosphyl–protein complexes, which are more suitable for forensic verification of exposure. Human acetylcholinesterase is expressed not only in the neural system but also on the membranes of erythrocytes; however, the kinetic properties of both types are comparable, indicating that erythrocyte acetylcholinesterase is a reliable surrogate parameter for its neural counterpart. The protocol used in OP pesticide poisoning cases (and probably with the Salisbury casualties) comprises the administration of three groups of drugs, including: the competitive muscarinic receptor antagonist, atropine; an oxime to reactivate the inhibited acetylcholinesterase; and a benzodiazepine to reduce neural damage. Although the neurotoxic effects of high-dose OP poisoning are well established, the impact on neurobehavioural functioning following low-level chronic exposure is worthy of attention. Cognitive functions such as memory, attention and psychomotor speed appear to be particularly vulnerable to the effects of OPs. Individuals with a history of low-level exposure, for example farmworkers or residents near arable farms, may be at increased risk of developing a mental health condition, particularly anxiety. However, this aspect of chronic toxicity is still under investigation to obtain additional evidence on issues such as dose–response relationships, time-course development of neuro­ behavioural problems and profile of cognitive and emotional sequelae. There is also a need to review evidence according to the populations under study, countries of origin and age of individuals.

4.11  Ecotoxicity of POPs, Biomagnification and Collateral Damage The particular chemical nature of POPs implies that profound detrimental effects of these compounds as individual or multiple contaminants are inevitable in a wide array of ecosystems. The prospect of biomagnification of these compounds underlines the gravity of current concerns, particularly for the

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well-being and survival of endangered marine predators. An additional issue is the exposure of these animals to multiple contaminants with individual and, possibly, synergistic toxicities. Biomagnification is a major toxicological process, with respect to PCBs and particular recalcitrant pesticides such as organochlorines. The aquatic/ marine ecosystem provides the ideal conditions for this accumulation whereby a particular contaminant proceeds successively up the trophic chain from prey to predator. Consequently seals, killer whales, polar bears (see Case Study 4.2 below) and crocodiles become severely contaminated, thereby compromising growth, reproductive capacity and survival of the most vulnerable species. The risks are even greater with the bioaccumulation of two or more legacy POPs, for example PCBs and organochlorine insecticides.

Case Study 4.2.  Polar bears in peril at top of the POPs Polar bears (Fig. 4.2) have existed, and indeed thrived, at the top of the Arctic trophic hierarchy, relying almost exclusively on a diet of fatty ringed seals for vital nutrients. However, wild prey animals also provide polar bears with harmful and potentially dangerous levels of POPs such as PCBs and pesticides that bioaccumulate in sequential steps in the food chain. For example, the fatty tissues of seals are known to be burdened with a wide range of POPs and other potentially harmful contaminants. It has been estimated that concentrations of pollutants may multiply at a rate of 5–10 times with each step in the trophic pathway. The relatively high concentrations of contaminants in polar bears have been attributed to pollution from Europe, North America and Asia. Consequently, top feeders such as polar bears and killer whales are at particular risk of developing a diverse array of toxicological syndromes that threaten the very survival of these and other predators. At Svalbard (Norway), for example, concentrations of PCBs in polar bears were classified as extremely elevated, with higher chlorinated congeners accumulating according to age, especially in males (Sporndly-Nees et al., 2019). In females, considerable quantities of organochlorine contaminants were transferred in the milk to offspring, a recurring observation for several other potentially toxic pollutants in predators. Regarding polychlorinated dioxins and furans, it is established that concentrations in ringed seals and polar bears are higher in East and Central Arctic than in more southerly marine ecosystems. The capacity to metabolize and detoxify ingested contaminants is under investigation but it is worth noting that skull size and bone density may be affected by exposure to POPs. A compounding factor is the emergence of new threats such as perfluoroalkyl compounds with the potential to precipitate cumulative and combined effects in polar bears including disruption of endocrine function and reproductive capacity. Biomagnification of polybrominated diphenyl ether and hexabromocyclododecane flame retardants has been confirmed in the polar bear food chain in Norway. Additional interactions may occur with increasing contamination of the food chain with mercury, a heavy metal tentatively associated with neurochemical, hepatic and renal dysfunction in polar bears. Whether these contaminants act independently or synergistically with POPs has yet to be ascertained. • Do marine predators have in-built mechanisms to detoxify POPs? • Why are different POPs so different in their environmental impact on marine animals?

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Fig. 4.2.  The polar bear and other marine and freshwater predators are at severe risk of extinction due to contamination of prey animals with a diverse range of organic and inorganic pollutants. Tissue and interorgan turnover add another dimension to the adverse effects of certain of these contaminants which may also serve as endocrine disruptors. (Image ‘I’m Not A Bad Looking Bear After All’ by Christopher Michel is licensed under CC BY 2.0.)

Although OP pesticides are assumed to be less persistent than the preceding organochlorine insecticides, stability in different ecosystems can still be a hazard. There is a broad spectrum of persistence of OP pesticides in nature, depending on chemical structure, physicochemical behaviour and microbial degradation, extending from a few days to several weeks, particularly in cold and slightly acidic soil conditions. Consequently, OP residues in soil and aquatic ecosystems present risks to wildlife. In the case of fungicides, extensive use of azoxystrobin, through its action as an endocrine disruptor and potential mutagen (in model zebrafish embryo systems), may induce adverse effects on diverse aquatic organisms. The herbicide, paraquat, has been demonstrated to be a high risk to aquatic organisms and recent data indicate adverse effects in fish, including hepatotoxicity through inhibition of antioxidant enzyme activity, increased lipid peroxidation, promotion of immune inflammatory responses and induction of apoptosis. Oxidative stress is a persistent risk, affecting many fitness-related traits in different ecological species. It has been proposed that exposure to paraquat, a pro-oxidant, may exert significant effects on resistance of birds and other species, for example earthworms, to oxidative stress at different stages in the life cycle. Chronic exposures to pesticides in current use, including the neonicotinoids, are also associated with adverse effects on beneficial insect species (Raymann et al., 2018). For example, neonicotinoids can alter the interaction

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Fig. 4.3.  Hover flies and other insects serve as major pollinators of food crops and add to the biodiversity of different ecosystems. However, a number of these invertebrate species have disappeared altogether, while others are declining in numbers. Habitat changes as well as the excessive and indiscriminate use of pesticides have been implicated in this decline. (Image ‘Hover-fly on flower’ by Thermaling Girl is licensed under CC BY 2.0.)

between bumble-bees and wild plants, while herbicides may damage the floral diversity available to these important insect pollinators, which are already in serious decline. These insects, together with hoverflies (Fig. 4.3), are essential for the production of world crops and for maintaining ecological balance. The detrimental impacts of neonicotinoids at field-realistic levels include disruption of reproduction, cognition, memory, foraging behaviour and navigation abilities of bumble-bees. In addition, neonicotinoids and pathogens may combine to increase mortality across the life cycle of these insects. Recent reports highlighted the severe risks of fipronil for honey bees, with work at the University of Wageningen demonstrating detrimental effects for reproduction in butterflies treated with this pesticide. Glyphosate exposure in bees is also associated with adverse effects, more specifically by perturbations of the beneficial gut microbes, potentially affecting bee health and their effectiveness as pollinators. Glyphosate exposure can also adversely affect spermatozoa and larval development in insects, as observed with honey bees.

4.12  Key Issues POPs exert diverse effects on human health and on survival of a wide range of wildlife species. In humans, effects range from reproductive dysfunction to neurological disorders and cancer. Of particular concern is the neurotoxicity, carcinogenicity and legacy issues associated with pesticides approved for agricultural use. Currently, there is considerable disquiet over the use and safety of metam sodium, chlorpyrifos, fipronil and glyphosate. Endocrine disruption is

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now recognized as a common underlying expression of the activity of ­several POPs. VOCs may contribute to the carcinogenic potential of traffic-related air pollutants. The concept of biomagnification is validated for a number of POPs and other environmental contaminants. Destruction of natural habitats and direct toxicity of pesticides are major factors driving populations of insect pollinators to the verge of extinction. Meanwhile, emerging evidence raises concerns over the environmental distribution and toxicity of perfluorooctanoic acid and flame retardants used widely for domestic and industrial purposes.

4.13 References Ewa, B. and Danuta, M.-S. (2017) Polycyclic aromatic hydrocarbons and PAH-related DNA adducts. Journal of Applied Genetics 58, 321–330. Raymann, K., Motta, E.V.S., Girard, C., Riddington, I.M., Dinser, J.A. and Moran, N.A. (2018) Imidacloprid decreases honey bee survival but does not affect the gut microbiome. Applied and Environmental Microbiology 84(13), e00545–18. doi: 10.1138/AEM.00545-18. Sethi, S. and Lein, P.J. (2019) The developmental neurotoxicity of polychlorinated biphenyls: a continuing environmental health concern. In: D’Mello, J.P.F. (ed.) A Handbook of Environmental Toxicology: Human Disorders and Ecotoxicity. CAB International, Wallingford, UK, pp. 156–172. Sporndly-Nees, E., Holm, L., van Beest, F.M., Ekstedt, E., Letcher, R., Desforges, J.-P., Dutz, R. and Sonne, C. (2019) Age and seasonal variation in testis and baculum morphology in East Greenland polar bears (Ursus maritimus) in relation to high concentrations of persistent organic pollutants. Environmental Research 173, 246–254. Tsygankov, V.Y., Gumovskeya, A.H., Koval, I.P. and Boyarova, M.D. (2019) Bioaccumulation of POPs in human breast milk from south of the Russian Far East and exposure risk to breastfed infants. Environmental Science and Pollution Research 27(6), 5951–5957. doi: 10.1007/s11356-019-07394-y. Tuomisto, J. and Viluksela, M. (2020) Dioxins III. Human exposure and health risks. In: D’Mello, J.P.F (ed.) A Handbook of Environmental Toxicology: Human Disorders and Ecotoxicology. CAB International, Wallingford, UK, pp. 187–205.

4.14 Exercises (i)  Numerous environmental contaminants cited in this chapter are referred to as ‘forever chemicals’ in the popular press. Explain what is meant by this term, giving examples. (ii)  Explain why the mammalian toxicity of herbicides was an unexpected ­observation. (iii)  Is the development of ‘herbicide-ready’ crop plants a wise strategy? (iv)  Comment on the carcinogenic potential of POPs. (v)  Discuss the different ways in which the brain might be affected by POPs. (vi)  Evaluate the health issues associated with POPs for mothers and their offspring during pregnancy and lactation. Use the paper by Tsygankov et al. (2019) for part of your risk assessment.

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5



Fossil Fuel Pollutants

5.1 Overview The extraction and transport of crude oil and shale gas and the combustion of coal are associated with severe pollution risks affecting human health, habitat ecology and biodiversity (Table 5.1). The effects are clear not only in the aftermath of petroleum spills in marine ecosystems but also in the routine combustion of fuel for power generation and domestic heating. The impact of urban ambient air pollution caused by fuel combustion in vehicles, and by implication in power generation and domestic systems, is presented in Chapter 3. The risks associated with fuel pollutants detailed below are based on specific case studies relating to accidental discharge events recorded following the Torrey Canyon oil spill in 1967. However, data derived from historical incidents should be carefully considered and recorded by all personnel concerned with risk assessment and clean-up in view of continuing worldwide fossil fuel pollution. For example, it has recently been estimated that 240,000 barrels of crude oil are discharged into the River Niger delta each year. In the UK, the Oil and Gas consortium indicated in 2019 that much more work is still required to curb hydrocarbon pollution in British coastal waters. Additional environmental risks are also associated with shale oil and gas extraction as well as coal utilization. The aims in this chapter are to: • highlight pollution incidents associated with extraction, transport and storage of fossil fuels, including wastewater and effluent discharges; • relate such episodes to chemical composition of different fuels; • outline routes of exposure of fuel contaminants; • discuss human health implications in communities affected by fuel pollution; • evaluate ecological biodiversity following pollution incidents; • review recovery of affected species; and • assess risk management strategies in the energy industries. 70.

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Table 5.1.  Fossil fuel pollutants as risk factors for human health and wildlife. Evidence derived from oil spills and associated discharges, following the Deepwater Horizon oil spill in the Gulf of Mexico and the fracking groundwater contamination incident in Pennsylvania (USA). Fuel

Outcomes

Crude oil

Volatile organic compounds in blood of residents, following oil spill, with persistence of single-ring aromatic compounds; immunocompetence and inflammatory responses compromised. Adverse mental health effects; adverse physical, physiological and biochemical effects in marine animals; variable recovery of wildlife species following Exxon Valdez contamination Wastewater risks from organic, inorganic and radioactive compounds; drinking water and aquatic ecosystems at risk in accidental discharges; health and psychosocial effects for residents living near fracking sites Combustion associated with release of sulfur dioxide, polycyclic aromatic hydrocarbons and particulates; respiratory disorders; heavy metals and radioactivity in coal ash storage sites

Shale oil and gas

Coal

5.2  Crude Oil Crude oil is a heterogeneous chemical mixture, with some of the components presenting potentially severe risks to human health and wildlife survival. The hazardous components include aliphatic, cyclic and aromatic hydrocarbons that are associated with adverse human health and ecological risk outcomes. One class of chemicals of considerable concern includes volatile organic compounds (VOCs), particularly benzene, toluene, ethylbenzene and xylene. The toxicology of crude oil is based on the considerable amount of evidence secured in the periods following major accidental spills around the world; at least seven have been recorded scientifically since 1967. Of these, the Deepwater Horizon platform explosion in 2010 (Fig. 5.1) and accompanying contamination in the Gulf of Mexico represented the largest marine oil spill in history. This event led to 11 fatalities and 17 critical injuries in the crew at the drilling platform. VOCs are associated with significant vapour pressure characteristics and represent airborne inhalation hazards for humans and other species. Due to the distance of the well from the coastline and the environmental conditions prevailing after the accident, the chemical characteristics of the crude oil that reached the shorelines differed in composition from that discharged at the drilling platform. The change in composition reflects the weathering process caused by exposure of the oil to sunlight and ambient temperature. Weathering tends to reduce levels of VOCs due to loss to the atmosphere and the overall changes affect the toxicological properties of the two types of oil. Another class of potentially harmful chemicals associated with the Deepwater Horizon oil spill was PAHs, some of which are established carcinogens (Chapter 4). Due to lower vapour pressure characteristics, PAHs are unlikely to represent inhalation hazards. It should be noted that the dispersants

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Fig. 5.1.  The Deepwater Horizon explosion in 2010 and accompanying crude oil spill in the Gulf of Mexico are destined to serve as iconic beacons of pollution and ecotoxicity, resonating long into the future. Global risks continue in several aspects, driven by the unremitting demand for fuel in transport, power generation and other industrial activities. For example, residents in the vicinity of a petrochemical complex in Mossmorran (Scotland) have objected to pollution from multiple sources, including noise, vibration, light, particulates and benzene, following routine flaring of waste gases. More significantly, higher cancer risks in a Louisiana (USA) town have been associated with proximity to petrochemical plants and refineries. (Image ‘Deepwater Horizon Fire’ by EPI2oh is licensed under CC BY-ND 2.0.)

used in clean-up operations following crude oil spills are also associated with detrimental properties towards humans and marine organisms alike. Risk assessments focused on three primary routes of exposure and were of concern for clean-up personnel and affected communities in the vicinity of the oil spill. Firstly, inhalation exposures were of concern, particularly for clean-up workers. This group was mostly exposed to recently discharged or superficially weathered oil which still retained a significant VOC emission potential. In contrast, coastal communities were less affected by this inhalation route as the oil had weathered significantly before it reached the shore. The second route, particularly for clean-up personnel, was dermal exposure, but the third primary route of concern was consumption of contaminated seafood. Extensive air monitoring was conducted to assess exposure potential in clean-up workers. VOC risks for clean-up workers were assessed and evaluated using a threshold-based approach where ‘occupational exposure limits’ and

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‘permissible exposure limits’ were employed as benchmarks. None of the air sampling data exceeded these limits. Additional analysis of air monitoring data collected by the oil company indicated that the greatest contributor to contamination related to diesel exhaust emissions from ships involved in the clean-up operations. The self-reported symptoms surveys conducted as part of the formal health hazard evaluation scheme identified headache, respiratory irritation and nausea as common ailments among response workers, but the signs of dehydration and heat exhaustion tended to confound interpretation of data, given the low ambient levels of VOCs at the time of exposure. Other evidence obtained in monitoring of coastguard personnel deployed in the clean-up operation indicated correlations between crude oil exposure and increased self-reported incidence of adverse respiratory symptoms, but reconciling these effects with the air sampling audit is proving problematic. Exposure of clean-up personnel and coastal communities to the crude oil spill in the Gulf of Mexico is naturally a cause for concern with respect not only to toxicology but also to the economic impact. The detection of specific VOCs in the blood in these residents implies contamination associated with oil spill, but is inconsistent with data showing low levels of VOCs in the weathered oil reaching the coast. Nevertheless, the concept of ‘petroleum hydrocarbon poisoning’ has been advanced to account for some of the adverse effects. Blood samples taken 5–19 months after the spill was capped indicated persistence of single-ring aromatic contaminants compared with alkanes, which may contribute to the symptoms reported by clean-up personnel and coastal residents. Furthermore, credence should be given to other observations with residents in Southern Louisiana, indicating that crude oil exposure was significantly associated with a range of physical health and behavioural conditions. Strongest correlations included burning sensations in nose, throat or lungs, dizziness and wheezing. Some of these physical health symptoms among coastal residents may also be related to the effects of the economic burden associated with the accident. These might be a result of increased stress levels post-accident which in turn may be linked to a range of ill-health manifestations, including headaches, abdominal discomfort and fatigue. In addition, systemic processes such as immune and inflammatory responses may be compromised, thereby increasing the vulnerability of oil-exposed residents to allergies and respiratory disorders. Furthermore, a number of the observations are consistent with the effects of the Exxon Valdez oil spill, including adverse mental health outcomes, particularly stress, anxiety and depression. Risk assessment in the Gulf of Mexico oil spill also focused on issues related to contamination of seafood. Regulatory decisions relating to closure and re-opening of fishing operations were coordinated by the US Food and Drug Administration and the National Oceanographic and Atmospheric Administration. In the reopening of fisheries, two chemical hazard protocols were adopted, one based on sensory evaluation and the other on PAH contamination of the edible portions of seafood. No seafood samples contained PAHs in excess of the ‘level of concern’ values for either cancer or other health risks. Crude oil pollution from the Deepwater Horizon explosion provoked immediate and long-term concerns for marine biodiversity (Lauritsen et al., 2017)

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as well as sensitive coastal habitats in the Gulf of Mexico. A considerable length of marsh shorelines was affected by the accident, causing near-complete destruction of dominant species and therefore exposing the coastline to wave erosion. For example, populations of marsh periwinkles were suppressed in heavily oiled vegetation for over 5 years, with ongoing impacts and incomplete recovery. The temporal and spatial extent of oiling are likely to affect other compartments of the local ecosystem, including marsh productivity, organic matter and nutrient turnover, marsh-estuarine food webs and well-being of associated predators. In assessments of sediment toxicity following this accident, a triad approach involving determination of chemical contaminants, in situ biological effects and macrofauna community structure indicated adverse effects as far as 25 km from the spill site. There were direct correlations between the presence of oil and biological and ecological effects of reduced macrofauna abundance and diversity. Dispersants used in the clean-up operations are also toxic, implying an additive effect in the biological and ecological impacts of crude oil pollution in marine and coastal ecosystems (Luter et al., 2019). Work with in vitro models show that chemically dispersed oil is cytotoxic and genotoxic to sperm whale skin cells, possibly due to higher PAH uptake. This notion is reflected in other evidence indicating that combinations of crude oil and dispersants are more toxic to deep-water octocorals than exposure to oil only. There are thus considerable and widespread risks for deep-water organisms in general in the aftermath of oil pollution, including that in the Gulf of Mexico. For example, samples of fish species collected in 2010–2011 indicated a tenfold increase in PAH concentrations, with mean values above the recognized threshold levels for adverse biological effects. This contamination declined to baseline values by 2015–2016. It might be assumed that cetaceans might be able to sense and avoid oil-polluted waters in the Gulf of Mexico and that, in any case, contact contamination would be minimal due to their resilient skin. However, photographic and on-site observations of these species swimming through polluted waters confirmed direct skin exposure to oil. In other evidence, common bottlenose dolphins in Barataria Bay (Louisiana) showed evidence of hypoadrenocorticism, a manifestation of adrenal dysfunction previously observed in animal models exposed to crude oil. Furthermore, these dolphins are more likely to develop moderate to severe lung disease, including alveolar interstitial syndrome and pulmonary congestion. These symptoms are significantly greater in incidence and severity than those observed in dolphins not affected by oil pollution. It should be stressed that the interaction between oil contaminants and disease in dolphins is an evolving issue, but is likely to be multifactorial in aetiology. In a preliminary assessment, 69 POPs, including PCBs, polybrominated congeners and organochlorine pesticides, were determined in blood and a subset of blubber samples at three Gulf of Mexico sites and an unimpacted reference location. It was concluded that the determined background levels of these POPs did not correlate with incidence of health abnormalities previously reported for coastal bottlenose dolphins exposed to oil pollution in the wake of the Deepwater Horizon explosion.

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Sea turtles (Fig. 5.2) are particularly susceptible to crude oil pollution due to their breeding and migration behaviour. Inhalation and swallowing contaminated water negatively affect growth and survival due to irritation of mucous membranes around the eyes, buccal cavity, lungs and alimentary canal. Absorbed PAHs can enter vital organs such as the lungs and liver, thereby adversely impacting on physiological functions. As part of the natural resource damage assessment scheme, avian toxicity observations were instituted after the Deepwater Horizon explosion. The evidence indicates both physical and physiological deterioration following exposure to crude oil and its contaminants. External oiling affected flight patterns, implying that migration might be affected as well as increased heat loss and energetic requirements due to plumage damage. For example, heat loss of heavily oiled mallards and scaup can be significantly higher compared with normal values, affecting rehabilitation due to plumage deterioration and loss of water repellence, particularly in oiled scaup. The changes in haematological end-points involve formation of Heinz bodies and cell counts, potentially compromising multiple organ systems, cardiac function and oxidative status.

Fig. 5.2.  Sea turtles exemplify the risks for marine species affected by crude oil pollution in the Gulf of Mexico following the Deepwater Horizon accident in 2010. These reptiles migrate to different habitats for reproduction and for foraging in the sea. Consequently, exposure to crude oil involves surface oiling, inhalation and ingestion of potentially toxic petroleum fractions such as PAHs which may adversely impact on critical organs, particularly the lungs and liver. (Image ‘sea turtle 3’ by deeje is licensed under CC BY-SA 2.0.)

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Biochemical effects include decreases in aspartate aminotransferase and ɣ-glutamyl transferase activities, which may correlate with increases in plasma urea and uric acid concentrations. Addressing the question of rehabilitation of oiled birds and extrapolation to different incidents is fraught with difficulties due to variations in the severity and physical and chemical characteristics of the crude oil discharged, and inherent differences among the various species impacted by oil pollution. Thus, whereas oiled scaup appear to be difficult to rehabilitate, clean-up and recuperation of little blue penguins affected by the oil spill off the coast of New Zealand in 2011 were judged to be successful, based on diving and foraging behaviour of these species. Furthermore, corticosterone stress hormone responses in rehabilitated birds were not affected by the clean-up protocols. Other ecological threats are still emerging almost a decade after the Deepwater Horizon oil spill. For example, high concentrations of the genotoxic metals chromium and nickel have been observed in tissues, including skin biopsies, of whales in the Gulf of Mexico. Whether this is a legacy of the oil spill or associated with the clean-up operations remains unresolved. However, it is known that the specific oil released in the accident contained aluminium, arsenic, chromium, nickel and lead. These metals are capable of damaging DNA structure and functions, with the propensity to bioaccumulate, consequently causing persistent exposure and biomagnification risks in marine and coastal ecosystems. The long-term recovery of populations of marine animals exposed to crude oil pollution is a matter of critical importance, reflecting efficacy of initial efforts at clean-up and rehabilitation, and the impact of natural phenomena in dispersal of contaminants and microbial degradation of the constituent hydrocarbons. The Exxon Valdez oil spill into pristine northern waters in 1989 provides evidence of the extent to which recovery is possible. The spill killed substantial numbers of different avian species and marine mammals, including sea otters and harbour seals, as well as contaminating much of the coastline in the impacted regions. The extensive clean-up and natural processes removed much of the oil over the 4 years following the spill to the extent that, by 1994, 20% had evaporated, 14% biodegraded and 14% cleaned. Significant quantities still remain deposited below the surface, with long-term implications for biodiversity. In the case of harbour seals, mortality was estimated at 300 in a population that had been declining and with 80% of seals contaminated with oil. However, these seals are now considered to have recovered, with population numbers stabilizing or increasing. Mortality in killer whales following the accident was also significant at 20% in 1990, compared with an expected level of 2% or less. Although the resident pod is showing signs of recovery, the transient population of killer whales is at risk due to loss of breeding females and reduced numbers of offspring. In contrast, sea otters, bald eagles, sea ducks and black oystercatchers are now deemed to have recovered since the Exxon Valdez oil spill. Nevertheless, it should be noted that sea ducks, oystercatchers and other species feed in intertidal habitats and were, therefore, highly vulnerable to crude oil exposure in these zones. An estimated 15% of the pigeon guillemot population died from acute oiling and, in addition, an increase in nest predation of incubating adult birds and chicks contributed to mortality in this

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species. Recovery was observed in fish stocks, including cutthroat trout, Dolly Varden trout, pink salmon, rockfish and sockeye salmon, but Pacific herring is still adversely affected by lingering oil, decimating a once-lucrative commercial enterprise. Recreation, tourism and subsistence economy also continue to be adversely impacted by this event. In summary, although clean-up workers are most likely to be directly contaminated in oil spills, significant accidents such as those in the Gulf of Mexico (see Case Study 5.1) and Alaska will have far-reaching consequences for coastal residents as well as for marine ecosystems, adversely impacting on biodiversity

Case Study 5.1.  Crisis in deep water not disappearing over the horizon any time soon Many conglomerates directly associated with the major environmental contamination crises of recent times wish that the detrimental effects and adverse publicity would disappear into oblivion with the passage of time, coupled with short memories of affected communities. However, the Deepwater Horizon explosion on an oil exploration platform in 2010 will remain the subject of environmental concern for several decades to come in view of human health impacts and degradation of the marine ecology in the Gulf of Mexico. Particular risks were identified for oil spill response personnel, including workers and volunteers and residents in communities of Texas, Louisiana, Mississippi, Alabama and Florida. The potential for toxicity arose from the consumption of contaminated seafood. Occupational exposure monitoring as well as sensory and chemical analyses of seafood were conducted in order to assess the potential risks for workers and community members via inhalation and/or dietary intake. The US Environmental Protection Agency employed air monitoring to determine the extent of exposure to volatile organic compounds. The US Food and Drug Administration and the National Oceanic and Atmospheric Administration developed fishery closure and reopening guidelines in order to minimize potential dietary exposures. The crisis in the Gulf of Mexico provided an opportunity to scrutinize the current regulatory and health risk assessment framework, which was designed primarily to deal with individual chemicals. Resolving the complexity of this event using the available assessment process proved to be a difficult process which highlighted many of the limitations of that approach. In addition, the implications for marine ecology are only now emerging in wide-ranging studies including genotoxic bioaccumulation in whales and flight patterns in avian species. A separate issue concerning disputes over the financial compensation to affected communities and interventions by the judiciary have only served to emphasize the gravity of this oil spill. Environmental toxicologists and stakeholders will need greater assurance that all the lessons have been learned. • Can you summarize the toxicological risks associated with the use of detergents in the clean-up process? Are there any alternatives? • What are the key steps in responding to future oil spills? • Which marine species are most susceptible to oil spills? • Sea horses are a protected species in the UK: explain how oil-drilling in coastal waters might affect their survival.

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and abundance of endangered species. Neither should the effects of crude oil dispersants on marine species be ignored (Luter et al., 2019).

5.3  Shale Oil and Gas The oil and gas industries in the USA and worldwide have changed significantly over recent times through the development of technologies such as directional drilling and hydraulic fracturing. These advancements have enabled the extraction of fuel from previously inaccessible sources, particularly shales. The marked economic impact of this fracking process is reflected in a dramatic alteration in the international oil and gas markets. However, the extraction of shale oil and gas results in large volumes of wastewater containing a diverse array of organic, inorganic and radioactive compounds with the potential to adversely affect human health and aquatic ecosystems. A complex variety of chemicals are added in the hydraulic fracturing of shale, including: • • • • •

glutaraldehyde as biocide; N,N-dimethyl formamide as corrosion inhibitor; polyacrylamide and petroleum distillate as friction reducer; borate salts for cross-linking; and ethylene glycol as scale inhibitor.

In addition, hypersaline saltwater (brines) and organic, inorganic and radioactive compounds from the formation water and shale matrix are mobilized and may appear in the wastewater. The brines contain sodium and calcium chlorides and a complex mixture of other minor elements. Iron rapidly oxidizes in the wastewater, forming a precipitate of iron oxide. Elevated concentrations of bromide and iodide originating from the shale and formation water, and high levels of ammonium compounds derived from the denitrification of organic matter in the shale, also occur in the wastewater. In the Marcellus Shale (USA), wastewater exceeded relevant water quality standards for barium, strontium, copper, lead, chromium, mercury, zinc, cadmium, arsenic and benzene by as much as 1000-fold. Petroleum hydrocarbons derived from the shale may also contaminate the wastewater. In addition, some VOCs may be released into the atmosphere as gases or vapour. The emission of gases and particulates associated with the drilling process is similar to that produced in large-volume traffic highways. Naturally occurring radioactive materials, including radium, uranium and thorium isotopes, during generation of wastewater, are an additional concern. Radium isotopes are produced during the decay of uranium and thorium present in shale. Radioactive substances may become increasingly more concentrated due to operational procedures involving flowback water. It has been suggested that fracking is likely to lead to a more acute radioactive contamination problem than in conventional crude oil production. Pollution risks are associated with accidental releases of flowback liquids and hydraulic fracturing fluids which may impact on the safety of ­ drinking water and nearby streams, thereby jeopardizing human health and aquatic organisms at different trophic levels. Investigations of groundwater

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contamination incidents linked to fracking sites in the USA revealed evidence of dissolved hydrocarbons and inorganic elements that possibly migrated from nearby wells with structural defects. In another incident, benzene, toluene, ethylbenzene and xylenes which exceeded statutory limits for drinking water were attributed to fracking operations. The US Environmental Protection Agency identified almost 500 spills that occurred at or near fracking installations. Risk assessments relating to toxicity of wastewater to living organisms are only now emerging. Initial evidence indicated failure of survival of cultured human lung cells after 10 days of exposure to 4% flowback wastewater. Other in vitro data based on gene expression and protein expression revealed a picture of cytotoxicity characterized by changes in cellular adhesion, cell–cell adhesion, inhibition of cell cycle, proliferation and migration following exposure to wastewater fractions. Overall, it was clear that at high concentrations wastewater was extremely toxic, even corrosive and capable of transforming some cell lines, or promoting growth, a hallmark of tumour promotion. Recent investigations into the potential risks for individuals and communities affected by fracking have caused concern. For example, evidence from Pennsylvania suggests that fracking confers significant risks to infant health, while other data imply psychosocial risks to communities associated with this process. In addition, the number of reported health symptoms was significantly higher among residents living less than 1 km from an active well compared with those living more than 2 km away from active wells, after adjusting for age, smoking and other demographic factors. Other evidence suggested that incidence of allergic, cardiovascular, pulmonary and cancer morbidity was higher than national averages among residents living near fracking plants. In-patient and visit rates for hospitals in specific zip codes associated with high-density fracking wells also increased for assessments in cardiology, dermatology, neurology, oncology and urology. There is, thus, a clear need for vigilance by environmental health agencies and delivery of due diligence by the fracking industry to identify and minimize adverse effects. The emergence of fracking technologies inevitably raised questions about potential impacts on ecology and biodiversity in the light of water contamination incidents near wells and in the disposal of wastewater (Brittingham et al., 2014). Elevated concentrations of mercury occur in streams near fracking sites, leading to bioaccumulation and possibly biomagnification of this toxic element in invertebrates at different trophic levels. A riparian songbird has been used as a bioindicator of pollution caused by fracking on the basis that, as a predator feeding on macroinvertebrates, it may be exposed to chemical contaminants released into the ecosphere by fracking. Feather composition tends to reflect blood dynamics and toxicology during exposure to localized pollution. It was found that feather barium and strontium concentrations were significantly higher in birds originating from fracking sites compared with areas without fracking. These findings point to the need for more detailed risk assessments to inform policymakers on mechanisms to protect vulnerable species at fracking sites. It has been suggested that such an evaluation should include spatial and temporal analysis, species-based modelling, vulnerability appraisals and toxicity assessments.

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5.4 Coal The combustion of coal at power generation plants is accompanied by the production of a number of harmful pollutants, including carbon dioxide, sulfur dioxide, PAHs and particulates which, in 1952, combined to precipitate the infamous smog of London (see Chapter 3). The resulting coal ash residue presents particular human health and environmental impacts which should be addressed within a toxicological perspective. This coal ash is stored in landfill sites and slurry ponds generally located close to residential areas often associated with economic deprivation. Significant risks of contamination arise when these impoundments are damaged or not fit for purpose, leading to soil and surface water pollution. Concentrations of metals in coal ash can be up to ten times that in the original coal, but other contaminants include arsenic, mercury, lead, cadmium, chromium, nickel, zinc and PAHs. High levels of these contaminants occurred in the largest coal ash discharge in 2008 at the Tennessee Valley Authority generation plant in the USA. Effluents from impoundments may contain major and trace mineral elements that exceed regulatory guidelines for drinking water and ecological safety. In addition, coal ash is increasingly acknowledged as a source of radioactive elements and the risks are perceived by some observers to be greater than hazards established for certain nuclear reactors and comparable to those for nuclear waste. The radioactive contamination of coal ash is determined by the distribution and concentrations of the different isotopes in the original coal. Following combustion of coal in power plants, isotopes of uranium, thorium and ruthenium and associated decay products are partitioned into the gaseous products and the ash fraction. Relatively high concentrations of radium isotopes have been found in coal ash, with radioactivity significantly exceeding levels occurring in ordinary soil. It is salutary to note, however, that even low levels of radiation are potentially harmful, with the propensity of isotopes to enter the body via the lungs and to circulate in the bloodstream, thus causing accretion in the bones and teeth. Epidemiological observations indicate that potentially severe public health risks exist for residents, particularly children and vulnerable adults, living near coal-fired power installations. For example, increased incidence of respiratory disorders, emotional, behavioural and cognitive deficits occur in children from these high-risk areas compared with those living further away from coal-fired plants. The immunocompetence of these children may also be compromised by exposure to particulates from combustion and coal ash. There are also preliminary indications that DNA damage may be induced by coal combustion particulates by mechanisms that include oxidative stress. Aerosolized coal ash particulates have recently been implicated as a risk factor for neurodegenerative disorders, thus confirming the diverse range of effects of residential or occupational exposure to these and other contaminants. Furthermore, on the basis of epidemiological studies in China, it has been concluded that domestic air pollution caused by bituminous coal combustion in domestic environments can be a major contributor to the incidence of lung cancer among non-smokers. Emerging evidence indicates that aerosolized coal ash may also endanger biodiversity and wildlife survival. For example, the global decline of bird populations

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and species is being attributed to multiple metals and mineral elements in coal ash known to adversely impact all aspects of the avian life cycle. However, the effects of other contaminants such as pesticides, radioactive isotopes and particulate matter may add to the hazards of coal ash exposure.

5.5  Key Issues The crude oil spill in the Gulf of Mexico in 2010 compromised immunocompetence, inflammatory responses and mental health among people in affected communities. Variable recovery of wildlife is expected, based on evidence of the Exxon Valdez contamination in 1989. Evidence from Pennsylvania suggest that fracking confers significant risks to infant health, while other data imply psychosocial risks to communities located in the vicinity of drilling sites. Increased incidence of respiratory disorders, emotional, behavioural and cognitive deficits have been reported in children living near to coal-fired power plants.

5.6 References Brittingham, M.C., Maloney, K.O., Farag, A.M., Harper, D.D. and Bowen, Z.H. (2014) Ecological risks of shale oil and gas development to wildlife, aquatic resources and their habitats. Environmental Science and Technology 48, 11034–11047. Lauritsen, A.M., Dixon, P.M., Cacela, D., Brost, B., Hardy R., Wallace, B.P. and Witherington, B. (2017) Impact of the Deepwater Horizon oil spill on loggerhead turtle Caretta caretta nest densities in northwest Florida. Endangered Species Research 33, 83–93. Luter, H.M., Whalan, S., Andreakis, N., Wahab, M.A., Negri, A.P. and Webster, N.S. (2019) The effects of crude oil and dispersant on the larval sponge holobiont. mSystems 4, e00743-19.

5.7 Exercises (i)  Summarize the likely impact of fuel constituents on human health in the aftermath of accidental exposure. (ii)  Evaluate the potential toxic effects associated with the petrochemical industries, citing two specific cases of interest. (iii)  Discuss the toxicological implications of crude oil spills and effluent discharges on marine species, commenting also on the effects of dispersants used in clean-up operations. The study by Luter et al. (2019) might be a suitable reference for part of your answer. (iv)  Using online resources, evaluate how well the energy industry is prepared for future fuel spills and effluent and gaseous discharges. You may wish to examine the mission statements and Annual General Meeting agendas issued by the major energy conglomerates in preparing your answer.

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6



Metallic Elements

6.1 Overview A wide range of mineral elements are essential for life, including for example calcium, phosphorus, sulfur, sodium, potassium, iron, copper and selenium. These must be present in the food, but excess intake can be detrimental to health. Thus, sodium chloride is generally consumed in quantities that exceed daily requirements, presenting risks for individuals with hypertension. However, another class, containing non-essential mineral elements, is associated with profound and overt manifestations of toxicity which regularly impact on human health and other organisms in specialized habitats (Table 6.1). These elements, including mercury, lead, cadmium and arsenic, are often classified as ‘heavy metals’. The ecological distribution and impact of toxic metals on unicellular life forms is highlighted in the work of Chu et al. (2019). Individual heavy metals are markedly different in intrinsic chemical properties, resulting in unique features, but common themes may be just as significant in several respects, including: • • • • • • • •

origin; environmental distribution; electronic waste recycling risks; uptake and bioaccumulation; target organs (Fig. 6.1) and adverse outcomes; mechanisms of toxicity; ecotoxicity; and monitoring and management of risk.

82.

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Table 6.1.  Metal toxicity. Evidence based on case studies and electronic waste recycling activities. Metal

Effects

Mercury (organic) Minamata disease (Japan); sensory impairment; ataxia; constriction of visual field; auditory defects; mortality in mass poisoning incidents; abnormal pregnancy outcomes; liver and renal lesions in polar bears Lead Oxidative stress; irritability; attention deficits; aggressive behaviour; reproductive disorders; high blood lead levels in particular free-ranging crocodiles Cadmium Kidney disorders; osteoporosis; multiple fractures; negative pregnancy outcomes; carcinogenesis Arsenic Carcinogenesis; disruption of cardiovascular, reproductive, nervous and immune systems

Fig. 6.1.  The central nervous system, particularly the brain, is the target organ for the action of a number of important organic and inorganic pollutants. The association between insecticides and neurotoxicity is legendary and an enduring theme. For example, in 2020, a major manufacturer announced discontinuation of the production of chlorpyrifos, a pesticide previously linked to brain damage in children. However, a definitive indication of actual harm is exemplified in the neurodegenerative effects of methylmercury which emerged with the incidence of Minamata disease. Lead exposure in humans is a persistent problem worldwide, even in affluent societies, causing functional disorders including irritability, attention deficits and aggressive behaviour. (Image “Brain Image” by SciTechTrend is licensed under CC PDM 1.0.)

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6.2 Mercury Mercury is ubiquitous, occurring in different forms and in diverse ecosystems. Anthropogenic activity accounts for a substantial quantity of the mercury entering the atmosphere, rivers, oceans and the biosphere. The predominant forms of mercury circulating in the environment are elemental (metallic) or oxidized (inorganic). The inorganic state will predominate in fracking wastewater and coal ash, although emissions from volcanic activity are also significant. In the aquatic ecosystem, methylmercury is generated by microbial or chemical processes and accumulates in most aquatic biota, attaining highest concentrations in fish and mammals near or at the apex of the trophic hierarchy. Human exposure to methylmercury therefore occurs via consumption of seafood and associated products. Methylmercury is rapidly and highly effectively absorbed from the gastrointestinal tract and transported in the bloodstream to all organs and tissues. It covalently binds to cysteine in the body to form cysteine-methylmercury, a structural analogue of the essential amino acid, methionine, so enabling it to cross the blood–brain and placental barriers via an amino acid transporter. Methylmercury is converted to its inorganic form in tissues of humans and other animals and excretion occurs via the bile into the faeces. Methylmercury can affect a variety of organs, but its neurotoxicity is the most significant manifestation of adverse effect, with historical evidence to support current concerns over ongoing pollution and contamination in the food chain. An outbreak of mass poisoning occurred in Iraq during the period 1971– 1972, involving the use of seed grain, treated with methylmercury fungicide, to prepare homemade bread in rural communities across the country. A total of 6000 hospital admissions ensued, with over 400 deaths linked to this incident. Symptoms reported by affected individuals included paraesthesia (sensory impairment), ataxia, constriction of visual field (tunnel vision) and auditory deficits. The LOAEL for paraesthesia was estimated at 50 μg g–1 for hair mercury concentration. For the developing fetus, the maternal hair mercury concentration that would have no observable adverse effects on offspring was estimated at 12–14 μg g–1, with provisional tolerable weekly intake calculated at 1.6 μg kg–1 body weight. The enduring case of methylmercury poisoning, however, relates to Minamata disease in Japan caused by industrial contamination as described in Case Study 6.1. Exposure to methylmercury among inhabitants bordering the Yatsushiro Sea occurred through consumption of contaminated fish and shellfish, with total mercury concentrations determined at extremely high concentrations in Minamata Bay and surrounding areas. Hair mercury concentrations in a selection of participants, including Minamata patients, were also markedly elevated between 1954 and 1959, with maximum levels of above 700 μg g–1. Even participants without overt symptoms in Minamata had significantly higher hair mercury levels than healthy residents outside the affected area. Other evidence pointed to high levels of exposure to mercury among fishermen in a wide coastal area of the Yatsushiro Sea. Hair mercury concentrations gradually ­decreased during the 1960s, following cessation of industrial pollution, although

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Case Study 6.1.  Better late than never for survivors of Minamata disease Minamata disease is a debilitating methylmercury intoxication of the central nervous system, observed in Japan during the 1950s and mid-1970s and coinciding with an era of rapid economic growth. In both cases, vast quantities of methylmercury were discharged into aquatic ecosystems following generation in acetaldehyde-synthesizing factories. The coastal area of the Yatsushiro Sea, including Minamata, and the basin of the Agano River in Niigata were affected by this contamination. Inhabitants in these areas were exposed to methylmercury primarily via a diet of fish and associated processed products. Methylmercury is rapidly and very effectively absorbed from the gastrointestinal tract into the bloodstream and transported to all tissues of the human body. Methylmercury covalently binds to cysteine in the body to form cysteine-methyl-­ mercury, a structural analogue of the essential amino acid, methionine, which can traverse the blood–brain barrier and the placenta barrier via an amino acid transporter. Methylmercury is converted to inorganic Hg in the body and excreted. However, during turnover, methylmercury affects a variety of organs, causing toxicity, but neurological derangements represent the most significant and distinctive manifestations of the adverse effects. The most susceptible sub-group to this neurotoxicity comprises pregnant women and an extensive database has been compiled to follow the neurodevelopmental effects at very low exposures to methylmercury. The incidence of abnormal pregnancy outcomes, including stillbirth and spontaneous abortion, increased significantly between 1956 and 1968 in Minamata and vicinity. Male-to-female birth ratios also declined in the late 1950s. In addition, the incidence of cerebral palsy was markedly higher during the period 1955–1958 in fishing villages bordering Minamata bay, ranging from 1% to 12%, compared with 0.2% for the general population of Japan. The protracted disputes that ensued meant that full responsibility for Minamata disease was not legally attributed to the company causing the methylmercury pollution until 1973. Experience with this case probably contributed to the modern concept that the ‘polluter pays’. It is also disturbing that, some 60 years after the identification of Minamata disease, steps to curb environmental mercury contamination on a global scale are only now being considered. • An abandoned Siberian chemical plant has been nominated as ‘The Next Chernobyl’ in some media reports. Can you suggest reasons for this? • What are the specific ecotoxicological risks which might be associated with deep-sea mining? • Can you suggest other situations where mercury contamination might be a problem for particular communities and ecosystems?

some residents continued to be exposed to methylmercury at hazardous levels. By 2004, hair mercury concentrations in Minamata were significantly lower than those in subjects across different sites in Japan. Epidemiological findings at the pollution sites bordering the Yatsushiro Sea indicated a wide range of effects in patients with Minamata disease. Increased incidence of neurological impairments, including sensory deficits, was observed, with strong indications that duration of exposure and frequency of fish consumption were significantly associated with the appearance of the different

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neurological manifestations. Congenital expression of Minamata disease in children is also associated with adverse effects, including neurological and functional defects. Methylmercury exposure was accompanied by increased prevalence of impaired intelligence, and mood and behavioural dysfunction. Due to natural and anthropogenic redistribution of mercury in the environment and consequent contamination of the atmosphere and food, efforts are continuing to elucidate the toxicological implications for humans and other living organisms. It is known that inorganic mercury damages the kidney, liver, gastrointestinal tract and the cardiovascular system. Mercury exposure is also associated with modulation of plasma concentrations of thyroid hormones, implying an endocrine disrupting effect. In addition, perturbation of reproductive processes by inorganic mercury results in fetal abnormalities. However, emerging evidence indicates that, despite the relative inability of inorganic mercury to traverse biological barriers, it still has the potential to induce motor deficits, cell death and oxidative stress in the motor cortex, as demonstrated in an adult rat model. Other observations suggest that the preferential cellular target of mercury is selenium rather than the sulfhydryl groups of cysteine. It is claimed that mercury has an inferior affinity for thiol groups, whereas the bonding to selenium-­ containing entities is considerably stronger. Thus, although binding to thiol groups enables transport of mercury across membranes and facilitates tissue and excretion dynamics, it does not account for the oxidative stress and organ damage associated with its toxicity. A comprehensive review of recent data indicates that the primary cellular targets of mercury are the selenoproteins of the thioredoxin system and glutathione peroxidase. It is suggested that mercury binds to the selenium component of these proteins, thereby inhibiting their functions and so irreversibly compromising intracellular redox status. Under these conditions, accumulating reactive oxygen species precipitate a wide range of adverse effects on glutamate and calcium metabolism. Mitochondrial damage may also occur, while lipid peroxidation exerts additional metabolic stresses. It has also emerged that methylmercury is a potent inhibitor of the thioredoxin system, partially accounting for its neurotoxicity. It is conceivable that the mercury–selenium interaction promotes demethylation of organic mercury, modulates interorgan dynamics of mercury, mediates the formation of an insoluble, stable and inert mercury–selenium complex and reduces absorption of mercury from the gastrointestinal tract. These effects are dependent on the form of mercury and selenium, the target organ and dose levels. Nevertheless, it is clear that different mechanisms operate in the development of the various manifestations of mercury toxicity in living organisms, raising questions about future strategies for attenuation.

6.3 Lead Lead is another ubiquitous element which has been subjected to redistribution by anthropogenic activity, resulting in a legacy of environmental contamination and human exposures via water and food. Industrial activities such as mining, smelting and combustion have contributed significantly to this

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contamination. The use of lead in paint, gasoline, plumbing, cosmetics, food cans, folk remedies, toys, batteries, ammunition and ceramics has ensured widespread risks not only for industrial workers but also for children in disadvantaged communities. Early case studies evoked scepticism among physicians and researchers about a link between lead exposure and human morbidity. However, evidence published in the 1950s to 1970s indicated that even small doses of lead could adversely impact several physiological functions, with irreversible neurodevelopmental consequences. With the enactment of legislation limiting or forbidding the use of lead in gasoline, paint, plumbing and specified commercial products, childhood blood lead levels have declined markedly in the USA and elsewhere. Like mercury, lead exists in elemental, inorganic and organic forms in different matrices and ecosystems. Not only is lead persistent in nature, but it can also bioaccumulate in soft and mineralizing compartments of the body. Uptake occurs through ingestion or inhalation of inorganic forms or ingestion, inhalation and dermal absorption of lipid-soluble organic forms. Drinking water distributed through lead plumbing systems will add to the health risks. The physiological fate of lead is independent of the route of exposure, with most being transported to and deposited in the bone, where it can persist with a half-life of 20 years. Fetuses, infants and children are considered to be at greatest risk following exposure to lead. In utero effects can occur when lead from the maternal blood crosses the placenta, which may be compounded in the newborn receiving breastmilk. Bone lead is generally more bioavailable during pregnancy and in children whose bones are developing. In children, bones can serve as a continuous source of endogenous lead exposure as their bones undergo regular restructuring. Children can also absorb lead more effectively than adults and they also store more of the metal in soft tissues such as the brain, spleen, liver, kidneys and lungs, where its bioavailability is greater than that in the bone matrix. Lead can affect almost every organ in the body, precipitating toxicity by at least three mechanisms: • Firstly, in common with other toxic elements, lead can induce oxidative stress which, in turn, can result in significant damage to critical molecules such as DNA, enzymes, proteins and cell membranes, culminating in cell death. ­Oxidative stress is the result of an increase in the production of ROS and a decrease in the antioxidant supply required to remove the resulting ROS. • In its second mechanism, lead can act as an analogue of, and replace, cations such as calcium, magnesium, iron, zinc and sodium, thereby disrupting several physiological processes, including cellular signalling, cell adhesion, protein structure, apoptosis, ionic transport, enzyme regulation and neurotransmitter release. Trace quantities of lead can disrupt the second messenger system through cation replacement of calcium. Lead forms stronger bonds than calcium, meaning that vital processes dependent on this cation are inactivated. It is the displacement of calcium that ­allows lead to cross the blood–brain barrier, thus disrupting neurological functions.

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• A third mechanism centres on the impact of lead on the developing brain by disruption of epigenetic gene regulation. It is possible that the lifelong effects of lead may be explained by this mechanism and that epigenetic alterations may be inherited across generations. An emerging and disturbing feature of lead is its ability to instigate adverse effects at very low doses, implying the absence of a threshold in human responses to this metal. Manifestations of, and susceptibility to, lead toxicity depend on a number of factors, including dose and duration of exposure as well as age, gender, nutritional status, stress and other individual characteristics. Acute toxicity is rare in present-day situations, but historical records include symptoms such as brain degeneration, comas, convulsions and even death. Chronic exposure to lead at lower levels causes a wide range of effects, including irritability, attention deficits, cognitive disabilities and aggressive behaviours, particularly in children. Other effects include abdominal pain, headache, tremors, lethargy, depression, memory loss, lack of coordination, speech defects, numbness and tingling in the extremities, delirium, convulsions and even coma. These manifestations imply that lead impacts multiple organ systems, but the most pronounced effects are on the central and the peripheral nervous systems. In adults, lead poisoning induces peripheral neuropathy, muscular weakness, fatigue and motor deficits. In children, the impact even at low exposures is greater on the central nervous system, leading to cognitive and behavioural disorders and possible interactions with respiratory disease (Taylor et al., 2019). The fetal nervous system is more susceptible to lead, as immature endothelial cells allow transport of the metal into the developing brain. Lead uptake by the brain results in disruption of synapse formation in the cerebral cortex, while impeding development of primary neurochemicals and depressing neuronal growth and altering the integrity of ion channels. Lead accumulates in astrocytes, where it serves as a reservoir for continued turnover, leading to defects in the repair processes in the brain and development of the blood–brain barrier by disrupting the myelin sheath which insulates neurons and increases impulse conduction. Childhood exposure to lead can decrease brain volume, particularly in the prefrontal cortex in adults. There is also limited evidence of later-life antisocial problems and criminal behaviour following prenatal exposure to lead. Furthermore, there is evidence that lead damages nerves associated with sense organs and control of bodily functions, which may result in later-life neurodegenerative/neurological disorders such as amyotrophic lateral sclerosis and Parkinson’s disease, Alzheimer’s disease and schizophrenia. Childhood lead exposure, for example, can result in later-life overexpression of Alzheimer’s disease-related proteins and histopathology. Lead is also associated with reproductive disorders, reducing fertility in males, while maternal exposure, for example in the final trimester of pregnancy, can increase the risks of spontaneous miscarriage, pre-term birth and low birthweights in offspring. Bone lead accumulated after years of exposure can, in pregnant women, serve as a source of prenatal exposure due to the marked bone turnover normally associated with gestation. This mobilized lead

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can readily cross the placenta during pregnancy and can be deposited in the developing fetus. Additional exposure will occur via breast milk during lactation. Lead exposures during the gestation and infant periods, at levels which are prevalent, for example, in the general US population, have been linked with permanent brain damage which may not be evident until later in the child’s life in terms of cognitive deficits. The adverse impact of lead on brain function will depend on whether exposure occurred at the fetal or paediatric stage. Animal studies indicate that lead delays onset of puberty by decreasing levels of circulating hormones, including oestradiol, luteinizing hormone and insulin-like growth factor. Similar risks have been observed in girls with prenatal and early childhood exposure to lead, but not in boys. Other health risks with lead are emerging, including adverse effects on renal, cardiovascular and immune functions. Sufficient evidence exists for decreased renal function in adults with blood lead levels of less than 5 μg dl–1. Adult blood levels of less than 10 μg dl–1 are associated with hypertension and even all-cause higher mortality, as well as reduced immunocompetence. Although the evidence for carcinogenicity is inconclusive, it is important to recognize that the field of lead toxicity is still evolving. The realization that there is no threshold range for lead toxicity in humans has provided the impetus for continuous monitoring of risks on a worldwide scale. For example, the frequent elevated concentrations of lead in particulate matter in Delhi (India) have been attributed to recycling of lead-acid batteries by small enterprises in the city. The effects of childhood exposure to lead on pubertal development have been evaluated in a Mexico City population, while routine screening of blood lead levels in New York City residents resulted in a reduction of national threshold levels to 5 μg dl–1. The need for surveillance is highlighted by the episode of childhood lead poisoning in Flint, Michigan (USA). This case resulted from a series of contributory factors, including corroding drinking-water infrastructure, deficiencies in implementation of regulations by utility companies and inadequate government oversight of industrial operations. All these factors contributed to a doubling of childhood lead poisonings in Flint.

6.4 Cadmium Cadmium is a metal with important physical properties, including corrosion resistance, high ductility and thermal and electrical conductivity, leading to its use as a stabilizer and colour pigment, as well as in cathodes and in corrosion protection. It is emitted into the environment as a result of both natural recycling and anthropogenic activities. As cadmium is an intrinsic part of the earth’s crust, volcanic eruptions, weathering of rocks and redistribution of deposited residues contribute to environmental dispersion. Anthropogenic sources include mining and smelting emissions, use of cadmium-containing fertilizers, combustion of fossil fuels, waste incineration and releases from landfills. The contamination of arable land is of concern as the metal is readily taken up by crops, for example rice, wheat or vegetables, as well as tobacco leaves. The

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principal global use of cadmium is with nickel in rechargeable batteries, but concerns over human health exposures have led to restrictions and ban of use in several applications. Although overall occupational exposures have declined since the 1970s, risks still occur for personnel in battery manufacturing and production of cadmium alloy and zinc smelting. Nevertheless, food is currently the major source of this metal, while smokers are additionally at risk due to uptake by tobacco plants. The absorption of cadmium in the gastrointestinal tract is relatively low, depending on nutritional status of individuals and on the presence of other food components, particularly fibre. Cadmium is efficiently retained in the kidney with a half-life of 10–45 years. Consequently, urinary cadmium is a good biomarker of lifelong kidney accumulation and a reflection of total body burden. Levels in erythrocytes and whole blood are considered to reflect recent uptake by the body. The toxicology of cadmium is associated with diverse effects in kidney, bone, reproduction, child health, cancer and cardiovascular function. Tubular damage is the critical effect of cadmium exposure, representing the primary adverse effect that occurs as the dose increases. Long-term exposure impairs renal tubular reabsorption, reflected in increased levels of low-molecular-weight proteins in the urine. Chronic kidney disease and the development of end-stage renal disease are major disorders worldwide and there is evidence of an association between high cadmium exposure and mortality from renal diseases. The high incidence of osteoporosis, a systemic skeletal disorder characterized by low bone mass and structural deterioration of bone matrix, is a major public health issue, with resulting fractures contributing to reduced quality of life and life expectancy and increased maintenance costs for individuals and communities. Itai-Itai disease, the most advanced manifestation of environmentally-induced poisoning, occurred after excessive and long-term intake of cadmium-contaminated rice. The disorder was characterized as a combination of osteomalacia, osteoporosis and renal damage, with affected individuals being prone to multiple fractures. Other investigations demonstrate statistically significant associations between higher cadmium exposure and reduced bone mineral density in various populations and exposure levels, suggesting that cadmium exposure may be a contributory factor in the public health burden of osteoporosis. The fact that these correlations were observed by the use of three different exposure assessment criteria (urine, blood and dietary intake) adds confidence to the validity of the conclusions regarding cause and effect. Tobacco smoking might be a confounding factor in cadmium-associated bone defects, as regular smoking increases exposure, which is very well reflected in blood and urine levels of the element. Nevertheless, there appears to be evidence of a link between low-level cadmium exposure and osteoporosis in the general population. There is increasing evidence to indicate that in utero exposure to cadmium may correlate with negative pregnancy outcomes, particularly low birthweights of offspring, and that this effect is restricted to girls. For example, in a birth cohort investigation in rural Bangladesh, urinary cadmium concentrations in early pregnancy were inversely associated with birthweight and head and chest

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circumferences in girls, while no such observations occurred in boys. There is also limited evidence that prenatal and childhood exposures to cadmium may adversely affect growth and that differences in attained weight and height are only apparent in girls. The mechanisms underlying the developmental toxicity of cadmium have been ascribed to disrupted placental functions, involving decreased micronutrient transfer and/or alterations of the epigenetic pattern in the placenta or cord blood. In childhood, cadmium exposure may interfere with bone remodelling or growth hormones, which would be expressed in impaired child growth. Early-life cadmium exposure can be detrimental for the development of cognitive abilities in children. Limited evidence indicates that cadmium can cross the blood–brain barrier, while other mechanisms may involve the induction of ROS, disruption of calcium signalling or changes in neurotransmitters or epigenetic profiles. In separate analysis, IARC concluded that there is sufficient data to classify cadmium as a group 1 carcinogen for humans. This evaluation was based on lung cancer risks following inhalation. It should be noted that the assessment of cancer risk was constrained by the limited number of cases associated with long-term high exposure, the inability to examine dose–response relationships across different investigations and the difficulties in excluding confounding factors, particularly smoking. Proposed mechanisms involved in carcinogenicity are thought to be indirect since there is minimal evidence for direct binding of cadmium to DNA or a mutagenic effect. Oxidative stress, disturbances in DNA repair and tumour suppressor genes and effects on cell proliferation are probable mechanisms. In summary, the results of several investigations support the concept that cadmium exposure is associated with mortality caused by renal disorders, cardiovascular disease and cancer. The renal injury data relates to a case of severe cadmium pollution in Japan.

6.5 Arsenic The history of arsenic is embedded in cases of deliberate fatal poisonings over the centuries. However, current concerns relate to chronic exposure associated with its ubiquitous occurrence and redistribution in the environment, particularly in water, natural sediments and soil. Anthropogenic sources include combustion of fossil fuels and releases from the semiconductor industry and from historical goldmine wastes. In parts of Asia and South America, groundwater and surface waters are naturally contaminated with arsenic, presenting risks for local communities through drinking water and the food chain. Arsenic also originates from industrial wastewater and agricultural use as pesticides. In China, for example, concentrations in groundwater may exceed national safety guidelines. Arable soils appear to be ultimate net sinks for arsenic, due to irrigation with contaminated water. WHO recommendations stipulate a maximum arsenic level of 10 μg l–1 in drinking water, but large populations worldwide, particularly in Asian countries, are exposed to potentially toxic levels of above 50 μg l–1.

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Inorganic arsenate and arsenite are common forms of this metalloid in aquatic and terrestrial ecosystems, with the former predominating in aerobic conditions, while the latter prevails in anaerobic environments. Arsenic is associated with both acute and chronic effects, affecting multiple organ and metabolic systems. Using a zebrafish model, arsenic exposure revealed over 30 potential markers of metabolic significance, implying a series of deleterious effects, including apoptosis, glycogenolysis and changes in amino acid metabolism and fatty acid profiles. Inorganic arsenic is classified by IARC as a carcinogen, being linked with malignancies of the liver, skin, lungs and kidney. In China, it has been suggested that carcinogenic risks are greater for adults than for children and that oral exposure is more important than dermal contamination. Whether these differences are due in part to occupational or inhalation sources of exposures or whether cigarette smoking is a contributory factor in adults remains unresolved. Analysis of diverse ecological zones in Pakistan indicate that arsenic-laden dust is an important source, implying that inhalation is a significant route of exposure in certain cases. Other significant features of arsenic toxicity include disruption of cardiovascular, reproductive, nervous and immune systems, thus implying diverse mechanisms in the aetiology of these disorders. Chronic effects of relatively high arsenic levels in drinking water (up to 100 μg l–1) are associated with peripheral arterial and coronary heart diseases. Evidence in USA, China and Italy indicate that even lower levels of about 50 μg l–1 increase risks of coronary heart disease and stroke, but smoking may be a confounding factor. Reducing arsenic exposure below the current US EPA standard of 10 μg l–1 may confer significant worldwide public health benefits in view of widespread contamination in drinking water, food and atmosphere particularly for smokers. US data from highly exposed populations suggest a synergistic impact between arsenic levels and smoking on health outcomes, supporting a policy to reduce exposure levels as a means of reducing ischaemic heart disease mortality. In view of worldwide concerns over environmental endocrine disruptors, investigations continue on the effects of arsenic on reproduction in humans and other vertebrates. It is generally accepted that prenatal exposure to inorganic arsenic causes adverse gestation outcomes and health effects in children. Some epidemiological evidence indicates that arsenic can induce premature delivery, spontaneous abortion and stillbirths. In animals, inorganic arsenic is also associated with fetal deformities, growth depression and fetal mortality. In males, it inhibits growth and development of the testes and accessory sex organs. Physiological effects, including reduced concentrations of testosterone and gonadotrophins as well as disruption of steroidogenesis, confirm the effects of arsenic as an endocrine disruptor. Exposure to arsenic is also associated with the incidence of neurological conditions, including arsenic-induced senescence in West Bengal and peripheral neuropathy throughout India. Epigenetic evidence indicates that senescence-linked micro-RNA is upregulated in relation to unexposed controls, particularly in individuals with peripheral neuropathy. The latter condition also occurs in Myanmar, with subjective and objective tests indicating low threshold

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levels for drinking-water exposure and recommendations that arsenic concentrations be reduced to less than 10 μg l–1 to improve neurological outcomes. Epidemiological and experimental evidence demonstrates that arsenic impairs immunocompetence, affecting both systemic and cell-mediated mechanisms. In particular, it modulates differentiation, activation and proliferation of macrophages, dendritic cells and T lymphocytes; underlying features include oxidative stress impacting on primary gene expression and DNA damage. In addition, epigenetic mechanisms may operate to affect DNA methylation and post-translational histone modification. The alterations in antibody production and the failure of T helper cells to synthesize interleukins is further compounded by transplacental transfer of arsenic. This inevitably raises questions about the effects of arsenic during the vulnerable periods of pregnancy and early life of infants, particularly regarding immune responses to natural infections and the efficacy of vaccines. There is also evidence that arsenic may prevent treatment of severe immune-related diseases. Unusually for a toxic metallic element, there is evidence of human adaptation in particular arsenic-rich ecosystems. Elevated arsenic concentrations are commonly observed in drinking water available to communities residing in northern Argentinian Andes. Recent investigations indicate that these individuals are endowed with unique mechanisms of metabolism, enabling an efficient methylation and excretion of the principal metabolite, demethylated arsenic, with a reduced excretion of the highly toxic monomethylated metabolite. Analysis of female genotypes within this population revealed strong correlations between the AS3MT (arsenic [+3 oxidation state] methyltransferase) gene and mono- and demethylated arsenic in urine, implying that AS3MT operates as a primary gene for arsenic metabolism in humans. Furthermore, strong genetic differentiation associated with AS3MT was observed in the Argentinian Andes population compared with a highly related Peruvian population residing in regions with considerably lower exposure to environmental arsenic. It is implied that this is unique evidence of human adaptation to a toxic metallic element.

6.6  Electronic Waste Recycling Despite regular and worldwide risk assessments and regulations, metal pollution associated with electronic waste recycling remains a serious and expanding problem in environmental toxicology. The range of elements include lead, mercury, cadmium, chromium, nickel, copper, zinc, aluminium and cobalt. These metals escape into the environment due to informal and unorthodox technologies employed in manual dismantling and open combustion for metal recovery and illegal deposition of discarded fractions in sites exposed to inclement weather conditions. At abandoned sites, surface soil contamination can exceed regional safety guideline levels. These activities are conducted primarily in developing Asian countries, in consignments exported from affluent economies. Consequently, human and wildlife exposures occurring through food, water and atmospheric contamination are serious issues in China, India and the Far East.

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It has been consistently reported that children living in the vicinity of electronic waste recycling sites endure health impairments due to heavy metal exposure. Health disorders include low birthweight, reduced anogenital distance, growth retardation, impaired pulmonary function and a greater prevalence of attention deficit/hyperactivity syndrome as well as higher DNA and chromosomal defects. Immunocompetence may also be compromised in affected children. For example, in China, reduced antibody levels in preschool toddlers have been linked with lead in electronic waste, with almost 50% of chronically exposed children unable to develop adequate immunity to hepatitis in response to vaccination. It is implied that different immunization strategies may be needed for children living in conditions of chronic exposure to lead and, perhaps, other toxic metals.

6.7 Ecotoxicity The ubiquitous distribution of potentially toxic metallic elements in aquatic/ marine ecosystems is a matter of profound concern, requiring immediate action to ensure the survival of a growing number of vulnerable species. Recent evidence of interactions with other pollutants has served to add urgency to evaluate risks and to increase efforts at remediation, insofar as this is feasible within the relatively short timescale available. For example, questions are emerging about the role of mercury in the aetiology of liver and renal lesions in East Greenland polar bears. Although recurrent infections and ageing are likely causes, the effects of long-term exposure to mercury cannot be excluded as liver and kidney concentrations of the metal can exceed threshold levels for lethality. In other investigations, high blood lead levels have been found in free-ranging crocodiles in South Africa. Despite the absence of overt clinical signs in these animals, there are concerns of potentially harmful or fatal effects on development and hatchability of eggs. Recent mortalities in the Kruger National Park in South Africa have raised the spectre of mercury, selenium and copper pollution in rivers caused by industrial/mining releases (du Preez et al., 2018). Eggshells had excessive contents of iron, possibly forming a thicker barrier to gas and water exchange as well as increasing the effort required for the hatchling to emerge. Based on biomarker evidence, it has recently been concluded that there are high levels of contamination of both metals and organochlorine pesticides in aquatic ecosystems in the Kruger National Park, with adverse implications for top predators such as the crocodile. In view of recent Nile crocodile nesting declines in South Africa, continued toxic metal and pesticide monitoring is essential. As indicated above, arsenic is associated with a wide range of toxic manifestations, but there are instances of human adaptation to this element in Argentina. Similarly, flamingos and specialized microbes are able to tolerate extremely high exposure to arsenic in an alkaline lagoon nestling within the caldera of an active volcano, also in Argentina. Concentrations of arsenic in the water are 20,000 times the level regarded to be safe for drinking water.

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It is assumed that these flamingos feed on the arsenic-resistant microbes and that the birds are also adapted to high levels of this element in the available water. Although selenium is an essential element for humans and other vertebrates, its presence in coal-ash wastewater represents an ecological risk. For example, release of this effluent containing selenium contaminated Herrington Lake, a large freshwater lake in Kentucky, USA, used for recreation and as a source of drinking water. This event resulted in major developmental deformities in fish and current projections indicate that this contamination could poison fish for at least 40 years. In China, electronic waste contamination of rivers is destined to be an ongoing problem due to the widespread use of low-technology processing methods, affecting organisms at all trophic levels. However, as with other environmental cases, there is a need to adopt a multidimensional analysis in delineating cause-and-effect issues. Thus, the effects of electronic waste contamination may not necessarily be related to emissions of heavy metals. For example, microbial community hierarchy and functions in sediments from electronic waste-contaminated rivers may be affected more by toxic organic pollutants than by heavy metals. A multifactorial analysis is also essential in the interpretation of the coal ash pollution evidence presented above.

6.8  Key Issues Both methylmercury and lead are associated with central nervous system deficits, observed after contamination incidents or exposure in polluted cities. Endangered predators may also show signs of toxicity to these heavy metals. Cadmium and arsenic, on the other hand, are linked to carcinogenesis. However, unique features are also apparent, with cadmium causing kidney disorders and arsenic implicated in disruption of cardiovascular, reproductive, nervous and immune systems. Concerns over heavy metal toxicity continue due to occupational and environmental exposures in electronic waste recycling and mobilization after deforestation and wildfires.

6.9 References Chu, W.-L., Dang, N.-L., Kok, Y.-Y., Phang, S.-M. and Convey, P. (2019) Heavy metal pollution in Antarctica and its potential impacts on algae. Polar Science 20, 75–83. du Preez, M., Govender, D., Kylin, H. and Bouwman, H. (2018) Metallic elements in Nile crocodile eggs from the Kruger National Park, South Africa. Ecotoxicology and Environmental Safety 148, 930–941. Taylor, M.P., Isley, C.F. and Glover, J. (2019) Prevalence of childhood lead poisoning and respiratory disease associated with lead smelter emissions. Environment International 127, 340–352.

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6.10 Exercises (i)  Discuss the practical significance of heavy-metal pollution. (ii)  Compare and contrast the toxicology of mercury and lead. (iii)  Explain the practical implications of ‘no threshold’ values in the toxicity of lead. (iv) Indicate how regular monitoring may contribute to improved health of communities exposed to heavy metals, citing specific examples to support your conclusions.

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7



Consumerism and Lifestyle Choices: Toxicological Perspectives

7.1 Overview The environmental impact of consumerism and lifestyle choices needs to be addressed, particularly with regard to emerging evidence of extensive toxicological risks. The supply-and-demand economics of recent decades has fuelled an unprecedented increase in pollution, impacting particularly on freshwater and marine species. In a highly competitive market, commercial organizations strive to improve their service to customers in terms of presentation, packaging and convenience. Meanwhile, society is preoccupied with the acquisition of goods irrespective of built-in obsolescence, resulting in an inexorable increase in pollution caused by discarded material. The insatiable desire to purchase articles with high turnover, including up-to-date electronic models, is a clear manifestation of prevailing throw-away attitudes, expressed vividly in affluent cultures. In addition, the availability and increased use of pharmaceuticals and personal care products has compounded the risks for species already made vulnerable by climate change and habitat degradation. These polymers and other compounds are sometimes considered under the collective title of ‘emerging pollutants’, but it is important to bear in mind that this type of pollution has been in existence for more than 50 years. Although manifestations of overconsumption and depletion of natural resources take many forms, such as excessive use of oil and gas as well as disposal of electronic hardware, there are emerging concerns over pollution caused by the ‘disposable culture’ in present-day society (Table 7.1). The need to prevent and reduce debris in marine ecosystems is emphasized by Kandziora et al. (2019). Salient issues emerging over the past 50 years include: • complexity of discarded polymers; • chemical nature of pharmaceuticals and personal care products;



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Table 7.1.  Adverse effects of plastics, synthetic fibres, pharmaceuticals and personal care products in marine species. Source

Adverse effects

Plastics and synthetic fibres

Entanglement; obstruction in digestive system; behavioural alterations; vectors for other pollutants Antibiotic resistance; residues in water; endocrine disruption Endocrine disruption; toxicity for endangered species and sensitive habitats

Pharmaceuticals Personal care products

• • • • • •

physical effects in marine species; polymers as vectors for disease organisms and other pollutants; endocrine disruption; antibiotic pollution; use of insect repellents and sunscreen lotions; and enhanced need for surveillance and control measures.

7.2  Plastics and Synthetic Fibres Pollution associated with plastic materials has become a popular subject in the media due to the visible and identifiable items discarded by retail outlets and consumers. Although ubiquitous in marine environments, rivers and estuaries, plastics are dispersed by rain, snow, prevailing winds and ocean currents to pollute pristine ecosystems around the world. The Great Pacific Garbage Patch located between Hawaii and California (Fig.7.1) is the world’s largest accumulation of ocean plastic. In the UK, significant plastic pollution has been observed on the banks of the Thames estuary near Purfleet, while the river Mersey is reported to be more polluted than the Great Pacific Garbage Patch. Rivers in Asia have been used for waste disposal for several decades, with plastic debris representing a large fraction of this pollution. It has recently been declared that just ten retail brands account for more than half the plastic litter on seashores. Plastics have been an underestimated source of pollution in rivers and oceans for several decades and their adverse effects on already endangered species are only just emerging in the scientific literature (Compa et al., 2019). The scale of the problem is encapsulated in a recent report of the presence of 40 kg of plastic bags in the gastrointestinal tract of a dead whale. Entanglement with large plastic debris can cause starvation, suffocation, lacerations, infections and mortality in a wide range of marine and freshwater species. Ingestion of plastic fragments by birds and turtles is also a common occurrence. Indeed, it has been estimated that almost 700 marine species ranging from microscopic organisms to the largest whales, including seafood destined for human consumption, are at risk from exposure to plastic in different physical forms.

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North Pacific

Subtropical Covergence Zone Kuroshio

California Eastern Garbage Patch or N. Pacific Subtropical High

Western Garbage Patch

North Equatorial

www.MarineDebris.Noaa.gov

Fig. 7.1.  The Great Pacific Garbage Patch above epitomizes the negative impact of consumerism in modern society. Also, of considerable concern is the recent (2019) headline that the ‘Mediterranean Sea is dying’ due to pollution with shipping oil, microplastics and sewage. Recent surveys indicate that the Greenland Sea is a significant reservoir of plastic particles, while similar debris jeopardizes important habitats for wading birds in estuarine ecosystems of the Thames (UK). All the major rivers in the UK are polluted with plastic debris, with the Mersey containing microbeads, fibres and fragments at concentrations exceeding those in the Great Pacific Garbage Patch. (Credit: NOAA https://marinedebris.noaa.gov/info/patch.html)

Of particular interest, however, is the impact of microplastic pollution on the welfare and survival of marine animals. Microplastics are defined as particles of less than 5 mm in maximum length. This pollutant is either industrially manufactured as small-sized particles, as abrasive beads for cosmetic products, or the result of physical breakdown (weathering) in the environment. A subset of ultrafine particles defined as nanoplastics are also of relevance, contributing special physiochemical properties. Microplastics and nanoplastics are now ubiquitous, occurring in freshwater and marine ecosystems, including deep sea sediments. Regardless of origin, once plastic material enters the marine ecosystem either as large fragments or as microplastics, it will thereafter be degraded and dispersed along different ocean compartments, including surface, water column, sediment and living organisms. Plastic characteristics such as polymer type and density will also affect dispersal along these compartments. The relatively small size of microplastics confers biological and potentially adverse effects in a wide range of marine species at all trophic levels. The ingestion of microplastics, the common route of exposure, creates particular risks for organisms with indiscriminate feeding habits which tend to capture particles of similar dimensions to their natural food. It is estimated that more than 200 species, including marine, freshwater and terrestrial organisms, have been ­observed to ingest microplastics. In some marine species, ingested particles

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can be retained and serve as obstructions in the alimentary canal or be translocated into tissues. Ingestion of microplastics by fish invariably leads to intestinal blockage, physical and histopathological changes in intestines, abnormal lipid metabolism and particle accumulation in the liver. Microplastics are composed of a long chain of monomers with a mixture of additives, both attributed with toxic properties. Furthermore, following physical degradation, the surface-to-volume ratio increases, enhancing the potential for adsorption, adherence and interactions with other non-polar toxic compounds and with microorganisms. Consequently, plastic fragments of diverse size can serve as vectors of pathogenic microorganisms, thereby creating risks for aquatic/marine species and the food chain. As a result, plastics can induce a range of effects from physical obstruction in the gut to physiological, cellular and molecular abnormalities. In turn, these impacts may further damage the balance of species in particular habitats due to adverse effects on growth and reproduction rates of organisms. Looking forward there is a need to correlate ecological end-points with the physical characteristics of the diverse variety of plastics in the environment. It is known that fibres are more detrimental than particles for certain aquatic species and that irregular-shaped microplastics are more toxic than spherical beads for some crustaceans. In view of the abundance of synthetic fibres and irregular-shaped particles in different ecosystems, there is a need for further elucidation of some fundamental concepts in the toxicology of plastics. In addition, type and composition of polymers may determine ecotoxicity of microplastics. Although plastics are considered to be almost inert due to their relatively large molecular size, reactions during polymerization are frequently incomplete, with monomers remaining within the polymeric materials being released during use and after disposal and degradation in the environment. Upon release, monomers can interact with cellular and molecular structures, leading to toxic effects. Some monomers, including those from polyvinyl chloride, are particularly hazardous to living organisms. In general, pollutants may bioaccumulate and undergo biotransformation following ingestion by organisms in a particular ecosystem. However, with plastics, the scope for such processes is limited. The long chains of monomers, with strong chemical bonds, resist biotransformation and degradation reactions, thereby conferring properties of persistence in the environment. Nevertheless, additives and other chemicals adsorbed on to plastic surfaces readily accumulate and may exert toxic effects or be neutralized by natural processes in oceans and sediments. Toxicity of plastics has been observed at different levels of biological organization, including biochemical, physiological, behavioural and ecological impacts. Current evidence is based on different investigative approaches covering a broad range of exposures, biomarkers and organisms. The wide range of exposures encompassing combinations of polymer type, microplastic dimensions, concentrations and duration create difficulties in the interpretation of observed data and prediction of environmental and biological impacts. At cellular and biochemical levels, new evidence indicates that microplastic exposure and uptake can induce oxidative stress, lipid peroxidation, DNA damage and activation of antioxidant enzymes. Immunological responses, including phagocytosis activity, inflammation and enzyme/protein responses, have also been observed.

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At the whole-organism level, microplastics can affect feeding activity, body­ weight and energy reserves, reproduction success and even survival, with most of the data based on studies with invertebrates with short life cycles or with model species. For example, polystyrene nanoplastics can inhibit reproduction and induce abnormal embryonic development in the freshwater crustacean Daphnia galeata, a common model species used in ecological risk assessments. In addition, investigations with D. magna demonstrate that nano­ plastics can interact in an additive mechanism with hydrophobic pollutants in the aquatic ecosystems, underlining the high potential risks of these ultra­ fine particles. Transgenerational effects of microplastics in D. magna have been observed, including parental mortality, reduced reproduction and population growth, leading to potential extinction of the population. Size-dependent effects of microplastics are apparent in several investigations with experimental organisms. For example, in the monogonont rotifer, microbead toxicity, expressed in terms of oxidative stress induction and activation of MAPK signalling pathways, occurred in a size-dependent manner. In view of the above evidence, there is clearly considerable disquiet about the implications for human health. A recent investigation indicated preliminary justification for this concern on the basis of tissue accumulation of microplastics and biomarker responses in mice indicating widespread potential health risks of exposure to these particles. Using fluorescent and pristine polystyrene microplastic particles, it was demonstrated that these particles accumulated in the gut, liver and kidney, with tissue accretion kinetics and distribution patterns strongly dependent on particle size. In addition, analyses of several biochemical biomarkers and metabolomic profiles revealed perturbations of energy and lipid metabolism as well as oxidative stress. Blood biomarkers of neurotoxicity were also altered, although the mode of action for these and other disturbances remains obscure. It may be relevant that, in the model zebrafish, enhanced uptake of bisphenol A in the presence of microplastics has also been associated with neurotoxic effects. Limited evidence indicates that microplastics can cause behavioural changes, including, for example, reduced swimming activities of marine planktonic crustaceans and seabass, jump height of beach hoppers and predatory performance of common gobies, among others. Neurotoxic effects and oxidative stress responses provide additional insights into the sub-lethal effects of microplastic beads on marine crustaceans. The analysis of ecological end-points, such as changes in population sizes or in dynamics of assemblages, is the ultimate issue of concern. However, the current evidence is limited to the structure of invertebrate benthic assemblages and population sizes of copepods, with both studies showing ecological perturbations associated with exposure to microplastics. One of the principal concerns regarding microplastics as pollutants is their role as vectors of other contaminants, including constituent additives, organic compounds and pathogens. The influence of cosmetic microbeads on the adsorptive behaviour of cadmium and lead within intertidal sediments is of concern as this provides a route for metal contamination of freshwater and marine trophic webs, ultimately impacting on food safety for humans. Similarly, experimental work with polybrominated diphenyl ethers adsorbed on to microbeads from personal care products demonstrate that ingested chemical pollutants can accumulate in fish, shellfish and filter feeders, thereby representing potential

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hazards for humans. It has been suggested that POPs adhering on microplastics can accumulate at concentrations of several orders of magnitude above those contaminating the ambient seawater. The observation that microplastics can aggravate the toxicity of organophosphorus flame retardants gives additional cause for concern. Consistent with widespread evidence of plastic contamination in marine ecosystems, focus is currently being directed at potential detrimental effects, particularly in human populations reliant on diverse forms of seafood, as in coastal communities. It is certain that human exposure to micro- and/or nanoplastics has occurred over several decades, although 90% or more of ingested particles are expected to be voided in the faeces. However, retention and clearance rates would vary with source, shape, polymer composition and chemical additives used in the manufacture of microplastics. Inferences from different investigations suggest a number of effects of ingested micro-/nanoplastics, including enhanced inflammatory reaction, size-related toxicity, transfer of adsorbed chemical pollutants and a dysfunctional gastrointestinal microbiome. It is also suggested that these particles can be transported across living cells, such as the M cells in the gut mucosa or dendritic cells into the lymphatic and/or blood circulatory system to accumulate in secondary organs, including the liver and gall bladder, adversely impacting the immune system. It is further implied that nanoplastic size and hydrophobicity enable transport to pulmonary tissues and across placental and blood–brain barriers, potentially sensitive sites for toxicity. The relatively large surface area-to-volume ratio in nanoplastics facilitates greater chemical reactivity, compared with microplastics. Similarly, it is proposed that, relative to microplastics, nanoplastics may be more readily absorbed from the gut. Current interventions include bans and voluntary agreements in the use of specified plastic materials such as microbeads and charges for single-use shopping bags. However, the widespread distribution of plastics in the marine ecosystem is still a formidable problem, requiring further legislation and remedial actions well into the future. Education and outreach initiatives should help to modify public attitudes to pollution with visible large plastics, but the issue of toxicity is primarily associated with micro- and nanoplastics already in the environment, creating challenges for the foreseeable future.

7.3 Pharmaceuticals The manufacture and personal use of pharmaceuticals can result in significant wastewater discharges of active chemical ingredients into diverse ecosystems, affecting wildlife at various trophic levels and, in certain cases, ultimately impacting human health. Adverse effects can occur locally or globally, as in the case of antibiotics and other prescribed medicines. Recent surveys highlight the extent of antibiotic pollution in rivers around the world, even including the Thames and Danube in Europe. For example, in the Danube clarithromycin was identified as an important contaminant, while rivers in Bangladesh contained excessive levels of metronidazole. In China, antibiotic pollution occurs in the major rivers, including the Yangtze and Pearl Rivers, and has also been found in tap water. Antibiotics including amoxicillin

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and 6-aminopenicillanic acid as well as almost 70 others have been identified at high concentrations in tap/surface water. Pollution in soil and rivers occurs via discharges in human and animal faeces, leaks from wastewater treatment sites and laboratories manufacturing pharmaceuticals. Dangerously elevated levels of antibiotics have been observed in a significant number of rivers worldwide, raising concerns about the development of antibiotic resistance among bacterial pathogens. It is maintained that considerable numbers of genes in human and veterinary pathogens arise from environmental sources. The general consensus is that, although concentrations are considerably lower than those used in medical treatments, the risks for the development of antibiotic resistance are sufficiently severe to reduce the efficacy of many antimicrobial drugs. An additional concern is that antibiotics in groundwater and arable soils may contaminate plant products destined for human and animal consumption. Furthermore, work with model systems indicate that antibiotics in manure and soil can inhibit the microbial breakdown of herbicides and possibly other pesticides, making them more persistent. While this reduction in biodegradability may be beneficial for crop protection, there would be deleterious implications for wildlife survival and diversity in arable environments. Antibiotic pollution also occurs in other ecosystems, including coastal waters in China and freshwater and saltwater marshes in Louisiana (USA). Norfloxacin and sulfamethoxazole appear to present high ecological risks in coastal waters in China. It also appears that the presence of antibiotic-resistant bacteria in wetland habitats is unaffected by salinity and that the risks to wildlife through the dissemination of antibiotic-resistant genes remains a potential threat to biodiversity in this ecosystem. A disturbing issue is the occurrence of pharmaceutical, recreational and psychotropic drug residues in surface waters in the Antarctic peninsula, generally regarded as a pristine environment. Concentrations for 16 compounds ranged in ng to μg l–I, with maximum values for analgesics deemed to present particular environmental risks. Furthermore, there is accumulating evidence linking illicit drugs in wastewater to contamination of surface and drinking water in urban watersheds. It is clear that a number of these drugs are not effectively removed during drinking-water treatment operations. Wastewater contamination is a persistent and worldwide problem, with substances such as analgesics, anti-inflammatories, anti-hypertensives and psychiatric drugs featuring regularly and at the highest frequency of detection in surveys. Another pharmaceutical of concern includes 17α-ethinyl oestradiol, a synthetic compound used in formulations of oral contraceptives. The active ingredient is excreted in the urine of women using this contraceptive and its worldwide occurrence at increasing concentrations contaminating major rivers and surface waters has been confirmed. The negative effects of steroid exposure on fertility and reproduction of children, men and wildlife should not be underestimated.

7.4  Personal Care Products The chemical residues of personal care products, applied as topical preparations, are ubiquitous in the environment, with the potential to adversely affect

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health and welfare of humans and wildlife via side effects as well as by direct mechanisms. Personal care products are derived from a range of compounds with diverse chemical, physical and toxicological properties. Oxybenzone (benzophenone-3) is used as a component of sunscreen lotions and personal care products designed to protect humans against the damaging effects of ultraviolet radiation. However, the dilemma between cancer protection and environmental damage should be considered (Raffa et al., 2019). Oxybenzone is a contaminant of concern in marine/aquatic ecosystems, being produced by swimmers and present in wastewater discharges from municipal, residential and shipping sources. Treatment plants do not effectively remove oxybenzone or octinoxate (another UV filter) from effluents during standard processing procedures. Thus, current reports of various concentrations in waterways and fish are consistent with widespread contamination worldwide; the implications for bioaccumulation and seafood safety are, therefore, of some concern. Recent evidence indicates that 97% of people tested had oxybenzone present in the urine, presumably as a result of skin application and absorption. This compound is a photo-toxicant, implying that adverse effects are exacerbated by exposure to sunlight. Consequently, toxicity in humans is expressed as contact and photo-contact dermatitis, but there are also suggestions that oxybenzone may act as an endocrine disruptor and may be a factor to consider in current observations of reduced fertility in humans. Oxybenzone acts as a genotoxicant to coral planulae and cultured primary cells, producing effects such as reef bleaching and threatening the resilience of these reefs to adapt to climate change. Insect repellents formulated with the active ingredient N,N-diethylmeta-toluamide (DEET) are currently used by millions of people worldwide. It is credited with an ‘excellent safety profile’, providing high protection against mosquitoes, ticks and other potentially harmful arthropods. Incidence of toxicity is rare and generally linked with incorrect or excessive use. Inhalational exposure, for example, can cause severe toxicity. It is suggested that side effects of DEET in humans may involve a number of molecular targets, including cholinergic, acetylcholinesterase, muscarinic and second messenger (nitric oxide) pathways. These networks are considered to be of subsidiary importance in the action towards target insects. Adverse effects of DEET include skin reactions and, even in more severe manifestations such as seizures, recovery occurs without long-term consequences. The continued use of DEET as a repellent is supported by national health and environmental agencies in the USA, with specific recommendations for its use on children. Emphasis is always placed on the requirement to follow the manufacturer’s instructions, not a resounding endorsement of safety. Environmental contamination occurs via sewage treatment plants, with DEET being detected in groundwater below and adjacent to onsite wastewater treatment operations. Regarding aquatic toxicology, there are persistent demands for the need to undertake environmental risk assessments for insect repellents. DEET is moderately toxic to non-target insects such as the aquatic midge and caddisfly, by impairing feeding and development rates as well as detoxification capacity and by inducing neurotoxicity, but the effects only emerge at concentrations significantly above environmental contamination levels. Potential toxicological

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effects in dinoflagellates have also been highlighted, particularly for populations in habitats characterized by low water circulation as in bays and lagoons. Surfactants of diverse chemistry are widely used in detergents and personal care products and in clean-up operations in industry. Although wastewater treatments are highly efficient at removing these compounds, the vast quantities used mean that contamination of aquatic ecosystems and habitats is unavoidable. As a result, surfactants are regularly detected in freshwater, coastal waters and associated sediments. Biodegradation tends to be less rapid in marine than in freshwater environments, although ecotoxicity is similar in both cases. As an approximate rule, surfactant ecotoxicity is determined by chain length and branching of the surfactant molecules. Surfactants with longer alkyl chain lengths and those with branched structures are associated with higher toxicity.

7.5  Key Issues Plastics, synthetic fibres, pharmaceuticals and personal care products are now recognized as major pollutants in rivers and oceans, associated with adverse physical and biochemical effects on freshwater and marine animals. Entanglement and obstruction in the digestive system are the primary effects of plastics and synthetic fibres, but these polymers may also act as vectors by interacting with other pollutants. Certain pharmaceuticals and personal care products may contaminate drinking water and disrupt hormonal balance, while others may facilitate development of antibiotic resistance in pathogens or endanger sensitive habitats such as coral reefs.

7.6 References Compa, M., Alomar, C., Wilcox, C., Lebreton, L., Hardesty, B.D. and Deudero, S. (2019) Risk assessment of plastic pollution on marine diversity in the Mediterranean Sea. Science of the Total Environment 678, 188–196. Kandziora, J.M., van Toulon, N., Sobral, P., Taylor, H.L., Rubbink, A.J. and Werner, S. (2019) The important role of marine debris networks to prevent and reduce ocean plastic pollution. Marine Pollution Bulletin 141, 657–662. Raffa, R.B., Pergolizz, J.V., Taylor, R. and Kitzen, J.M. (2019) Sunscreen bans: coral reefs and skin cancer. Journal of Clinical Pharmacy and Therapeutics 44(1), 134–139. doi: 10.1111/ jcpt.12778

7.7 Exercises (i)  Describe the different grades of polymers that pollute marine ecosystems. (ii) Compare and contrast the detrimental impact of the different grades of plastics on marine species, including effects at various levels of biological organization. (iii)  Summarize the risks associated with pharmaceutical pollution. (iv)  Explain why there are particular concerns over personal care products in aquatic and marine ecosystems.

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8

Radiation

8.1 Overview Evidence concerning the wide-ranging effects of radiation is based primarily on an abundance of historical case studies and ongoing lapses in the maintenance of safety at modern nuclear power generation installations. It is also becoming clear that the combustion of coal and the extraction of shale oil and gas by fracking are associated with low-level radioactive emissions. Furthermore, delays in decommissioning of obsolete nuclear-powered hardware present long-term occupational and residential hazards. Additional human health risks arise as a result of exposure to radon in enclosed environments and to UV in sunlight (Table 8.1).

8.2  Ionizing Radiation It is instructive to summarize legacy issues and contemporary events that stimulate interest in and apprehension over the long-term hazards of ionizing radiation. • The detonation of two atomic weapons over Hiroshima and Nagasaki in 1945 by the USA marked an ignominious phase in human history, providing a toxic legacy for future generations to endure. • Whereas the infrastructure has now been largely restored in both cities, the adverse effects for survivors continue to present toxicologists with a diverse array of syndromes, particularly cancer. • Moreover, major events, including the Three Mile Island accident in 1979, the Chernobyl explosion in 1986 and the Fukushima nuclear accident in 2011 as well as regular radiation discharges from nuclear power plants and storage facilities on both sides of the Atlantic, have highlighted the 106.

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Table 8.1.  Radiation toxicology. Source

Human health effects

Ionizing radiation Radon UV

Radiation sickness; cancer; mental health disturbances Cancer Cancer

•

• • •

need for continued vigilance and monitoring of local communities for deleterious effects. In addition, the recommendation by Japanese authorities in 2019 that previous residents should return to Fukushima, ahead of the Tokyo Olympics, despite high levels of radiation appears reckless and cannot be justified on long-term health grounds. Similarly, the commissioning of a floating nuclear plant in Russia has caused concerns for safety and international auditing of radionuclide emissions. It is also worth noting that some 60 years after testing of nuclear weapons, radiation in parts of the Marshall Islands in the Pacific are higher than in Chernobyl and Fukushima, as determined in a 2019 study. Thus, radiation risks at the present time are ongoing, but legacy issues still remain.

The explosion at the Chernobyl nuclear reactor (Fig. 8.1) caused widespread and long-term contamination of the environment, adversely impacting air quality, food safety and human health. This accident unleashed volatile radioactive elements, including radioiodine 131I and radiocaesium 137Cs, across extensive areas of the former Soviet Union and Western Europe. The pattern of radioactive contamination was complex: in Western Europe, maximum deposition of radiocaesium isotopes occurred in regions where rainfall intercepted the pathway of the radioactive plume. Less volatile nuclides, including isotopes of strontium and plutonium, were deposited primarily within 30 km of the failed reactor, in the form of small particles of radioactive fuel. The radiobiological impact of released isotopes varied with time after the nuclear accident, due to differences in the half-life of the respective elements. In the first few weeks following the accident, the radiation dose to humans was primarily associated with radioiodine, with contributions from other short-lived isotopes. Over succeeding months to years, longer-lived isotopes, particularly 137Cs, with contributions from 134Cs and 90Sr, formed the major part of the dose. Physical decay of these isotopes is accompanied by the emission of α, β, and ɣ radiation, each with particular characteristics. Heavy elements such as uranium, thorium and radium emit α particles which are identical to the nucleus of the helium atom. In view of their heavy mass and charge, α particles are highly ionizing and are easily absorbed. They travel just a few centimetres in air and cannot penetrate the skin but are harmful after they enter body organs via inhalation or ingestion of contaminated food. In contrast, β particles are identical to electrons and are able to travel further in air but cannot penetrate much beyond the skin of humans. Consequently, like α rays, β radiation is only harmful when the rays are inside the body; external exposure, however,

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Fig. 8.1.  The explosion at the Chernobyl power plant in 1986 caused severe radionuclide contamination in Ukraine, Belarus and the Russian Federation. Recent assessments of the 30-year legacy indicate increased risks of leukaemia and thyroid cancer among individuals exposed to radiation as children and adolescents. Media reports indicate that natural recovery is occurring, with lush greenery, wild horses and packs of wolves observed in the exclusion zone around the disabled reactor. In a separate development, considerable disquiet has emerged over recommendations to release into the Pacific Ocean radioactively contaminated water from the destroyed reactor in Fukushima. The residual tritium in this discharge is deemed to be non-toxic to humans, but other evidence indicates genotoxic effects as well as modulation of immune, neural and antioxidant pathways in marine species. (Image ‘IMG_2974’ by Porco-Rosso is licensed under CC PDM 1.0.)

can cause skin burns. Emissions of ɣ rays are, in effect, electromagnetic radiation, similar to light, but with enhanced energy, and are produced along with α or β particles. In view of the great penetrating power, intensity of radiation can only be reduced with thick blocks of concrete, lead or other high-density materials. This penetrating power can deliver whole-body doses from external and internal exposures. For practical purposes, the gastrointestinal route is the most significant pathway for the entry of radionuclides in the body. In special circumstances, pulmonary and dermal routes may present additional exposures, as for example in the Three Mile Island, Chernobyl and Fukushima accidents. Monitoring and minimizing contamination of food is, therefore, a key strategy in risk management. Radioactive particles are removed from the atmosphere by precipitation in the form of rain or snow. Human consumption of radioactive substances occurs from contaminations in food crops, meat and meat products and milk and derived dairy products. The relative importance of the different pathways will depend upon the physical half-lives of the radionuclides, the rate and route by which

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they pass through the food chain and the dietary preferences of the population. An important pathway is the pasture–cow–milk–human link, at least in the immediate aftermath of a contamination event such as the Chernobyl or Fukushima explosions. After this period, other factors particularly relating to the processes involved with the longer-lived particles become relatively more important. Acute toxicity of radiation follows proportional dose–response characteristics, with effects ranging from nausea, vomiting and diarrhoea to internal bleeding, coma and death. At high dosages, radiation can induce instantaneous mortality. Such progressive manifestations of toxicity would be expected to occur in the immediate aftermath of a nuclear attack (as in Hiroshima and Nagasaki) or of accidental explosions (as in Chernobyl and Fukushima). The accident in Chernobyl resulted in a significant number of cases of acute radiation sickness among plant employees and first responders, but not among evacuees or the general population. Initial diagnosis was based on the classical symptoms for this condition, but mortality was also an important feature. In the initial phase, underlying bone marrow failure was the primary cause of death. Skin exposures were also high, leading to infection of large area burns caused by β radiation. Other evidence indicated the expression of neurophysiological markers of ionizing radiation. It is relevant here that updated review on the 20th anniversary of the Chernobyl disaster concluded that mental health effects were the most significant public health issue of this contamination. Among first responders and clean-up personnel with greatest exposure, rates of depression and post-traumatic stress disorder remain high two decades after the explosion. Within the general population, clinical and sub-clinical depression, anxiety and post-traumatic disorder were also recorded. Chronic exposure to radioactive particles is associated with significant health deterioration among clean-up personnel attending nuclear power plant explosions and the general population, particularly those residing near nuclear installations and illegal storage sites or in close proximity to coal-fired power stations or fracking operations. Following the Three Mile Island accident, minor increases were recorded for cancer of the bronchus, trachea and lung and for leukaemia, and although thyroid cancer incidence was higher than expected, a direct link with the accident could not be established. However, the most significant community health manifestation was the incidence of mental illness, including psychological disorders in mothers of young children and in emergency personnel. It is instructive to compare these effects with evidence for the Chernobyl contamination event (see Case Study 8.1). It is clear that the toxicology of radionuclides centres around the main issue of carcinogenesis (see Fisher et al., 2019). It has recently been estimated that by 2065, the Chernobyl accident will have led to more than 40,000 cases of cancer. Following this accident, the highest incidence of thyroid cancer occurred among children residing in a particular region (Bryansk) with radiation-contaminated sediment. Exposure in utero to radioactive fallout at Chernobyl and the incidence of thyroid cancer raises important implications for risk assessment protocols (Hatch et al., 2019). The increased incidence of late-onset thyroid cancer due to ionizing radiation is a health hazard in the aftermath of a nuclear power plant explosion due primarily to the emission

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Case Study 8.1.  The Chernobyl debacle Exposure to low-dose ionizing radiation is a regular feature of modern life arising with the use of medical diagnostics, air travel and occupational sources. At relatively low doses of radiation, toxicity in humans may be expressed in terms of nausea, but higher doses can result in vomiting, diarrhoea, internal bleeding and death. This spectrum comprises the ‘radiation sickness’ syndrome associated with nuclear explosions, either intentional or accidental. The linear, no-threshold response also implies quantitative effects between chronic ionizing radiation exposure and the induction of cancer. The Chernobyl explosion in the Ukraine in 1986 has now become one of the most significant pollution events in history, adversely affecting human health and biodiversity in ecosystems of several European countries. The release of radionuclides is the primary cause for concern even to the present day. Current assessments of the 30-year toxic legacy indicate increased long-term risks of leukaemia and cardiovascular disease among clean-up personnel as well as thyroid cancer in individuals exposed to radiation as children and adolescents. In Belarus and over 30 other regions of Europe, rates of childhood leukaemia were higher in the post-accident period. In addition, mental health effects appear to be the most significant public health issues in the heavily contaminated regions of Ukraine, Belarus and the Russian Federation. Other long-term adverse effects may be inferred from emerging investigations with atomic bomb survivors in Japan. For example, statistically significant increases have been reported for the incidence of heart disease, stroke, digestive dysfunction and respiratory diseases in these subjects. As might be predicted, radioactive emissions in the wake of the Chernobyl accident continue to induce wildlife abnormalities. For example, a significant impact on rates of reproduction and survival of the barn swallow have been observed. However, 30 years after this contamination, there is still a lack of data relating to the genetic effects on the ecology of higher plants, although media coverage shows luxuriant recovery of shrubs and trees. • Can you predict likely long-term human health and ecological outcomes, for the Fukushima nuclear plant explosion? • Despite high radiation levels, former residents are being urged to return to Fukushima: explain how you would argue against this advice. • Can you suggest reasons for any differences in ecological indicators between Chernobyl and Fukushima in the post-accident recovery period?

of radioiodine in the fallout. This risk is higher for individuals exposed during infancy and adolescence. Extensive screening in Fukushima revealed a high detection rate for thyroid cancer among young individuals. The elevated prevalence of childhood thyroid cancer has been attributed to mass screening and direct comparison with other evidence pertaining, for example, to sporadic/ spontaneous cases is made difficult due to differences and limitations in methodology. Particular constraints include the current lack of molecular signatures or genetic biomarkers that would correlate epidemiological evidence with biochemical/physiological mechanisms. Thus, cause-and-effect relationships have yet to be established for the increased incidence of thyroid cancer.

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Difficulties are also encountered in the interpretation of data for long-term effects of radiation. For example, it has recently been observed that solid cancer risks among atomic bomb survivors in Japan remain high more than 60 years after exposure. However, even after using improved dose estimates and adjusting for cigarette smoking, doubts about the shape of the dose–response relationship precludes formulation of reliable and definitive conclusions to inform radiation protection policy-makers. Nevertheless, it is consistently stated that the long-term association between exposure to radiation and cancer is well established, with some justification. For example, the occurrence of meningioma among Hiroshima atomic bomb survivors has increased since 1975, with significant correlation between incidence and the radiation dose in the brain. Recent assessments of the incidence of leukaemia, lymphoma and multiple myeloma among atomic bomb survivors within the Radiation Effects Research Foundation’s Life Span Study cohort indicated a significant increase in leukaemia risk in Hiroshima and Nagasaki. Ionizing radiation compromises key pathways in haematopoiesis by damaging functional stem cells and the capacity of bone marrow to support regeneration, exacerbated by apoptosis of mature components of the blood. At the molecular level, radiation damages DNA, gene expression and transcription and disrupts signalling networks. The overall clinical outcome of these perturbations is the induction of leukaemia, a critical haematological manifestation, with risks, for example in atomic bomb survivors, persisting throughout the follow-up period up to 55 years after initial exposure to radiation. Ukrainian children exposed in utero to the Chernobyl fallout showed significant increases for all leukaemia types, including the lymphoblastic form. Similarly, rates of childhood leukaemia were higher in the period after the Chernobyl accident. However, in Sweden, incidence of acute childhood leukaemia did not correlate with degree of radioactive contamination after this accident. Overall mortality, particularly from non-cancer diseases in impacted populations, is another factor of importance in assessing radiation risks. Evidence that radiation affects non-cancer mortality is convincing, with significant increases recorded for cardiovascular, digestive and respiratory causes among atomic bomb survivors. However, emerging surveys suggest that the long-term risks for respiratory disease may be attributed to coincident cancer or other underlying disorders associated with radiation exposure in these subjects. Ecological indicators of the impact of radiation are gradually emerging, with the limited evidence showing significant negative effects on rates of reproduction and survival of, for example, barn swallows in the Chernobyl region. Differences in the abundance of animals between Chernobyl and Fukushima have also been observed and attributed to the direct effects of radioactivity in Fukushima, whereas additive effects of radiation and mutation accumulation over long-term exposure may have contributed to the observations in Chernobyl. Recent reports indicate limited ecological recovery in Chernobyl with the return of lush vegetation and wildlife.

8.3 Radon Radon is a rare inert radioactive gas formed by the decay of three natural isotopes, namely radon-219, radon-220 and radon-222, that are in turn products Downloaded from https://cabidigitallibrary.org by Ivanov Ivan, on 11/04/24. Subject to the CABI Digital Library Terms & Conditions, available at https://cabidigitallibrary.org/terms-and-conditions

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of the radionuclides uranium-235, thorium-232 and uranium-238, respectively. These radionuclides occur widely in soil and rocks such as granite. Escaping radon from rocks and soil are transported by air and to a limited extent by dissolving in water. Radon-222 produces progeny comprising solid entities via several stages culminating in the stable element lead-206. Two of the isotopes produced during this decay, including polonium-214 and polonium-218, are alpha emitters. These solid decay products can be inhaled as free entities or, more commonly, as particles adhering to dust. These particles lodge in the bronchial epithelium with the potential to damage the cell nucleus and cause genetic aberrations. Historically, radon emission has been associated with lung cancer in mineworkers, but epidemiological evidence indicates that residential exposure is the second leading risk factor for lung cancer after cigarette smoking in the general population. In 1988, IARC recognized radon exposure as a causal factor for lung cancer, based on evidence obtained with mineworkers exposed to high concentrations of this gas. Low-level radon exposure and lung cancer mortality are clearly an important issue and continues to attract attention (Chain et al., 2019). The relative risk for lung cancer is proportional to cumulative radon exposure. There is epidemiological evidence for an increased risk of lung cancer caused by synergism between radon exposure and smoking in mineworkers and in the general population. It is estimated that 17% of all lung cancer cases in Alberta (Canada) during 2012 are attributable to residential radon exposure. Possible links to leukaemia and interactions with ambient PM2.5 are now being investigated. Radon exposure is not associated with any specific histological type. Initial autopsy investigations on miners exposed to high levels of radon identified an excess of thoracic tumours, classified as lymphosarcoma, but in all probability representing the expression of small-cell lung cancer. Subsequently, this form of cancer was also detected in autopsies of uranium miners. This was, therefore, firm evidence of an association between radon exposure and the incidence of proximal lung tumours. Moreover, miners showed all histological types, including small-cell lung cancer, non-small-cell lung cancer, adenocarcinoma and squamous-cell carcinoma. Similarly, in one European trial involving the effects of residential radon exposure, all histological types were identified. The underlying mechanisms leading to the expression of lung cancer are chromosomal degradation, gene mutation, synthesis of free radicals and cell cycle modification due to production of inflammatory cytokines and proteins. For example, gene deletions are known to occur in glutathione S-transferases and these abnormalities may increase risk on exposure to radon. Higher incidence of cytogenetic damage in peripheral lymphocytes has been observed in individuals exposed to radon, with the occurrence of polymorphism in certain DNA repair genes, which may represent genetic markers of chronic radon exposure. Furthermore, chromosomal abnormalities have been observed in miners and non-miners exposed to radon. In the light of epidemiological evidence, minimizing radon risk is warranted for both occupational and residential circumstances. It is imperative that radon testing is performed where subsoils have high uranium contents and to prescribe remedial or preventive measures. In summary, as with other

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environmental contaminants, the absence of distinctive pathological features in radon carcinogenesis presents difficult cause-and-effect issues in resolving disputes, following occupational or indoor exposures or during risk assessment in mines and housing developments.

8.4  Ultraviolet Radiation Ultraviolet (UV) radiation can be subdivided into UVC, UVB and UVA categories, based on electrophysical properties. UVC radiation (at 200–280 nm) presents the highest energy and the lowest penetration capacity in UV radiation. It is absorbed by atmospheric ozone and generally does not reach the earth’s surface. UVB radiation (at 280–320 nm), representing 5% of the UV that reaches the ground, is almost entirely absorbed by the epidermis of the skin. UVB is directly absorbed by DNA, inducing molecular rearrangements and forming specific photoproducts. UVB is responsible for diverse forms of damage, representing the most cytotoxic and mutagenic type of solar radiation. UVA radiation (in the range 320–400 nm) comprises 95% of the solar radiation reaching the earth’s surface, penetrating deeply into the epidermis and causing physiological and molecular damage. The skin is an extensive organ in the body, serving as the first barrier designed to protect an organism from excessive loss of water or from potentially harmful agents such as microbial pathogens and solar radiation. Furthermore, the skin is a sensory organ due to the presence of nerve endings and receptors related to the sense of touch and temperature. Chronic exposure of the skin to UV radiation is the primary event that initiates several disorders, including inflammation, immunosuppression, photo-ageing and skin cancer. This radiation induces DNA damage and can cause mutations of the p53 gene, which promotes tumour growth, causing immunosuppression and oxidative stress. Apart from these adverse effects, UV exerts other important functions, particularly melanogenesis and vitamin D synthesis. In response, the body can instigate a variety of defence reactions, for example DNA repair and stimulation of the immune and innate antioxidant systems. The incidence of skin cancer increases with decreasing geographical latitude, representing particular risks for fair-skinned individuals in the western hemisphere. Three types of skin cancer are recognized, including squamous cell carcinoma, basal cell carcinoma and cutaneous melanoma. The latter occurs less frequently, but is associated with high mortality. Skin cancer is the most rapidly-growing malignant disease worldwide, representing health risks particularly for non-melanoma cancer in outdoor workers. Extensive analysis of existing data using different mathematical models suggests that the development of squamous cell carcinoma is dependent on total UV exposure, whereas basal cell cancer and particularly cutaneous melanoma are also dependent upon exposure patterns, with intermittent exposures presenting greater risks. According to IARC, UV is classified as a complete carcinogen due to its ability to induce mutagenic DNA photoproducts, in particular cyclobutene pyrimidine dimers in epidermal keratinocytes. In addition to causing DNA

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damage, UV can also suppress anti-tumour mechanisms and stimulate metastasis of skin neoplasms. The effects on cancer cells and anti-tumour immunity occur by modulating the expression of specific cytokines and chemokines, which are now emerging as targets for therapeutic strategies to prevent and treat skin cancer. Photo-carcinogenesis conforms with the multi-stage model of cancer initiation in which UV-induced DNA damage results in mutations that activate oncogenes or silence tumour-suppressing genes. Endogenous mechanisms, particularly the nucleotide excision repair pathway and apoptosis, exist to counteract these mutations and inhibit skin neoplasms, but other factors may determine the eventual outcome. For example, the UVB-sensitive transcription factor aryl hydrocarbon receptor (AHR) attenuates the clearance of DNA photoproducts. AHR is a ligand-activated transcription factor implicated in the toxic effects of a number of POPs (see Chapter 4). It is thought that activated AHR can intervene as a negative regulator of defence processes, repressing nucleotide excision repair and apoptosis, thereby contributing to UV-induced carcinogenesis. In the case of cutaneous squamous cell carcinoma, long-term UV exposure and chronic wounding are the dominant risk factors and efforts are continuing to identify the common and specific signature molecules that determine and characterize this interaction. Controversially, exponentially increasing incidence of cutaneous malignant melanoma in Europe may be associated with low personal annual UV doses. It is suggested that intermittent UV exposures result in sub-optimal cutaneous levels of vitamin D3, while the exponential spread of human papilloma virus may also contribute to this form of skin cancer. It is clear that current understanding of the UV–skin-cancer relationship is still evolving, both in terms of the risk factors and the underlying molecular mechanisms as well as the potential for compounds, such as plant polyphenols, to prevent the development of harmful effects.

8.5  Key Issues Radiation toxicology is dominated by the issue of carcinogenesis, although the clinical effects are different for the three major sources of exposure. Whereas ionizing radiation is associated with blood and thyroid cancer, radon and UV exposures are linked with malignancies of the lung and skin, respectively. However, there are questions concerning exposure patterns, dose–response effects, cigarette smoking and, in the case of UV radiation, vitamin D3 status. Skin cancer incidence has risen markedly over recent years, particularly among young individuals.

8.6 References Chain, R.O., Young, S.S. and Krstic, G. (2019) Low-level radon exposure and lung cancer mortality. Regulatory Toxicology and Pharmacology 107, 104418. doi: 10.1016/j.yrtph. 2019.104418.

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Fisher, S.B., Cote, G.J., Bui-Griffith, J.H., Lu, W., Tang, X. et al. (2019) Genetic characterization of medullary thyroid cancer in childhood survivors of the Chernobyl accident. Surgery 165, 58–63. Hatch, M., Brenner, A.V., Cahoon, E.K., Little, M.P., Shpak, V. and Bolshova, E. (2019) Thyroid cancer and benign nodules after exposure in utero to fallout from Chernobyl. The Journal of Clinical Endocrinology & Metabolism 104, 41–48.

8.7 Exercises (i)  Compare and contrast the human health risks associated with ionizing radiation and UV exposure. (ii)  Explain to what extent epidemiological evidence is supported by empirical observations in radiation toxicology. (iii)  Outline the confounding factors that have to be taken into account in radiation toxicology. (iv)  Using reports available online and recent observations at Chernobyl, describe the extent to which ecological recovery is possible in Fukushima.

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9



Adaptation in Microbes and Higher Plants

9.1 Overview It is widely accepted that microbes and higher plants are endowed with an extensive array of metabolic mechanisms to adapt to changing environmental conditions, including, for example, reduced pH, water deficit, increased carbon dioxide emissions and a diverse range of organic and inorganic contaminants. Metabolic versatility is maximized in microorganisms compared with plants (Pei et al., 2019). Animals have limited capacity to metabolize or neutralize complex biogenic compounds and POPs, except those species harbouring symbiotic gut microflora. It is instructive to examine the biochemical pathways involved in detoxification processes in microbes and plants and to explore the potential for bioremediation in contaminated ecosystems.

9.2 Microbes Microbial activity can confer both beneficial and detrimental outcomes in the metabolism and final disposition of biological toxins. For example, the tropical forage legume Leucaena leucocephala contains a toxic amino acid, mimosine. The toxicity of Leucaena is determined by geographical differences in rumen microbial ecology in cattle, sheep and goats. The adverse effects are critically dependent upon the rate and extent of bacterial degradation of mimosine to its metabolite, 3-hydroxy-4(1H)-pyridone. Ruminants in Australia, the USA and Kenya lack the requisite bacteria to complete the degradation of this metabolite and consequently succumb to its goitrogenic effects if relatively high intakes of Leucaena are maintained over protracted periods of time. However, in other regions where Leucaena is indigenous (Central America) or is naturalized (Hawaii and Indonesia), ruminants there possess the full complement of

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bacteria that are required for 3-hydroxy-4(1H)-pyridone degradation, which accounts for the absence of Leucaena toxicity in these countries. In contrast, the toxicity of the non-protein amino acid, S-methylcysteine sulfoxide, present in forage brassicas, is mediated only after metabolism by rumen bacteria to a reactive metabolite, dimethyl disulfide. This product precipitates a severe form of haemolytic anaemia within 1–3 weeks in ruminants fed mainly or exclusively on Brassica forage. Extensive evidence indicates that microbes have the biochemical mechanisms to detoxify POPs at contaminated sites. For example, contaminated sediments from a wastewater lagoon in Virginia (USA) contained microbial communities dominated by Proteobacteria, Firmicutes and Clostridia with the potential to dechlorinate PCBs. Data indicated the presence of PCB reductive dehalogenase genes to support such a mechanism. Other evidence points to the microbial degradation of dioxins and furans at a site with multiple contaminants in Oregon (USA). Regarding petroleum pollution following the Deepwater Horizon blowout, there are clear indications of biodegradation and greater expansion of microbial diversity in marsh sediments impacted by this accident. It is generally concluded that microbial activity has contributed to the ongoing recovery in the impacted ecosystem. The potential role of microbial extremophiles in petroleum hydrocarbon degradation is explained by Kumar et al. (2019). Of particular significance is potential for microbial degradation of plastic debris in waterways and oceans. Emerging evidence indicates low distribution of microbes with polyethylene terephthalate hydrolases in marine and terrestrial ecosystems. It is important, however, that transgenics are not used to enhance capacity in the natural environment.

9.3  Higher Plants Trees in the Amazon basin (Fig. 9.1) and elsewhere play a key role in global environmental protection and regeneration. Benefits arise due to assimilation of atmospheric carbon dioxide, with the concomitant emission of oxygen and also involvement in the mineral dynamics of the rhizosphere. Prevention of erosion and water conservation are other vital functions. But these facts are often ignored in countries such as Brazil and Indonesia where deforestation is actively promoted in favour of intensive farming. Acid rain represents one of the most widespread manifestations of pollution, capable of severely inhibiting plant growth and even survival. Interaction between acid rain and UV radiation on photosynthesis implies complex multifactorial responses in plants exposed to a range of physical and chemical stimuli (Liu et al., 2020). Acid rain is caused by the deposition of acidic compounds contained in rain, snow, hail and fog with a pH lower than 5.6. In general, pH values in the range 4.4–2.3 have been recorded, but a value of 1.4 has been reported in Italy. Acidic compounds result from global emissions of sulfur dioxide and nitrogen oxides into the atmosphere.

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Fig. 9.1.  The forests in the Amazon basin, central Africa, South East Asia and Australia are critical for curbing the impact of rising global levels of carbon dioxide by utilizing this greenhouse gas in photosynthesis, thereby generating oxygen. However, deforestation due to programmed or spontaneous fires is causing concern not only for climate change reasons but also for potential toxicological effects. For example, the devastating wildfires in Australia during the 2019/2020 summer and the subsequent torrential precipitation, the mobilized nutrients and heavy metals, particularly mercury, from the charred debris and soil contaminated drinking water supplies, rivers and the marine ecosystem. Furthermore, particulate emissions in smoke presented risks for the exacerbation of pulmonary and cardiovascular disorders in vulnerable individuals. (Image “File:River RP.jpg” by Jlwad is licensed under CC BY-SA 4.0.)

Acid rain destroys the waxy cuticle of the leaf surface, damaging the epidermal structure, with the constituent acids diffusing into the cell or via the stomata. Leaf integrity is critical for maintaining water balance in the plant and for gaseous exchange. It is also important for protection against pathogen invasion and entry of other pollutants. Visible leaf injury indicators, including appearance of necrotic spots, defoliation and discoloration, are not evident until pH values fall to below 4.0, with the size of necrotic spots increasing with decreasing pH. Leaf chlorophyll content directly reflects foliage damage and consequent loss of plant productivity caused by acid rain. Chlorophyll synthesis is decreased by acid rain due to foliar leaching of nutrient elements, particularly magnesium, one of the major components of the pigment. Degradation of chlorophyll is also increased by acid rain, leading to the formation of pheophytin. Leaf chlorophyll contents of deciduous species are more sensitive to acid rain than evergreen species. The photosynthetic apparatus is one of the most stress-sensitive physiological systems in plants, and the major target site of acid rain is the chloroplast, which is affected both structurally and functionally.

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Acid rain also affects the rhizosphere by changing the pH value of the soil and altering the availability of nutrients. Root morphology, as expressed in root length, surface area, volume and number of root tips, is all reduced by strongly acid rain (e.g. pH 2.5), arising partly from decreased macro-elements and increased trace element status of roots. When soil pH declines to 4, most of the essential nutrients, including magnesium, calcium, phosphorus and soluble nitrogen, in plant roots are decreased, resulting in deficiency and abnormal morphology of plants. These effects have been attributed to a decrease in the activity of plasma membrane H+-ATPase, which provides the energy for nutrient transport into the cell and extrusion of positive charges (H+) and the creation of membrane potential. The plasma membrane of the plant cell acts as an important barrier, separating and shielding the cell from its environment. Its main components include lipids, proteins and carbohydrates, with the lipid fraction consisting of sterols, phospholipids and glycolipids providing an optimal environment for membrane function, particularly permeability and enzyme activity. There is increasing evidence that acid rain increases levels of reactive oxygen species, which precipitates peroxidation and loss of membrane integrity, thereby disrupting cellular ionic status and functional metabolism. Oxidative stress is a critical and common manifestation of exposure to acid rain as well as other abiotic factors, although plants possess adaptive defence mechanisms to counteract this effect. This defence system comprises enzymatic systems, including superoxide dismutase, catalase, peroxidases and glutathione reductase. In addition, non-enzymatic antioxidants involving lipid-soluble membrane-associated compounds such as α-tocopherol, β-carotene, ascorbic acid and glutathione provide protection. Different components of these systems are upregulated in scavenging ROS and other potentially toxic products induced by acid rain. Combined effects of acid rain and other abiotic stress factors may also occur to affect plant productivity adversely. For example, such pressures can activate Al3+ in soil to cause secondary aluminium toxicity by inhibition of root morphology and growth, reducing important bacterial activity in soil and increasing mortality of soil invertebrates. Acid rain also increases the mobility of heavy metals in soil and their uptake by plants. In addition, ambient ozone may interact with acid rain to reduce net photosynthetic rates. The effects depend on species of plants, environmental factors and concentrations of pollutants. The role of amino acids and specific peptides as mediators of abiotic stress tolerance is increasingly recognized as an important feature of defence systems in plants. The secondary metabolism of amino acids results in the synthesis of a number of signalling compounds (or phytohormones) which coordinate the responses of plants to abiotic stress factors such as acid rain, salinity, anoxia, drought and exposure to heavy metals. For example, methionine metabolism results in the synthesis of S-adenosylmethionine, an important contributor in the production of polyamines and the phytohormone, ethylene. Although ethylene is associated with fruit ripening, it also interacts with other signalling molecules, particularly under abiotic stress conditions, such as salinity and cold. Metabolism of phenylalanine in higher plants results in the formation of a significant signalling compound, namely salicylic acid. It is widely accepted

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that salicylic acid is a critical signal transduction molecule for the induction of immune responses of plants towards biotic stress induced by pathogenic fungi. However, it is now also implicated in plant responses to salinity, ozone, heat and drought. In addition to the provision of phytohormones, amino acids and associated enzymes may be directly involved in abiotic stress responses of higher plants. For example, ROS generated by abiotic stress signals the expression of glutamate dehydrogenase which, under conditions such as salinity, creates intracellular hyper-ammonia and potential metabolic toxicity. Released ammonium ions are therefore incorporated into glutamine and glutamate by glutamine synthetase/glutamate synthase, thus directing the pathway towards proline biosynthesis. It is well known that proline accumulates in response to a variety of environmental stressors, including wilting, drought, salinity, anoxia and exposure to heavy metals. This accumulation varies with plant species and has been linked with improved plant performance under diverse abiotic stress conditions. Proline accumulation during abiotic stress is the result of a trade-off between biosynthetic and catabolic pathways. In transgenic plants, overexpression of a synthetase gene results in increased proline production and improved tolerance to high salinity, freezing and osmotic stress. In its function as an osmo­ protectant, proline accumulates in the cytosol and chloroplasts, as opposed to other solutes such as organic acids and sugars, which are partitioned in the vacuole of plant cells. Proline is endowed with specific attributes, including: • • • • •

regulation of cellular homeostasis; osmoprotection; signal transduction; gene expression; and the property to scavenge free radicals (e.g. ROS), thereby providing cells with a mechanism to avoid oxidative stress.

In addition, proline confers important physical properties associated with its cyclic structure which protects the cellular structure of proteins and membranes during dehydration. Consistent with its signalling role, proline induces expression of certain stress response genes to enhance salt tolerance via upregulation of pathways to synthesize stress-protective proteins. Glutamate is a major precursor of ɣ-aminobutyric acid produced via the action of glutamate decarboxylase. This metabolite is also associated with stress responses, with rapid accumulation to high levels following exposure of plants to anoxia, low pH, drought, salinity and osmotic and mechanical manipulation. There is speculation that ɣ-aminobutyric acid accumulation serves in osmoregulation, pH regulation and glutamate homeostasis during exposure to abiotic stress. Polyamines, derived from arginine and ornithine, also accumulate in response to a variety of adverse environmental factors, including: • exposure to drought; • salinity;

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chilling; hypoxia; ozone; UV radiation; heavy metals; mechanical wounding; and herbicides.

Mutant plants deficient in polyamine accumulation show impaired tolerance to stressors such as salinity, which can be reversed by exogenous application of polyamines. A consistent feature of plant adaptation to adverse environmental conditions is the overproduction of alanine and the role of its aminotransferase in regulation of this process. It is envisaged that alanine acts by stabilizing the quaternary structure of cellular proteins and membranes, by regulating pH balance during anoxia and by mitigating some of the biochemical aberrations associated with hypoxia. Glycine and choline are precursors of glycine betaine, a low-molecular-mass molecule considered to act as a compatible solute during adaptation to high salinity and low environmental temperature. Glycine betaine accretion is more effective in chloroplasts than in the cytosol for protection against abiotic stress, but there are species differences in responses of plants to this accumulation. The xenobiotic non-protein amino acid β-aminobutyrate, which acts as a glycine receptor agonist in animals, is also effective in priming plants against pathogens and osmotic stress, while significantly enhancing acquired thermotolerance. As such, there is accumulating recognition of the role of this amino acid in a general role of potentiating stress resistance in plants. However, any practical exploitation of β-aminobutyrate as a protectant would be subject to satisfactory environmental and toxicological evaluation. In summary, a pathway of events in the adaptation of plants to abiotic stress may now be considered. For example, salinity generates ROS, which precipitates oxidative stress. Gene expression follows, resulting in the upregulation of pathways leading to the synthesis of signalling compounds such as salicylic acid, which stimulate the production of osmolytes, particularly amino acids, as outlined above. The accumulating amino acids act by providing structural stability to proteins, including enzymes, membranes and key organelles, such as chloroplasts and mitochondria, thereby restoring cellular integrity and homeostatic mechanisms and enabling impacted plants to survive and grow. It is envisaged that such a scheme would only apply to transient and/or moderate salinity, but elucidating elements of this pathway might assist in the development of stress-resistant crop plants. Two significant mechanisms exist in plants to reduce the impact of deleterious metal ions, involving specific amino acids and peptides. The general notion of metal–amino acid linkages in living organisms is well recognized. For example, the replacement of sulfur with selenium in the structures of methionine, cysteine and cystathionine in certain leguminous and brassica plants to form equivalent analogues has long been established. Indeed, selenomethionine has been declared a ‘canonical’ amino acid, with formal inclusion in the list of 21 amino acids that are essential for protein biosynthesis. In addition,

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proline represents a prominent exponent of amino acids with metal-complexing attributes, based on biophysical properties. Proline accumulation is associated with protective activities towards nitrate reductase, glucose-6-phosphate dehydrogenase and against heavy metals by forming proline–metal complexes, attributed to its cyclic structure. The role of histidine in nickel hyperaccumulation in certain plants of the genus Alyssum is also well established. Coordination of nickel by histidine has been demonstrated and it is suggested that this amino acid serves as a ligand for the element, thereby promoting hyperaccumulation. Mimosine, occurring in the tropical legume, Leucaena leucocephala, is also attributed with biophysical properties by chelating iron, aluminium and zinc in different experimental systems, in vivo and in vitro. In order to circumvent the deleterious effects of metal stressors, relatively efficient and complex mechanisms exist in plants for chelation, transport and vacuolar sequestration within plant cells through the action of phytochelatins. The phytochelatins are a group of cysteine-rich peptides synthesized exclusively from reduced glutathione. There is extensive evidence exemplifying a broad spectrum of functional attributes of phytochelatins in homeostatic regulation and metal stress tolerance in higher plants. For example, phytochelatin synthesis is essential for survival in zinc-contaminated soils and is positively correlated with arsenic and lead under saline conditions and tolerance to cadmium, notwithstanding the complex interactions between cadmium and copper homeostasis. It should be emphasized, however, that a greater definition of specified metal/abiotic stressors needs to be considered for different plant species before practical measures can be recommended, in view of contrasting effects regarding tolerance and disruption of mineral homeostasis. Nevertheless, it is instructive to consider the model recently proposed for phytochelatin-mediated arsenic tolerance in plants. It is proposed that soil arsenic is absorbed and transported by a high-affinity phosphate transporter into root cells. Arsenic reductase reduces arsenic (V) to the (III) form, which is conjugated by phytochelatin and transported by ABCC1 and ABCC2 transporters to vacuoles where it is sequestered, thereby inducing arsenic tolerance in the plant. It would be premature to adopt this model for universal application for all toxic metals and for all species of plants, as there is evidence of a lack of stoichiometry in the relationship between phytochelatin expression and metal status in certain plants. Other roles for phytochelatins have also been suggested, including cell wall re-modelling, metabolism of phenylpropanoids and even auxin biosynthesis. Another factor for consideration is the possible chelation of valuable inorganic nutrients which might compromise optimum enzyme function and the synthesis of certain secondary compounds serving in defence roles against biotic pressures.

9.4  Key Issues Microbes are endowed with extensive biochemical mechanisms to detoxify harmful compounds, vastly exceeding the neutralizing capacity of higher

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organisms. The potential for microbial remediation of contaminated sites is considerable, particularly for PCBs, dioxins and crude oil fractions. Plants are also capable of metabolizing potentially deleterious organic molecules; however, pathways also exist to chelate and sequester heavy metals in a mechanism that provides tolerance to the plant. Nevertheless, questions remain as to adaptation mechanisms, for example in herbicide-resistant plant species (Baucom, 2019).

9.5 References Baucom, R.S. (2019) Evolutionary and ecological insights from herbicide-resistant weeds: what have we learned about plant adaptation and what is left to uncover? New Phytologist 223, 68–82. Kumar, J.R., Bhuyan, B., Das, N. and Pandey, P. (2019) Environmental applications of microbial extremophiles in the degradation of petroleum hydrocarbons in extreme environments. Environmental Sustainability 2, 311–328. Liu, J., Zhao, Y., Song, H., Chen, J. and Long, Y. (2020) Antagonism of synergism? Combined effects of enhanced UV-B radiation and acid rain on photosynthesis in seedlings of two C4 plants. Acta Ecologica Sinica 40(1), 1–112. Pei, H., Wang, C., Wang, Y., Yang, H. and Xie, S. (2019) Distribution of microbial lipids at an acid mine drainage site in China: insights into microbial adaptation to extremely low pH conditions. Organic Geochemistry 134, 77–91.

9.6 Exercises (i)  Comment on the possible role of microorganisms in environmental remediation of contaminated sites and marine ecosystems. (ii)  Speculate on the capacity of higher plant communities to recover from the devastation caused by the Fukushima nuclear explosion in Japan. (iii)  Write a short essay on phytoremediation in ecosystems polluted by heavy metals. (iv)  Discuss the practical viability of the remediation methods cited in the exercises above.

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10.1 Overview Over recent decades, risk assessment in environmental toxicology has emerged from its anecdotal/speculative origins into an advanced and quantitative discipline, permitting firm, albeit alarming, conclusions for policymakers, statutory protection agencies and government leaders. Nevertheless, environmental contamination is destined to present intractable dilemmas, as individuals and corporate organizations seek to protect vested interests, despite unequivocal evidence of harm caused by worldwide and local pollution. Bold measures are needed, but weak governmental leadership and regulatory authorities in paralysis mean that progress in environmental protection will not match the rate of decline in human health outcomes and perils for endangered wildlife species. The primary aims in this volume are to emphasize alarming evidence that major contaminants originating from biological sources as well as pollutants generated spontaneously or as a result of anthropogenic activity cause: • human morbidity by exacerbating conditions such as asthma, COPD and cardiovascular disease (CVD); • neurodegenerative disorders; • cancer; • endocrine disruption in humans and wildlife; • premature mortality; and • ecotoxicity, resulting in likely extinction of vulnerable species of insects, birds and marine predators. Full details of the underlying data are reviewed in A Handbook of Environmental Toxicology: Human Disorders and Ecotoxicology, edited by D’Mello (2020). A diverse array of potentially toxic agents regularly appears in the atmosphere, soil, water and food, thereby compromising both human health and biodiversity in natural and managed ecosystems. The occurrence of 124.

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these contaminants in complex mixtures adds to the toxicity and also creates difficulties in risk management.

10.2  Contaminants in Diverse Ecosystems It is instructive to review the distribution of the wide range of potentially toxic pollutants in the major ecosystems that might impinge on human health and biodiversity in the natural environment. Such risk assessments are essential to improve the efficacy of intervention and remediation measures. Atmospheric pollution emerged as a major human health risk as long ago as 1952, following the Great Smog episode which resulted in illness and death among residents in London. Such pollution events still occur regularly in urban conurbations around the industrial world. New Delhi (India), for example, has acquired the reputation of the most polluted city in the world. The main pollutants are those present in exhaust fumes, namely particulates, nitrogen dioxide and sulfur dioxide, as well as ozone arising during photochemical smog formation. In rural areas dominated by intensive agriculture, air quality is regularly compromised by ammonia emissions and particulates, adding to the human health risks caused by pesticide aerosols. The soil ecosystem carries a heavy burden of contaminants arising from the application of fertilizers and pesticides in agriculture and from industrial activities such as shale oil and gas extraction as well as power generation by-products in routine operations and following accidental discharges. For example, heavymetal pollution around a coal-fired power station in China has recently been reported. The complex range including Pb, Cd, As, Hg, Cu and Cr in nearby soils and severe contamination of cabbages grown in that area is a cause for concern, particularly as these metals may be accompanied by emissions of PAHs. In Tennessee (USA), the rupture of a dyke caused the discharge of vast quantities of coal ash into the Emory River. In the ensuing clean-up emergency, unprotected personnel were exposed to heavy metals and other contaminants, subsequently causing mortality and debilitating illnesses. Legal proceedings are being brought against the power company responsible for the security of the dyke. In the case of radionuclides, there is strong correlation between soil contamination and internal exposure of residents living in regions affected by nuclear accidents. Consumption of locally grown foods is considered to be the source of this exposure. In 1996, 10 years after the Chernobyl accident, Ukraine was divided into zones based on soil contamination of radionuclides. The Fukushima accident caused serious 137Cs deposits in soils in a range of terrestrial ecosystems. The dynamics of 137Cs in relation to soil fractions, particularly clay minerals in surface layers, is considered to modulate radionuclide behaviour in the environment, affecting mobility and bioavailability of 137Cs. In both Chernobyl and Fukushima, 137Cs dispersion was faster in forest soils than in grassland soils. There is, therefore, a strong perception that geochemical behaviour of radionuclides in terms of spatial and vertical distribution in surface soils constitutes an important prerequisite in risk assessment for humans.

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Pollution of aquatic ecosystems deserves particular mention as it adversely impacts on diverse species of animals already on the verge of extinction due to climate change and habitat degradation (see Case Study 10.1). The safety of drinking water is often jeopardized by a wide range of contaminants. Given the ubiquitous distribution of pollutants and contaminants in the environment, the adverse impacts on food and drinking water safety are entirely predictable. As a result, human health is regularly compromised by these exposures. The recent past has been characterized by an unremitting series of food scares associated with decades of pollution, careless deregulation and underfunding of services in monitoring, compliance and enforcement of statutory directives. These constraints are likely to be exacerbated by ongoing ­austerity

Case Study 10.1.  Breach over troubled waters In virtually all geographical regions and societies, rivers and estuaries are perceived as conduits for waste disposal, while lakes and oceans are used as receptacles for harmful contaminants, left as a legacy for future generations to rectify. Thus, all the major rivers in the UK are polluted with plastic debris, with the Mersey containing microbeads, fibres and fragments in concentrations exceeding those in the Great Pacific Garbage Patch. Emerging concerns include the distribution and environmental fate of nanoparticles in wastewater streams in industrialized countries. In 2020, a Scottish utility company pleaded guilty to a charge of polluting the Clyde with untreated sewage. The paltry fine is unlikely to deter this and other companies from further breaches of environmental regulations. The Ganges in India and the Santiago river in Mexico contain a diverse burden of contaminants, including tannery effluents, heavy metals, sewage and animal wastes as well as organochlorine pollutants at levels well in excess of acceptable limits. In China, the Yangtze and Pearl rivers are contaminated with antibiotics at concentrations below medical doses, but nevertheless representing risks for the potential development of resistance in human pathogens. Changes in agricultural practices, including certain conservation measures, have inadvertently resulted in the development of harmful algal blooms in western Lake Erie (Canada). This effect is attributed to increased agricultural phosphorus and nitrogen loading from tributaries draining into the lake. Farm pollution is responsible to a large extent for the destruction of coral reefs around the world. Longterm data relating to PAHs in the Gulf of Mexico indicate extensive and ongoing exposure of fish species to Deepwater Horizon oil contamination. The term ‘breach’ also refers to the act of a whale in leaping clear over the surface of the sea. It is not known why whales perform this spectacular feat, but there is speculation that it might be used to remove parasites or for vocalization to other individuals in the pod. Breaching may also assist whales in leaping over oil spills and plastic debris or provide a mechanism for avoiding sound pollution from marine traffic. • • • • •

Can you summarize the effects of pollution on drinking water quality in your vicinity? List the main contaminants in water from your supplier. What local or national regulations are there for these contaminants? How do pollutants affect reproduction in endangered marine species? Can you think of other reasons for breaching behaviour in whales?

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measures and the pursuit of isolationist policies, particularly by elected administrations in North America and Europe. Pesticide residues in vegetables and fruit remain a persistent problem worldwide, with a distinct lack of progress in reducing levels of contamination or consumer concerns. Other POPs, including dioxins and dioxin-like PCBs in foods of animal origin, are also under constant scrutiny, for example in farmed salmon. Levels of dioxins in milk supplies are often higher in samples obtained from farms in close proximity to urban and industrial sites than in those from farms in rural locations. Radionuclides in milk and meat emerged as a significant issue in Europe following the Chernobyl accident in 1986 (D’Mello, 2003) and the subsequent Fukushima explosion has compromised food safety further. Estuarine and marine pollution is now a serious issue resulting in contamination of seafood. In particular there are persistent concerns over mercury concentrations in fish which have been linked to reduced fertility in men and cognitive deficits in children, following prenatal exposure. The quality and safety of water used for direct consumption or for irrigation of food crops are markedly affected by prevailing levels of pollution. Concentrations of lead and nitrates continue to cause concern among environmental health investigators. In addition, the occurrence of pathogenic enteric microorganisms derived from sewage pollution is a worldwide issue, contributing to outbreaks of serious digestive disorders.

10.3  Human Health Emergency: Environmental Pollutants Contributing to Increased Morbidity and Premature Fatalities Ambient air pollution has been specifically and consistently linked with premature human mortality in all industrialized countries (Landrigan, 2017). In the UK, for example, recent estimates suggest that between 28,000 and 36,000 premature deaths are attributable to air pollution. It has recently been estimated that vehicle fumes are worse for pulmonary health than smoking 20 cigarettes per day. The European Environment Agency estimated that air pollution caused 400,000 preventable deaths in Europe in 2016. This mortality is the result of exposure to exhaust gases from the combustion of petroleum and solid fuels in vehicles, power generation plants and from other sources. Vulnerable individuals, including patients with underlying disorders such as asthma, COPD and CVD, are at particular risk. A number of air pollutants are associated with exacerbating these conditions, often resulting in premature mortality. For example, increased exposure to atmospheric ozone and nitrogen dioxide has been implicated in aggravation of idiopathic pulmonary fibrosis. Acute infections of the lower respiratory tract account for significant mortality in young children worldwide which has been attributed to ambient air pollution caused by petroleum combustion, in particular levels of PM2.5. Furthermore, air pollution increases the risk of young children with cystic fibrosis developing antibiotic-resistant bacterial infections. Long-term exposure to ambient air pollutants, particularly ozone, is significantly associated with emphysema progression and with deterioration of lung function. In the case of asthma, both nitrogen dioxide and sulfur dioxide exposure are frequently implicated in the exacerbation of morbidity, increased hospitalization and

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premature death. Other evidence implicates PM2.5, nitrogen dioxide and sulfur dioxide as risk factors for COPD. There are also considerable and continuing concerns over the relationship between air pollution and CVD, with particular reference to the role of PM2.5 and PM10 in the incidence of heart disease and stroke. The possible effects of ambient air pollution on metabolic syndromes have been proposed recently. For example, the effects on childhood obesity have been examined in a longitudinal, multilevel analysis, with the conclusion that traffic pollution may be associated with the development of obesity via biochemically plausible mechanisms. Emerging data also tentatively point to an effect of air pollution on the incidence of type 2 diabetes, although credible mechanisms for such a relationship have already been advanced. In addition, air pollution has been linked to increased incidence of skeletal fractures due to decreases in bone density. The association was significant with chronic exposure to PM2.5 which enter the bloodstream via the lungs. Other evidence indicates that air pollution may reduce fertility in women, presumably involving an endocrine-disrupting mechanism. Of considerable concern is the detection of black ultrafine carbon particles in the placenta of women exposed to vehicular pollution during pregnancy, implying risks for offspring. Air pollution may also increase the risk for the development of glaucoma, attributed tentatively to the influence of PM2.5 on accumulation of ocular fluids. An emerging and inevitable question relates to possible effects of ambient air pollution on carcinogenesis. In 2020, the World Cancer Research Fund announced that overall UK cancer incidence had increased markedly over recent years, with lung malignancies constituting 20% of total cases. The increase occurred despite falling cigarette smoking in the general population. It is proposed here that environmental pollution may be an important factor to consider in this respect. Outdoor air pollution and particulates are now considered by IARC as Group 1 carcinogens and there is support for the hypothesis that traffic-generated air pollution may be linked to the development of breast cancer, especially in menopausal women. In addition, an association between ambient nitrogen dioxide and lung cancer incidence has also been proposed, with residential proximity to polluted streets being a significant risk factor. Volatile organic compounds, including benzene, toluene, ethylbenzene and xylene (BTEX), are recognized traffic-associated air pollutants, with benzene representing a significant cancer risk in high-exposure groups. Furthermore, acetaldehyde present in vehicle exhaust emissions can induce DNA adduct formation and may, therefore, contribute to cancer risks associated with urban air pollution. The US National Institutes of Health classify acetaldehyde as ‘reasonably anticipated to be a carcinogen’. It has also emerged that exhaust particles with contrasting PAH and metal contaminants may induce differential effects, for example in terms of pro-inflammatory responses. It is advocated, therefore, that the chemical composition of particulate emissions may be a determining factor in the development of adverse effects. The existence of complex interactions in carcinogenesis is therefore implied, with attendant difficulties in elucidation and quantification. The impact of air pollutants on cognitive competence and neurological functions are an additional source of concern, with in utero exposure implicated

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in incidences of autism, attributed specifically to ambient ozone, and of dementia linked to traffic-related particles, ozone, nitrogen dioxide and carbon monoxide. Air pollution can also increase the risk of miscarriage in pregnant women. Other evidence links PAHs in fine particulate matter to the onset of childhood asthma, adult hypertension, heart attack and cancer by mechanisms yet to be elucidated. An additional complication may be source of PAHs: it has been suggested that children exposed to particulates emanating from wood combustion may be at greater risk of developing lung cancer due to increased burden of PAHs. Persistent organic pollutants in the forms of PCBs, dioxins and pesticides remain in particular focus due to continuing and debilitating morbidity in humans. Maternal exposure to dioxin-like PCBs are associated with the risk of asthma in offspring that may persist into adulthood. Furthermore, gestational exposure to PCBs may induce lifelong and transgenerational effects on body weight, hormones and hypothalamic gene expression. However, the overriding issue with PCBs centres on the association with endocrine disruption and breast cancer incidence and survival. Gestational effects also occur in the activity of dioxins as reproductive disruptors. It is generally accepted that TCDD alters fecundity and endometriosis in primates and causes reproductive disorders in animals, including humans. However, the predominant concern is the classification of TCDD as a Group 1 carcinogen, and supporting epidemiological evidence is now emerging. Breast cancer has also been associated with exposure to organochlorine pesticides, consistent with a role as environmental oestrogens, but the effects on cognition should not be ignored. Laboratory studies indicate that environmentally relevant glyphosate concentrations can induce growth of human breast cancer cells via oestrogenic receptors. Profound effects of organophosphorus pesticides on respiratory function are emerging, with recent conclusions that paediatric symptoms may reflect onset of childhood asthma. In addition, the neurotoxic effects of organophosphorus pesticides are well established. For example, residential proximity to such applications in arable farming has been linked with accelerated decline in cognitive and motor functions among Parkinson’s disease (PD) patients. Logic dictates that fungicides and herbicides should solely affect target organisms without causing adverse effects in humans. There are also mechanistic reasons for this notion, since the mode of actions of these pesticides primarily reside in biochemical pathways restricted to fungi and higher plants, respectively. However, current evidence indicates that residential and occupational exposure to the fungicide ziram is associated with markedly increased risk for the development of PD and for early-onset cases. In addition, increased incidence of PD has been observed in rural communities exposed to drift from farm applications of paraquat and among operators applying the herbicide without adequate protection. Questions have also been raised about the safety of the herbicide, glyphosate, following a recent cancer judgement in the US courts apportioning sole liability to the manufacturer. Toxicologists are currently seeking clarification about its putative role in other debilitating conditions, including autism and depressive-like behaviour, as implied in experimental evidence.

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For particular locations, activities at gas and petrochemical plants often impact on the health and well-being of nearby residents due to diverse sources of pollution. For example, during 2019, residents near gas flaring operations at a petrochemical plant in Fife (Scotland) complained about vibration, noise, light, odour and smoke pollution leading to health manifestations such as sleep deprivation, headaches, sore throat and asthma. In Louisiana (USA) a location is identified as ‘cancer alley’, due to 50% higher malignancy rates attributed to chloroprene and ethylene oxide emissions from petrochemical plants. Chloroprene is classified by EPA in the USA as a ‘likely human carcinogen’, but the issue is being contested by the petrochemical companies and remains unresolved as at 2019. Chronic methylmercury exposure continues to present concerns due to contamination of seafood and profound effects affecting cellular metabolism, cardiovascular and pulmonary functions and central nervous system activity. The neurological effects of lead, including impairments in intelligence, memory, attention, processing speed, motor skills and behaviour, are also under regular scrutiny. In 2017, it was reported that lead poisoning was higher in parts of California than in Flint, Michigan, with the USA now providing important case studies in modern lead intoxication. It should be noted that heavy-metal pollution is a worldwide issue. For example, La Oroya in Peru is universally recognized as ‘toxic town’ due to exposure of inhabitants to lead from a local smelter. Lead-acid battery recycling has also resulted in lead toxicity in residents at Haina in the Dominican Republic and in Dakar, Senegal. In the latter case, 18 children died from a rapid-onset and progressive CNS disorder. In Agbogbloshie, Ghana, processing of electronic waste caused the release of unspecified heavy metals, while in Norilsk, Russia, activity at a major producer of non-ferrous and platinum group of metals has been linked to high mortality and premature births in the local community. Following remediation, blood levels can be reduced significantly, as in the Dominican Republic case. However, corrective measures and regulations for different heavy metals are often applied inconsistently even in the same country. For example, routine screening for lead exposure has been implemented in USA with meticulous care for the general population as well as for refugee children resettled in USA. In contrast, water authorities voted to weaken control standards for mercury pollution in the Ohio River, placing human health and aquatic life at unacceptable risks. Radiation carcinogenesis remains a substantive public health issue due to persistent and diverse environmental risks. The incidence of non-melanoma skin cancer in white populations is increasing, attributed to UV radiation, although the pattern of exposure that promotes the different types of malignancy varies. Interactions with cutaneous synthesis of vitamin D3 and possibly viral infections may complicate interpretation in the epidemiology of UV carcinogenesis. Residential exposure to radon is definitively linked to lung cancer incidence, but the scope is now shifting to possible associations with leukaemia and interactions with ambient PM2.5. Regarding radionuclide contamination, although the infrastructure in Hiroshima and Nagasaki has now been restored following the detonation of two atomic weapons in 1945, the toxic effects for survivors

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remain to this day. For example, the incidence and analysis of myelodysplastic syndromes afflicting these subjects have been investigated as recently as 2018. In reflecting on the 30-year legacy of the Chernobyl nuclear accident, investigators have emphasized increased long-term risks, including leukaemia and CVD among first-responders and thyroid cancer in individuals exposed to radiation as children and adolescents, as well as mental health decline. Notwithstanding the foregoing, it is important to appreciate that other environmental contaminants can induce malignancy. For example, the aflatoxins synthesized by certain strains of Aspergillus have been implicated in hepatic cancer. Cadmium and arsenic are also well-established carcinogens. Recently, trihalomethanes, arising from disinfectants and present in drinking water, have been correlated with 1300 bladder cancer cases in the UK.

10.4  Ecological Emergency: Wildlife in Peril Environmental contaminants are associated with profound effects in the degradation of natural habitats, as exemplified by the crude oil and nuclear accidents of recent decades, adding to the detrimental effects of climate change for numerous species. The advent of novel exploration technologies in oil extraction, such as hydraulic fracturing (fracking), creates different risks for the local ecosystem. An alarming decline in populations of insects, amphibians and apex predators has raised questions about the possible role of pollutants on the dynamics of habitat biodiversity. As might be predicted, microbial communities are endowed with the metabolic capacity to adapt to pollutants. In an assessment of the Deepwater Horizon oil spill in the Gulf of Mexico, deposits on the shore caused a shift towards recognized hydrocarbon-degrading microorganisms. Although this observation may be reassuring, it should be noted that PAHs are significantly more recalcitrant and that detoxification pathways are limited in marine animals. Consequently, adverse effects should be expected in vertebrate ecology and behaviour, as demonstrated by the negative impact on marine mammals and sea turtles following the Deepwater Horizon oil spill (Frasier et al., 2020). Severe risks of crude oil pollution in the future cannot be discounted in view of recent decisions by energy conglomerates to substantially increase production over the next decade. It has been reported that, in 2018, 137 oil spills occurred in USA. At the same time, at least one industry body in the UK announced in 2019 that ‘much more needs to be done to prevent crude oil and gas leaks into the North Sea’. Also, in 2019 an oil spill off the coast of Brazil was designated as an environmental disaster for that region. It is concluded that petroleum and gas companies are undermining environmental goals. The loss of beneficial insects and other species such as amphibians is a matter of considerable concern, particularly in managed ecosystems. The role of pesticides used in crop production is consistently associated with this decline in populations. For example, herbicides can alter the floral diversity available for insect pollinators such as bees, butterflies and hoverflies which may also be affected directly by multiple pesticide residues on these flowers. Recent findings at the University of Wageningen (The Netherlands) highlighted the

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deleterious effects of the insecticide, fipronil, on survival of honey bees and butterflies. There are also alerts on the potential detrimental effects of herbicides on the fitness and survival of anurans (frogs) in agroecosystems. In 2019, work at the University of Saskatchewan implicated a common farm pesticide, imidacloprid, in weight loss and delayed migration in white-crowned sparrows. In other environments, artificial light pollution may be an important factor threatening the survival of insects. For example, the characteristic bioluminescence signals emitted by fireflies is obliterated by light pollution in cities, meaning that these insects cannot see each other for mating and propagation of the species. Light pollution is also associated with adverse effects on foraging activity and reproductive functions of nocturnal mammals. For example, seasonal oestrus is determined by photoperiod in such species and any variation introduced by human intervention will impact on the timing of reproduction. Anthropogenic sound is another potential stressor for all animals, but particularly so for marine species, which often become disorientated by engine noise from ships and other vessels. Emerging evidence points to multiple risks for apex predators as a result of biomagnification of contaminants in prey animals caused by trophic transfer via the food chain. Concentrations can increase 5- to 10-fold with consecutive steps in the food chain. This is particularly the case in marine ecosystems, where seals, polar bears and killer whales may harbour a diverse array of environmental pollutants in body fat depots acquired from contaminated prey. As a consequence, polar bears, feeding almost entirely on seals, are one of the most highly contaminated species of all Arctic mammals. Compounds include PCBs, chlorinated pesticides, perfluoroalkyl residues, dioxins, furans and mercury. These contaminants may compromise health outcomes and also prejudice reproductive capacity. Of particular significance is the reduction in penile (baculum) bone density and fragility as well as size of testes in male bears by environmental changes and pollutants causing mating and fertilization failure, thus threatening the very survival of the species. Climate change can only add to a precarious environment for polar bears and other apex predators. Concerns have also emerged over the possible extinction of killer whales due to constraints imposed by food supplies and environmental toxicology. Under conditions of nutritional stress, POPs mobilized from endogenous lipid depots present additional risks due to cumulative interactions with other factors. This redistribution is maximal during low seasonal availability of prey. These factors combine to limit population growth, due to adverse impacts on pregnancy outcomes. There is evidence that pollutants such as PCBs and polybrominated diphenyl ethers (PBDEs) are continuing to enter the food chain of killer whales, emphasizing the toxic legacy of anthropogenic activity. Blubber concentrations of PCBs can exceed toxicity thresholds for immunosuppression and severe reproductive impairments for marine mammals. Additionally, high levels of dichlorodiphenyldichloroethylene (DDE), selenium and mercury have been detected in stranded whales, with mercury concentrations exceeding thresholds for hepatic damage in marine mammals. Vessel exhaust may also contribute organic contaminants in the form of PAHs, emphasizing the need to continue with existing spatial guidelines separating ships from killer whales.

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Recent mass mortality of crocodiles in the renowned Kruger National Park in South Africa has raised questions about specific pollutants transported via rivers as a result of industrial, mining or agricultural activities in the respective catchment areas. The contaminants implicated in this pollution include heavy metals and organochlorine pesticides. It has been reported that mercury, selenium and copper in crocodile eggs and eggshells occurred at levels of concern. In addition, high concentrations of iron possibly contributed to thicker eggshells, which may have inhibited gaseous and water exchange and increased the effort required for the hatchlings to emerge. In free-ranging crocodiles in South Africa, relatively high levels of lead have been observed which, although not associated with overt toxicosis, might be detrimental to egg development and hatchling health. In North-east Mexico, high levels of cadmium, chromium and lead above local pollution regulations were found in scutes and eggs of crocodiles. There are additional risks in regions where pesticides are extensively used in agriculture and disease-vector control. For example, in Belize, organochlorine pesticide residues of the DDT type have been found in 72 of 96 crocodile caudal scutes tested, with methoxychlor occurring in all 72 samples. As might be expected, higher levels of contamination were associated with crocodiles from lagoon compared with river habitats. Attention is also focusing on ‘unconventional’ pollutants associated with unintended consequences of disposal/discharge of pharmaceuticals and personal care products. For example, oxybenzone (benzophenone-3) is a UV filter present in sunscreen lotions and personal care products providing protection against the deleterious effects of UV radiation in humans. However, it is viewed as a serious contaminant in marine ecosystems, as a result of discharges from municipal, residential and shipping sources as well as use by swimmers. Following light activation, oxybenzone elicits effects as a genotoxin and skeletal endocrine disruptor towards corals (Fig. 10.1). It is a hazard to coral reef conservation by reducing resilience to climate change. Contamination of waterways and fish has been reported worldwide as treatment plants do not effectively remove this compound prior to effluent discharge into the aquatic ecosystem.

10.5  Constraints in Risk Management Considerable challenges lie ahead, not least in environmental surveillance and auditing, at a time when prevailing socio-economic pressures take precedence in consumer-oriented societies of the industrialized countries. For example, it is difficult to envisage any significant reduction in road traffic emissions over the next decade, given the political disadvantages of restricting ownership and use of vehicles. A major constraint to progress in pollution containment/reduction is the vested interests of political leaders and industrial conglomerates, with stated environmental policies that are not delivered and fail to inspire confidence in self-regulation (see Case Study 10.2). An additional constraint to progress in safeguarding human health and the welfare of endangered animal species is the lack of leadership and expertise that covers the full spectrum of adverse effects. This situation is exacerbated

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2016

2017

Most severe bleaching

Most severe bleaching

No or negligible bleaching

No or negligible bleaching

Cairns

Cairns

Townsville

Townsville

Mackay

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0

75

250

500 Kilometers 300 Miles

Mackay

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500 Kilometers 300 Miles

Fig. 10.1.  The Great Barrier Reef (shown above as at 2016 and 2017) and other coral systems are habitats with unique ecology, now under threat due to bleaching caused by climate change, pollution and bacterial diseases. Although indiscriminate and excessive use of fertilizers and pesticides have been consistently implicated in this bleaching effect, pharmaceuticals, personal care products, particularly sunscreens, are now emerging as additional contaminants with similar degrees of potency. The Caribbean coral reef ecosystem is also in peril due to environmental acidification and pollution. (Image “Great Barrier Reef The Conversation” by planeta is licensed under CC BY-SA 2.0.)

when expert advice is offered in one-sided arguments. The current debate on fracking amply illustrates the point. Fifty reputable geoscientists have recently (9 February 2019) advocated the relaxation of current thresholds for seismic events to allow extraction of gas and oil in the UK. It was argued that the existing rules were ‘not absolute’ and should be ‘subject to continuing review’. However, questions regarding impacts on human health and ecotoxicity were completely ignored. Questions about leadership, both political and scientific are explained in further detail in Case Study 10.3.

10.6 Implications It is critically important that environmental toxicologists are not deterred by the intransigence and impotence of our political leaders as they pursue policies of denials and half-measures in environmental protection in their single-minded pursuit of electoral success. They seek refuge and solace in current scepticism associated with epidemiology, choosing to ignore previous well-established correlations between: cigarette smoking and lung cancer; alcohol abuse and

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Case Study 10.2.  Attempts to defeat the ends of environmental justice It is now regular practice for multinational corporations to issue statements on environmental impact assessments relating to their respective business plans and output. While this effort is reassuring in theory, recent developments highlight the importance of vigilance by regulatory agencies. It is salutary to note that 20 fossil fuel companies are responsible for one-third of global carbon emissions, providing indications of the scale of the problem. Confidence in self-regulation by multinational corporate organizations has been severely undermined by a series of serious incidents. For example, the discharge of untreated sewage into the Thames over several months by a major UK utility company has been labelled an ‘environmental disaster’, deservedly attracting a severe penalty. In 2016, a cruise line incurred a substantial fine for illegally dumping oil and associated waste via a ‘magic pipe’ off the UK coast. Meanwhile, it was widely reported in 2020 that a major cruise operator continued to pollute oceans with oil and other wastes, even entering a guilty plea but remaining undeterred by earlier penalties imposed by the courts. In 2017, the appearance of a ‘radiation cloud’ presumed to originate from a nuclear fuel plant in the Urals was widely reported but remains unexplained. The ‘stop demonizing diesel’ campaign has been in a fully active mode, supported by a powerful lobby, but there is a clear need for medical experts to ensure that the arguments on both sides of the divide stand up to critical analysis based on sound scientific evidence. The impact of vigilance and surveillance is, undeniably, best exemplified by the conclusions of the US Environmental Protection Agency that numerous well-established Germanmanufactured motor vehicles had been fitted with ‘defeat software’ designed to falsify emissions performance. In a separate development, a number of petroleum companies have recently announced intentions to participate in the Oil and Gas Climate Change Initiative, working collaboratively towards solutions to mitigate environmental risks. At the same time, however, these companies threatened to withdraw from the EU concord if directives to reduce pollution and to enhance adoption of clean energy were enacted. Thus, it appears that delivering on pious environmental statements is not unconditional. In view of political confusion and the upsurge of protectionism by the major economies, it is imperative that international organizations charged with environmental protection are given all the monitoring and legal instruments to safeguard human health and the ecosystem as a whole. At the local level, too, regional authorities must take appropriate steps to reduce gaseous and particulate emissions in congested conurbations. In addition, there is a critical need for profound changes in public attitudes and actions in the face of continuing and widespread pollution, remembering always that higher crude oil usage and pollution are driven primarily by unrelenting consumer demand. • Can you provide other examples of corporate misdemeanours? • Identify the sources of VOCs in your locality. • Explain the possible mechanisms whereby maternal exposure to vehicle exhaust pollutants can influence the mental competence in offspring. • New Delhi is the world’s most polluted city: can you summarize the health hazards for its inhabitants? • What are the disadvantages of using biofuels in place of gasoline in internal combustion engines?

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Case Study 10.3.  Follow the leader Environmental issues, pressing as they undoubtedly are, continue to divide opinion at individual, corporate and international levels, particularly in the heavily industrialized countries. At the extreme end of the spectrum there are commentators who perceive existing predictions as the work of uninformed activists. There is clearly a marked level of indifference and denial among large sections of society and commercial conglomerates as to the deleterious effects of urban and industrial emissions on human health and ecological conservation. These attitudes are fuelled by pernicious commentaries by journalists on the right wing of the political spectrum. Inaction, therefore, appears to be the modus operandi even in the most affluent countries where international directives, for example on global warming or illegal traffic emissions of nitrogen dioxide and particulates, are recklessly disregarded. Attitudes may change as more robust evidence is gathered by environmental and medical toxicologists. However, it is critically important that emerging conclusions are presented in a manner that will resonate with a general audience, by minimizing the use of jargon and alarmist arguments. It is essential that key findings are not ‘lost in translation’ due to lack of clarity in presentation. It is also imperative that significant environmental health and ecological implications are perceived as action points for individuals as much as for corporate organizations. It is axiomatic that regulatory institutions at international and local levels exert the requisite controls over pollution. Addressing these issues will require outstanding leadership with powers of persuasion to emphasize to stakeholders that plastic recycling on its own will not be enough to redress the imbalance caused by consumerism and decades of atmospheric and marine pollution. The challenges are all the more daunting given the confused signals and denials emanating from political leaders on both sides of the Atlantic. It is now opportune for prominent and experienced scientists to directly demonstrate eloquence and activate awareness in matters such as urban pollution, persistent organic compounds, oil spill legacy issues, heavy-metal contamination, clean-up risks after nuclear accidents and conservation of biodiversity in natural habitats. • Can you evaluate the ecotoxicological risks of consumerism? • Who should monitor the emission of pollutants implicated in the health emergency? • Are there any steps we can adopt to protect top marine predators in the unfolding ecological emergency?

liver cirrhosis; and lifestyle factors in obesity-related disorders. Nevertheless, it is also important that future research is directed towards identifying signature molecules that would more precisely assist in resolving cause-and-effect issues in environmental toxicology. It is extremely difficult to portray emerging evidence in environmental toxicology in optimistic terms. Although the impact of urban pollutants on human morbidity has been known for at least two decades, control measures to ameliorate effects have been at best meagre. It can be stated categorically that issues such as COPD, asthma, CVD and even some neurological conditions will be ­exacerbated by ozone, nitrogen dioxide and particulate emissions in congested

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city streets around the world. With regard to pesticide safety, current risk assessments based primarily on carcinogenic potential are not enough as there are other consequences, currently being pursued through the courts. The levels of banned organochlorine pesticide and PCB residues have barely declined with the passage of time. Heavy-metal contamination in rivers and oceans is widespread and is increasing, due to industrial activity and deforestation. The role of pollutants as endocrine disruptors is only now emerging, but the consequences are likely to be profound, particularly for endangered predators. There is also particular concern over biomagnification of pollutants and the risks for a wide range of marine and freshwater animals.

10.7 Conclusions It is instructive to summarize the major issues associated with environmental pollution with a view to identifying continuing risks for human health and biodiversity as well as for establishing priorities for action (Table 10.1). Interactions with other environmental factors are important, as emphasized in this summary. Environmental contaminants are definitively associated with critical human health risks due to initiation or exacerbation of adverse effects. Spikes in air pollution, for example, trigger significantly higher episodes of respiratory and cardiac stress, compared with days when the air is cleaner. Enhanced measures are now overdue to improve outcomes for individuals already burdened with life-threatening conditions such as asthma, COPD and CVD. It is also clear that determinations of only nitrogen dioxide and particulates may not be sufficient measures of air quality. The roles of ozone, sulfur dioxide and PAHs in human morbidity should not be ignored. It should be noted that particulates from vehicle tyres, brakes and road surfaces should also be factored into any programme of remediation. The toxicological risks associated with pesticides continue to be grossly underestimated with respect to association with neurodegenerative disorders in humans or to detrimental effects on rural biodiversity, leading to possible extinction of key insect species. In particular, there is an urgent need for an independent agency, similar to IARC, to grade pesticides and endocrinedisrupting compounds according to the potential to induce neuro-behavioural dysfunction in humans. In the case of endocrine-disrupting contaminants, there is a clear existential threat to apex predators, with the effects of climate change and habitat degradation adding to the risks. Historical as well as recent determinations indicate that environmental toxicology is no longer the domain of scientists alone, with interventions by the judiciary in cases such as the Exxon Valdez and Deepwater Horizon oil spills. The successful lawsuit in 1996 against a major utility company for contaminating drinking water with hexavalent chromium in California (USA) represented a key event in securing environmental justice for stakeholders, for others to emulate. The Corby poisoning case in the UK, concerning exposure of pregnant mothers to multiple contaminants including heavy metals and dioxins, was successfully pursued in a class action against the local authority.

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Table 10.1.  Risk status for different classes of environmental contaminants. The toxicology of contaminants as presented in this volume should also be considered in the context of climate change and habitat degradation. Source

Contaminants

Risk Status (as specified in this volume)

Microbes Vehicular exhaust emissions

Mycotoxins; algal toxins Nitrogen dioxide; sulfur dioxide; ozone; PAHs; particulates

Industrial/legacy/ lifestyle Agricultural/ horticultural

PCBs; dioxins; endocrine disruptors Pesticides

Increasing human exposures Critical for individuals with asthma, cystic fibrosis, emphysema, COPD and CVD Class 2 carcinogen (IARC) Implicated in aetiology of autism Critical for carcinogenesis Critical for apex predators Critical effects associated with neurodegenerative disorders; unintended and continuing consequences for human health with farm applications of pesticides Critical for biodiversity on farms, with largescale extinction of insect species and reduction of avian populations Contamination of rivers and marine ecosystems causing algal blooms and destruction of coral reefs Severe ecotoxicity particularly in accidental oil spills and coal ash effluents

Fertilizers

Fossil fuel industries

Industrial/ domestic/ legacy Radiation: legacy and ongoing contamination

Hydrocarbon fractions; particulates; radioactivity; toxic metals Heavy metals; plastics

UV; radionuclides

Continuing exposures to mercury and lead Severe risks for marine animals Significant incidence of cancer

Substantial compensation was agreed for 19 children born with hand and other deformities. Pollution occurred during the dismantling and reclamation of an abandoned steelworks in Corby. Significantly, the glyphosate-cancer trial in the USA and the air pollution-asthma judgement in London may form the model for redress in the future, not only for individuals but also entire communities affected by, for example, traffic pollution in cities around the globe. The role of the judiciary in enforcing environmental regulations in the future is an optimistic and welcome prospect for all victims of pollution, including endangered species. There is also scope for individuals to pursue action through the courts as shown by the successful legal action to protect fragile seahorses from potential oil pollution in Poole Bay, Dorset (UK), widely reported in 2019. Above all, it is patently clear that the emphasis solely on climate change and the need to limit emissions of greenhouse gases is not sufficient. The current

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approach is unacceptably restrictive as there is unequivocal evidence of human health and ecological emergencies associated with: • • • • • • • • •

vehicle exhaust fumes; POPs, including pesticides; endocrine disruption; fossil fuel extraction, transport and refining; heavy metals associated with electronic waste recycling; worldwide escalation in consumerism; particulates; radionuclides from legacy sources; and historical and ongoing leaks in the nuclear power industry.

It is now abundantly clear and, indeed, imperative that international agreements should be extended to all aspects of the three pollution emergencies described above and not restricted entirely to measures incorporated in treaties such as the Paris Climate Accord of 2015. The development of a cohesive strategy to limit all the major pollutants cannot be overstated. However, it must be stressed that setting environmental targets is relatively straightforward; achieving them and confirming beneficial outcomes is altogether a different matter, given the intransigence and double-standards of political leaders around the world and the reticence of individuals, communities and corporate organizations to adopt policies that are less toxic. There is an urgent need to establish an international agency, comparable to IARC, to evaluate the adverse health risks of pollutants with particular respect to cardiac, pulmonary and neurodegenerative disorders. Another branch of that organization should be charged with reducing the impact of legacy and current pollutants on the loss of biodiversity in different ecosystems. For example, an ‘insect apocalypse’ has been predicted, with over 40% of species on the verge of extinction, unless measures are implemented to improve habitats and reduce dependence on toxic pesticides. Above all, it is critical that environmental protection agencies work for the welfare of humans and wildlife species. Scrutiny of pesticides, for example, must be conducted with a more robust examination and application of scientific evidence. Similar comments apply to the control of vehicular pollution in congested cities. Recent cases in the courts suggest that monitoring and safety agencies are irredeemably fractured and dysfunctional at all levels, exacerbated by weak governmental leadership and a well-organized industrial lobby. The outlook at present appears bleak both for human health and for numerous species of wildlife on the verge of extinction. In the February 2020 spate of flooding in the UK, the Environmental Protection Agency declared that staff could not protect everyone. Other events such as the bushfires in Australia and California also highlighted how rapidly regulatory agencies and front-line services can be overwhelmed. Such a scenario, if replicated globally, suggests that environmental protection agencies are inadequately prepared to implement even the basic WHO guidelines for air pollutants such as particulates and toxic gases. In Europe, 400,000 premature deaths have been attributed to atmospheric pollution. Mortality on a similar scale will continue in the

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f­oreseeable future, as current international regulations are totally inadequate and not comprehensive enough. In addition, there are at present minimal efforts to ensure adequately the safety of pesticides or to protect biodiversity in vulnerable habitats and ecosystems. Nevertheless, it is crucial that the urgency for change should be expressed in the pages of this volume, in educational curricula at all levels, in the actions of medical and ecological experts and, ultimately, in decisions enforced by the judiciary.

10.8 References D’Mello, J.P.F. (ed.) (2020) A Handbook of Environmental Toxicology: Human Disorders and Ecotoxicology. CABI, Wallingford, UK. D’Mello, J.P.F. (2003) Food Safety: Contaminants and Toxins. CABI, Wallingford, UK. Frasier, K.E., Solsona-Berga, A., Stokes, L. and Hildebrand, J.A. (2020) Impacts of the Deepwater Horizon oil spill on marine mammals and sea turtles. In: Murawski, S., Ainsworth, C., Gilbert, S., Hollander, D., Paris, C., Schlüter, M. and Wetzel, D. (eds) Deep Oil Spills. Facts, Fate, and Effects. Springer, Cham, Switzerland, pp. 431–462. Landrigan, P.J. (2017) Air pollution and health. The Lancet Public Health 2, e4–e5.

10.9 Exercises (i)  Discuss the relationship between urban air pollution and pulmonary disorders in humans. (ii)  In 2020, the British Heart Foundation announced in newspaper advertisements that ‘air pollution affects your heart’. Comment on the physiological mechanisms involved in this effect, illustrating your answer with an appropriate diagram. (iii)  Evaluate the endocrine-disrupting effects of pollutants, with examples relating to humans and marine predators. (iv)  Discuss how applications of pesticides may affect human health and wildlife survival in managed ecosystems. (v)  Write an essay on ‘environmental carcinogenesis’. (vi)  Draw up an inventory of coastal oil pollution in your country. (vii)  Discuss the human health and ecological implications of the 2019/2020 wildfires and subsequent heavy rainfall in Australia. (viii) Satellite images published by the European Space Agency show high levels of pollution in China prior to the onset of the Coronavirus (COVID-19) pandemic in 2019/2020. Is it possible that this pollution exacerbated the severity of the symptoms in patients predisposed to respiratory disorders? Is there any evidence for such a hypothesis? Are there any parallels with the Italian COVID-19 outbreak? (ix) Write a review on the ecological impact of the COVID-19 pandemic in 2019/2020. (x)  ‘To see and not perceive’. Use this theme to prepare a review of the political debate now unfolding on the three environmental emergencies presented in this volume. Include names of agencies that might be interested in your conclusions.

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Index

Note: bold page numbers indicate figures; italic page numbers indicate tables. acetaldehyde  42, 85, 128 acetylcholine/acetylcholinesterase 7, 19–20, 55, 56, 65, 104 acid rain  4, 31, 36, 117–119 acute toxicity  6–8 aflatoxins/alfatocixosis  21–22, 23, 24–25, 131 agriculture  9, 10, 21–22, 38, 117, 125 see also fertilizers; fungicides; herbicides; pesticides air pollution  1, 10, 30–31, 64, 125, 128, 139 and regulation/court judgements  36, 39, 40, 138 seasonal factor in  33, 34 toxic effects of 31, 35–38, 127–130, 128, 137 see also gases, ambient; particulates Alaska (USA) see Exxon Valdez oil spill algal toxins/blooms see cyanobacteria allergens  34, 35–36 aluminium  76, 93, 119, 122 Alyssum 122 Alzheimer’s disease  33, 37, 52, 58, 59, 88 Amazon 117, 118 amino acids  12–13, 17, 20, 27, 28, 32, 59, 85, 92 and microbes  116–117 and plants  119–122

amphibians  131, 132 anatoxin-a 19–20 Antarctic 103 antibiotics 98, 98, 102–103 resistance to  103 antioxidant defences  13, 14 aquatic ecosystems  4, 5, 6, 8, 67, 97, 126 acidification of  36 and algal blooms see cyanobacteria and fracking 71, 78 and heavy metals  17, 84–86, 94–95 and PAHs  45 and personal care products see personal care products and plastics see plastics Argentina  93, 94–95 arginine  27, 59, 120 arsenic (As)  5, 76, 78, 80, 82, 91–93 adaptation to  93, 94–95, 122 sources/forms of  91–92 toxicity of  83, 92–93, 95, 131 Aspergillus  21, 57, 131 A. flavus  21, 23 A. fumigatus  22, 23–24 A. ochraceus 22 A. parasiticus  21, 23

141

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142 Index asthma  4, 8, 9, 10, 31, 33, 39, 124, 127–128, 129, 136, 137, 138, 138 and nitrogen dioxide  35–36, 40, 127–128 and sulfur dioxide  36, 37, 127–128 atomic bombs  1, 106, 109, 110, 111, 130–131 Australia  2, 9, 19, 38, 116, 118, 134, 139 autism  4, 8, 53, 54, 60, 129 azoxystrobin  57, 63, 67

bacteria see microbes, adaptation in; microbial toxins Bangladesh  90–91, 102 batteries  87, 89, 90, 130 bees  6, 57, 68, 131, 132 behavioural dysfunction  5, 47, 50 and heavy metals 83, 83, 86, 88 Belize 133 benzene  42, 71, 72, 78, 79, 128 bioaccumulation and heavy metals  76, 79, 82, 84, 87 and microplastics  100 and POPs  46, 49, 55, 59, 66 bioassays see lethality tests biodiversity  3, 5, 13, 14, 131–133, 136, 139 and fossil fuels  70, 73–77, 80–81 and pesticides/herbicides  131–132 biogenic compounds  3–4, 16–29 algal toxins see cyanobacteria and climate change  4, 16, 17, 21, 22, 23 and secondary metabolism  16–17, 21 three classes of  16, 17 see also microbial toxins biomagnification  42, 65–66, 67, 69, 76, 79, 95, 132, 137 biomarkers/bioindicators  8, 13, 18, 24, 40, 45, 79, 94, 100 biopesticides  17, 26, 28, 29 bioremediation  5, 16, 116, 117, 122–123, 131 birds  6, 20, 21, 67, 94–95, 98, 111, 132 and fossil fuels  75–77, 79, 80–81 Bolivia  17, 24 bone abnormalities  43, 66, 83, 87, 88, 90, 91, 109, 128

bottlenose dolphin  74 brain  8, 33–34, 37, 51–52 and heavy metals  83, 87, 88 see also neurodegenerative disorders; neurotoxins Brassica  27, 29, 117, 121 Brazil  38, 117, 131 breast milk  9, 10, 13, 21, 24, 42, 47, 52, 54, 66, 87, 89 Britain (UK)  22, 130, 131, 134, 135, 139 Clean Air Act (1956) 36 court judgements in  40, 137–138 plastic pollution in  98, 99 Torrey Canyon oil spill in (1967) 4, 70 see also London; Thames, River BTEX group  42, 71, 79, 128 Bulgaria  22, 24 butterflies  6, 68, 131, 132

cadmium (Cd)  5, 78, 80, 82, 89–91, 101, 125, 133 toxicity of 83, 90–91, 95, 131 uses of  89–90 California (USA)  2, 130, 137, 139 cancer  4, 8, 12, 19, 37–38, 124, 128, 138 and fracking  79 and heavy metals 83, 90, 91, 92, 95 and IARC  24, 45, 50, 60, 91, 92, 112, 113 and mycotoxins  23, 24 and phytotoxins  27, 29 and POPs  43, 44–45, 46, 47, 48, 49, 50–51, 68, 129 and radiation  106, 107, 108, 109–111, 112, 130, 131 and VOCs  42 carbon dioxide  3, 10, 80, 117, 118 carbon monoxide  32, 38, 129 cardiovascular disease see CVD cattle  27, 28, 116 cause-and-effect issues  9, 39, 40, 90, 95, 110, 113, 136 central nervous system  8, 20, 30 and Minamata disease  5, 83, 83, 84–86, 95 see also brain cereals  21, 22, 24, 56, 57, 84 storage of  23, 25 cetaceans  74, 76, 98, 132

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Index

143 Chernobyl disaster (1986) 2, 5, 106–107, 108, 125, 131 and bioremediation  16 and ecological recovery  110, 111 and food contamination  107, 108–109, 127 children/infants  10, 22, 25, 33, 34, 38, 104, 109, 128 and fossil fuels  79, 80, 81 and heavy metals  86, 87, 88, 89, 90, 91, 94, 127 and POPs  48, 50, 54, 56, 83 Chile  24, 38 China  24, 36, 80, 91, 92, 93, 94, 95, 102–103, 125 chlorpyrifos  55, 56, 68, 83 cholinergic toxicity  7 chromium (Cr)  76, 78, 80, 93, 133, 137–138 chronic obstructive pulmonary disease see COPD chronic toxicity  6, 8 Claviceps purpurea  21, 23 climate change  2, 3, 5, 10, 14, 97, 104, 132, 136, 137 and biogenic compounds  4, 16, 17, 18, 20, 21, 22, 23, 29 coal  1, 5, 36, 43, 70, 80–81, 106 coal ash 71, 80, 81, 84, 95, 125, 138 coastal communities  72, 73, 77, 84–85, 102 coastal habitats/species  5, 9, 70, 74, 76, 103, 105 coffee 22 consumerism/lifestyle choices  5, 97–105, 139 issues with  97–98 and obesity  4, 33, 34, 128, 136 and personal care products see personal care products and pharmaceuticals see pharmaceuticals and plastics see plastics COPD (chronic obstructive pulmonary disease)  4, 8, 9, 124 and air pollution  31, 33, 36, 37, 39, 127, 128, 136–137, 138 copper(Cu)  78, 93, 94 coral reefs  10, 12, 104, 105, 133, 134, 138 Corby poisoning case (UK)  137–138 corporations 135 court cases  39, 40, 60, 61, 129, 135, 137–138, 139, 140 crocodiles 66, 83, 94, 133

CVD (cardiovascular disease)  4, 8, 9, 13, 14, 55, 118, 124, 131 and air pollution  30, 39, 127, 128, 137, 138 and heavy metals  86, 89, 90, 95 cyanobacteria  2, 16, 17–20, 138 classification of  17 and climate change  17, 18, 20, 29 cytotoxins  17, 19 exposure routes for  20 hepatotoxic  17, 18–29 Lake Erie case study  18, 19 neurotoxins  17, 19–20 toxic properties of 17 cyanogens  27, 28 cycads 20 cyclodienes  51, 52–53 cystic fibrosis  9, 10, 31, 138 cylindrospermopsin 19 cysteine  84, 85, 86, 121, 122 cystic fibrosis  9, 10, 31, 127, 138 cytochrome P450 12, 14, 44, 55, 62 cytokines  32, 35, 37, 39, 59, 112, 114 cytotoxins/cytotoxicity  8, 17, 17, 18, 45, 74, 79, 113 D, vitamin  113, 114, 130 dairy produce  10, 21, 24, 108–109, 127 Dakar (Senegal)  130 Daphnia galeata 101 D. magna  7, 101 DDE (dichlorodiphenyldichloroethylene)  52, 132 DDT (dichlorodiphenyltrichloroethane)  51–52, 62 ban on  51, 52 Deepwater Horizon oil spill (2010) 2, 4, 40, 71–76, 71, 72, 77, 81, 137 and air monitoring  72–73 and biodiversity  73–77, 81 and bioremediation  117, 131 and birds  75–76 and coastal habitats  74 and fisheries/seafood  72, 73, 77 implications for future of  77 risk assessments for  72 and sea turtles  75, 75, 131 and seafood  72, 73, 77 and sediment toxicity  74 and toxic effects on humans of  73

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144 Index DEET (N,N-diethyl-meta-toluamide) 104 deforestation  5, 95, 117, 118, 137 depression  73, 88, 92, 109, 129 dermatitis  9, 20, 104 dermatoxins 17, 17 detergents  77, 105 developing countries  5, 38, 54, 59 diabetes  4, 33, 50, 51, 128 dioxins/furans  3, 4, 42, 46, 60, 63, 132 and bioremediation  117, 123 and cancer  49, 50–51 classification/structure of  49 and diabetes  50, 51 exposure routes/metabolism of  49, 50 risk assessment of  64–65, 127 toxic effects of 43, 49–51 diphenyl esthers  66, 101–102, 132 disposal culture see consumerism/ lifestyle choices DNA damage  8, 57, 63, 76, 80, 87, 91, 93, 94, 100, 111, 113–114, 128 DNA-adducts  13–14, 44, 45 Dominican Republic  130 dopamine system  34, 46, 52, 53–54, 56, 58 drought  2, 21, 119, 120 electronic waste  82, 93–94, 95, 97, 139 emphysema  31, 127, 138 endocrine disruptors  3, 4, 8, 14, 33, 92, 98, 124, 128, 137, 138, 139 compounds involved in  60–61 and female reproduction  62–63 metabolism of  62 and POPs  42, 45, 49, 60–64, 68–69, 129 and thyroid function  64 and urinogenital system  63 endosulfan  53, 54 environmental fate  13, 45, 126 environmental justice  10, 40, 135 environmental protection  34, 117, 124, 134, 135 agencies  6, 39, 61, 139 see also EPA enzymes  12, 13–14, 27, 37, 44, 63, 87, 119, 121 cytochrome P450 12, 14, 44, 55, 62 inhibition of  7, 19 see also acetylcholine/ acetylcholinesterase

EPA (Environmental Protection Agency, US)  50, 54, 61, 92, 130, 135 Erie, Lake (USA/Canada)  18, 19, 126 ethylbenzene  42, 71, 79, 128 ethylene  78, 119, 130 European Union (EU)  22, 26, 38, 58, 60, 135 Exxon Valdez oil spill (1989) 2, 4, 71, 73, 137 recovery of species following  76–77, 81 eye conditions  20, 37, 48, 128

fertilizers  2, 17, 18, 89, 125, 138 fetal development  39, 47, 49, 52, 86, 88–89, 92, 129 Fife (UK)  130 fipronil  68, 132 fish  6, 7, 20, 45, 57, 77, 84, 95, 101, 127 flamingos 94–95 Flint, Michigan (USA) 10, 89, 130 Florida (USA)  20 food contaminants  4, 6, 7, 90, 126–127 biogenic  16, 17, 21, 22, 25 particulates 38 and POPs  43, 46 route of entry of  9, 43 see also seafood fossil fuels  3, 4–5, 34, 43, 70–81, 138, 139 and radiation 71, 80, 81, 106, 109 and risk assessment  70 see also coal; oil pollution; vehicle emissions fracking  5, 106, 125, 131 and cancer  79 chemicals added during  78 and risk assessments/management  79, 134 wastewater from 71, 78–79, 84 France 54 fruit juices  22 Fukushima disaster (2011) 2, 5, 106–107, 110, 125 and food contamination  108–109 and release of contaminated water  108 fungi  3, 16, 120 see also mycotoxins fungicides  42, 57, 84 classification of  56 toxic effects of 43, 56–57, 63, 129

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Index

145 furanocoumarins 28 furans see dioxins/furans Fusarium  21, 22, 57 future for environmental toxicology  39, 54, 61, 86, 106, 131, 136, 136–137, 138–140

gases, ambient  3, 4, 30–41 and additive/synergistic interactions  37, 39 and urban environment  32, 33, 39 see also nitrogen dioxide; ozone; sulfur dioxide gastrointestinal disorders  20, 43, 84, 85, 86 gene expression  4, 12, 24, 49, 79, 93, 121 Germany 50 Ghana 130 giant hogweed  26 glutathione  12, 14, 35, 44, 119, 122 glycine  12, 59–60, 121 glycosides  27, 28 glyphosate  57, 58, 59–60, 61, 68, 129, 138 grain see cereals Great Barrier Reef (Australia)  9, 134 Great Pacific Garbage Patch  98, 99 Guam dementia  20, 59 gut microbes  44, 59, 60, 68, 116

habitat degradation  1, 4, 5, 69, 97, 131, 137 see also oil pollution Haina (Dominican Republic)  130 heavy metals  2, 3, 3, 5, 14, 66, 82–96, 118, 130, 133, 137, 138, 139 and ecotoxicity  94–95 and electronic waste  82, 93–94, 95 and fossil fuels 71, 76, 80, 125 and plants  119, 121, 122, 123 and pregnant women 83, 85, 87, 88–89, 90–91, 93, 137–138 and reproductive dysfunction 83, 90, 95 toxicity of 83 see also specific metals hepatitis  22, 23, 24, 94 hepatotoxins 17, 17, 18–19, 67 see also liver

herbicides  40, 42, 43, 57–60, 68, 123 and biodiversity  132–133 classification of  57 glyphosate  57, 58, 59–60, 61, 68, 129, 138 in interactions  57 paraquat  57, 58–59, 67, 129 toxic effects of  58–59 hexachlorocyclohexanes  52–53, 56 Hiroshima (Japan)  1, 106, 109, 110, 111, 130–131 histidine  12, 122 history of environmental toxicology  1–2 hormones  33, 44, 47, 48, 50, 62, 63, 89, 91 hoverflies 57, 68, 131 hydrogen sulfide  17 hydroxylation  12, 44, 62

IARC (International Agency for Research in Cancer)  24, 45, 50, 60, 91, 92, 112, 113 idiopathic pulmonary fibrosis  4, 127 immune function  80, 81, 100, 102 and heavy metals 83, 89, 93, 94, 95 and POPs  43, 43, 46, 49, 62 in utero exposure  4, 9, 26, 50, 53, 54, 62, 87, 90–91, 109, 111 India 1, 10, 23, 36, 92, 93 Indonesia  22, 38, 116, 117 insect pollinators  68, 69 see also bees; butterflies; hoverflies insect repellents  98, 104–105 insecticides  83, 132 nicotinoid  6, 67–68 organochlorine see organochlorine insecticides organophosphate see organophosphates see also pesticides insulin resistance  33, 64 interactions, additive/synergistic  9–10, 11, 37, 39, 42, 50, 57, 58, 66 International Agency for Research in Cancer see IARC Iran  22, 24 Iraq 84 Italy  50, 92

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146 Index Japan  2, 6, 48, 91 impacts of atomic bomb in  1, 106, 109, 110, 111, 130–131 mercury poisoning in  5, 84–86 see also Fukushima disaster (2011) Kentucky (USA)  95 Kenya  22, 23, 24–25 kidneys 8, 17, 19, 24, 66 and heavy metals 83, 86, 87, 89, 90, 91, 92, 95 killer whale  66, 76, 132 Kruger National Park (South Africa)  94, 133 La Oroya (Peru)  130 lakes  6, 95 algal blooms in  17, 18, 19, 20, 126 landfill sites  63, 80, 89 lawsuits see court cases LD50/LC50 values  6, 7, 22, 56, 57 lead (Pb)  5, 10, 76, 78, 80, 82, 86–89, 93, 101, 125, 127, 133, 138 exposure route of  87 and monitoring  89 threshold for  88, 89 toxicity of 83, 83, 87–89, 95, 130 uses of  87 leadership  133–134, 136 legumes  25, 27, 28 lethality tests see toxicity assessments Leucaena leucocephala  27, 116–117, 122 leukaemia  108, 109, 111, 112, 130, 131 lifestyle choices see consumerism/lifestyle choices light/noise pollution  3, 9, 72, 130, 132 lipids  32, 33, 35, 37, 67, 119 lipopolysaccharide endotoxins  17, 20 liver 8, 17, 19, 23, 24, 46, 49, 134–136 and heavy metals  86, 87, 92 see also hepatotoxins London (UK) 10, 39, 40 smog event in (1952) 1, 36, 37, 80, 125 Louisiana (USA) 72, 73, 74, 77, 103, 130 lung cancer  8, 80, 112, 134 lungs  10, 13, 14, 19, 30, 31, 31, 39, 74, 87, 92, 118, 127

and nitrogen dioxide  35–36 and ozone  32–33, 34 and sulfur dioxide  36 see also COPD; emphysema

maize  21, 22, 23 marine environment  5, 137, 138 acidification of  10, 36 and biogenic compounds  16 and biomagnification  66, 67 and heavy metals  84–86, 94 and oil spills see oil pollution and plastics see plastics memory impairments  33, 52, 56, 59, 65, 68, 88, 130 mental health  65, 71, 81, 107, 109, 129 see also depression mercury (Hg)  5, 9, 17, 66, 78, 79, 80, 82, 93, 94, 118, 127, 132, 138 absorption pathway of  84, 85, 86 and fungicide  84 and Minamata disease  5, 83, 83, 84–86 sources/forms of  84 toxicity of 83, 95, 130 Mersey, River  98, 99 metabolic responses to toxins  11–13 metallic elements see heavy metals metam sodium  54, 68 methane emissions  2, 3 methylmercury see mercury Mexico  126, 133 Mexico City (Mexico) 10, 33, 89 microbes, adaptation in  116–117, 122–123, 131 see also bioremediation microbial toxins  3, 11–12, 138 microplastics 99–102 and chemical adsorption  100, 101, 102 as human health risk  101–102 ingestion by organisms of  99–100 interventions for  102 and microbes  16, 101 monomers 100 and particle size/shape  100 toxicity of  100–101 as vectors for diseases  100 milk  10, 21, 24, 108–109, 127 see also breast milk

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Index

147 Minamata disease  5, 83, 83, 84–86 mining  5, 86, 89, 91, 94, 112, 113, 133 mitochondria  37, 58, 59, 86, 121 molluscs see shellfish monitoring  5–6, 22, 72–73, 82, 89, 94, 133, 139 see also risk assessment/management motor dysfunction  51, 58, 59 Myanmar 92–93 mycotoxins  16, 20–25, 57 and aflatoxins  21–22, 24–25 and cancer  23, 24 and climate change  21, 22, 29 control of  25 and food analysis  24–25 and fungicide resistance  21 importance of  21 relevant fungi species  21 toxic effects of  22–25 toxic properties of 17

Nagasaki (Japan)  1, 106, 109, 110, 111, 130–131 neonicotinoid insecticides  6, 67–68 nettle 26 neurodegenerative disorders  6, 13, 52, 56, 58, 59–60, 83, 124, 137, 138 see also Alzheimer’s disease; Parkinson’s disease neurotoxins  4, 7, 17, 17, 19–20, 27, 30, 33–34, 55, 104 heavy metals  84–86, 87, 92–93, 130 POPs 43, 46, 47, 48, 51–52, 53–54, 59, 68, 129 New Delhi (India)  89 smog in  1, 10, 125 New Zealand  76 nickel (Ni)  76, 80, 93, 122 Niger, River  70 Nigeria 22 nitrogen dioxide  1, 2, 3, 4, 30, 31, 39, 125, 138 and asthma  35–36, 40, 127–128 and ozone  32, 35, 36 toxic effects of 31, 35–36, 37, 136–137 and vehicle emissions  34 noise/light pollution  3, 9, 72, 130, 132 Novichok  7, 54, 65

nuclear power stations  2, 5, 106–107, 131, 135, 139 see also Chernobyl disaster; Fukushima disaster; Three Mile Island accident nuclear weapons  1, 106, 107, 109 nuts  22, 23, 25 obesity  4, 33, 34, 128, 136 oestrogen  47, 60, 62, 63, 129 oil pollution  1–2, 9, 14, 43, 71–78, 131, 138 and bioremediation  117, 123 future prevention of  131 and long-term recovery of species 76–77 and PAHs  71–72, 71, 73, 74, 75 and petrochemical plants  72, 130 risk factors 71 and shale oil/gas see fracking and VOCs  71, 71, 72–73 see also Deepwater Horizon oil spill; Exxon Valdez oil spill; Torrey Canyon oil spill

organochlorine insecticides  42, 43, 51–54, 66–67, 94, 137 bans on  51, 52, 53, 54 and biomagnification  66, 133 classification of  51 cyclodienes/hexachlorocyclohexanes  52–53 DDT 51–52 dieldrin 53–54 endosulfan 54 exposure routes of  51 and low-level exposure  65 and neurological disorders  51–52, 53–54 persistence of  51, 52, 53, 54, 67 organophosphates (OPs)  7, 20, 42, 43, 54–56, 102 classification of  54–55 exposure routes of  55 risk assessment of  65 toxic effects of  55–56, 129 osteoporosis 83, 90 oxidative stress  13, 32–33, 37, 80, 119, 121 and heavy metals 83, 86, 87, 91, 93 and POPs  48, 53, 57, 58, 59, 60, 64, 67

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148 Index oxybenzone  104, 133 ozone  3, 4, 14, 30, 39, 125, 127 and animal models  34 at-risk groups  32, 33, 34 and nitrogen dioxide  32, 35, 36 toxic effects of 31, 32–34, 136–137 PAHs (polycyclic aromatic hydrocarbons)  4, 42, 43–45, 125, 131, 137, 138 and aquatic organisms  45, 132 biotransformation of  44 and carcinogenesis  44–45 and fossil fuels  43, 71–72, 71, 73, 74, 75, 80, 128 metabolization of  44 and risk assessments  45 structure of  43, 44 toxic effects of  43–44, 43 Pakistan 92 paraquat  57, 58–59, 67, 129 parathion  54, 55 Parkinson’s disease  33–34, 52, 53–54, 56, 58, 59, 88, 129 particulates 3, 3, 4, 33, 37, 71, 72, 118, 125, 138, 139 and coal combustion  80, 81 composition/size of  38–39 sources of  9, 38 toxic effects of 31, 128, 136–137 patulin 22 PBDEs (polybrominated diphenyl ethers)  62, 66, 101, 132 PCBs (polychlorinated biphenyls) 3, 4, 42, 45–48, 74, 127, 137, 138 ban on  46 and biomagnification  66, 132 and bioremediation  117, 123 and cancer  47, 48 classification/structure of  45–46 commercial production of  46 as endocrine disruptor  60, 62, 63 exposure routes/metabolism of 46–47 toxic effects of 43, 47–48, 129 PCDDs (polychlorinated dibenzo-pdioxins)  49, 50, 65 PCDFs (polychlorinated dibenzofurans)  49, 50, 65 peanuts  21–22, 23 penguins 76

Penicillium  21, 22, 57 Pennsylvania (USA) 71, 79, 81 peptides  13, 18, 33, 119, 121, 122 persistent organic pollutants see POPs personal care products  5, 9, 10, 14, 63, 97, 103–105 insect repellents  98, 104–105 microbeads from  101–102 sunscreen/oxybenzone  98, 104, 133 surfactants 105 Peru  24, 93, 130 pesticides 2, 3, 4, 9, 19, 36, 67–68, 69, 81, 94, 125, 127, 137, 138, 139 bio- 17, 26, 28, 29 and biodiversity  14, 131–132, 133 as endocrine disruptor  60, 63, 64 lethality tests on  6, 7 see also insecticides petrochemical plants  72, 130 pharmaceuticals  5, 6, 7, 9, 26, 29, 97, 102–103, 133 and Antarctic  103 contraceptives 103 see also antibiotics phospholipids  32, 35, 119 photosynthesis  2, 16, 57, 117, 118 phytochelatins  13, 122 phytotoxins  16, 25–29 and binary action  26 and biopesticides  17, 26, 28, 29 case study  26 classification of  27 glycosides 27 non-protein amino acids  27, 29 and pharmaceutical pollution  29 toxic effects of  26, 27, 28 toxic properties of 17 plants and acid rain  31, 36, 117–119 adaptation in  4, 5, 117–122, 123 and amino acids  12–13, 119–122 and heavy metals  119, 121, 122, 123 metabolic responses in  12–13, 119–120 and polyamines  119, 120–121 routes of entry in  9 see also phytotoxins plastics  3, 5, 14, 45, 60, 98–102, 98, 105, 138 impacts on wildlife of  98 and microbes  117 see also microplastics

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Index

149 polar bear  66, 67, 83, 94, 132 policies/regulations  2, 30–31, 36, 39, 46, 77, 133–137 bans  46, 51, 52, 53, 54, 56, 59, 90, 137 and corporations  135 failures of  1, 5–6, 133–134, 136–137 international agreements  136, 139 and leadership  133–134, 136 see also court cases polyamines  119, 120–121 polybrominated diphenyl ethers (PBDEs)  62, 66, 101, 132 polychlorinated biphenyls see PCBs polychlorinated dibenzo-p-dioxins (PCDDs)  49, 50, 65 polychlorinated dibenzofurans (PCDFs)  49, 50, 65 polycyclic aromatic hydrocarbons see PAHs POPs (persistent organic pollutants)  2, 3, 4, 14, 42–69, 74, 102, 114, 139 accumulation in body fat of  49, 51, 55, 62 and beneficial insect species  67–68 and biomagnification  42, 65–66, 67, 69, 132 and bioremediation  116, 117 dioxins/furans see dioxins/furans and endocrine disruption  42, 45, 49, 60–64, 68–69 fungicides see fungicides herbicides see herbicides insecticides see organochlorine insecticides; organophosphates and oxidative stress  48, 53, 57, 58, 59, 60, 64, 67 polychlorinated biphenyls see PCBs polycyclic aromatic compounds see PAHs and risk assessments  45, 64–65, 127 toxic effects of 43, 129 potato 27 power generation plants  34, 36, 80, 125, 127 see also nuclear power stations predator species see biomagnification pregnant women and air pollution  39, 128, 129 and heavy metals 83, 85, 87, 88–89, 90–91, 92, 93, 137–138 and POPs  52, 54, 56, 62, 63 see also fetal development; in utero exposure

proline  12–13, 28, 120, 122 puberty-related conditions  62–63, 89 pulmonary diseases see lung cancer; lungs radiation  2, 3, 3, 5, 14, 78, 106–115, 125, 131, 138, 139 α/β/γ particles, properties/effects of 107–108 and bioremediation  16 exposure pathways of  108–109 and food contamination  107, 108–109, 127 and fossil fuels 71, 80, 81, 106, 109 long-term effects of  111 and mental health  109 and radon  5, 106, 111–113 toxicology of 107, 109–111, 130–131 ultraviolet (UV)  5, 21, 106, 113–114 radioiodine  107, 110 radium  78, 107 radon  5, 106, 111–113 regulations see policies/regulations reproductive dysfunction  4, 17, 62, 128 and biogenic contaminants  24, 26, 27 and heavy metals 83, 90, 95 and POPs  43, 43, 45, 47, 48, 68 respiratory disorders 31, 33, 38, 56, 71, 73, 81, 88, 111, 129, 137 see also asthma; lung disease risk assessment/management  13–14, 64–65, 70, 108, 113, 124, 125–127, 137, 138 constraints in  133–134 and fossil fuels  70, 72, 79 need for international agency for  139 TEF approach  64 see also monitoring rivers  17, 20, 84, 94, 95, 98, 99, 102, 103, 133, 137, 138 Romania 24 ROS (reactive oxygen species)  57, 87, 91, 119, 120, 121 rotifer 101 Russia  9, 107, 130 salicylic acid  119–120, 121 salinity  16, 119, 120, 121, 122 Salisbury incident (2018) 7, 54, 65 saponins  27, 28

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150 Index sarin  7, 54 saxitoxins  19, 20 seafood  5, 72, 73, 77, 84–86, 98, 102, 127 seals  66, 76, 132 selenium  82, 86, 94, 95, 121 sewage  10, 20, 99, 127 shale oil/gas see fracking sheep  27, 28, 116 shellfish  20, 84, 101–102 Shinji, Lake (Japan)  6 sick building syndrome  4, 21 signature molecules  13–14 skin disorders  9, 20, 37, 48, 50, 92, 104, 109, 113–114 smog  1, 36, 37, 125 smoking  8, 37, 90, 92, 111, 112, 134 soil contamination  6, 36, 67, 80, 89, 91, 93, 119, 122, 125 South Africa  24, 94, 133 species extinction  14, 124, 138 sperm whale  74 stroke  33, 37, 128 strontium  78, 79, 107 sulfur dioxide  2, 3, 4, 30, 31, 31, 39, 71, 80, 117, 125, 137, 138 and asthma  36, 37, 127–128 toxic effects of 31, 36–38 sunscreen  98, 104, 133 surfactants  61, 105 lung  32, 35

tannins 28 TCDD (2,3,7,8-tetrachlorodibenzo-pdioxin)  49, 50–51, 64, 65, 129 TEFs (toxicity equivalency factors)  65 Tennessee (USA)  80, 125 Thames, River  98, 99, 102, 135 thorium  78, 80, 107, 112 Three Mile Island accident (1979) 2, 106–107, 108, 109 thyroid  47, 48, 50, 51, 64, 108, 109–110, 114, 131 tobacco see smoking toluene  42, 71, 79, 128 Torrey Canyon oil spill (1967) 4, 70 toxicity assessments  6–10

acute 6–8 chronic 8 and complex interactions  9–10, 11 toxicity equivalency factors (TEFs)  65 Tunisia  22, 24 turtles  9–10, 75, 75, 98, 131 ultraviolet (UV) radiation  5, 21, 106, 113–114, 138 United States (USA)  20, 60, 95, 104, 116, 117 court judgements in  60, 61, 129 EPA  50, 54, 61, 92, 130 fossil fuels in  78, 79, 80, 125, 131 heavy metals in  87, 89, 92, 130 oil spills in see Deepwater Horizon oil spill; Exxon Valdez oil spill POPs in  47, 50, 53, 54, 58, 60, 61 see also California; Louisiana; Pennsylvania uranium  78, 80, 107, 112 vehicle emissions  5–6, 8, 14, 31, 34, 70, 127, 128, 133, 138, 139 and corporations  135, 136 and particulates  9, 38, 39 and VOCs  42 vine fruits  22 Virginia (USA)  117 VOCs (volatile organic compounds)  42, 69 and fossil fuels  71, 71, 72, 78, 128 wastewater  18, 70, 78–79, 84, 95, 102, 103, 105, 117 water contamination  4, 6, 7, 29, 60, 61, 118, 126, 131 biogenic  16, 17 and bioindicators  13 and fossil fuels  70, 71, 78–79 and heavy metals  86, 87, 89, 91, 92, 93, 95 and irrigation  20, 91, 127 and pharmaceuticals see pharmaceuticals route of entry of  9

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Index

151 WHO (World Health Organization) 10, 32, 55, 61, 65, 91, 139 wildfires  2, 38, 95, 118, 139 women  32, 33, 47, 62–63, 103, 128 see also pregnant women

xylene  42, 71, 79, 128 zebrafish  57, 63, 67, 92, 101 zinc  78, 80, 87, 90, 93, 122 ziram  56–57, 63, 129

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