Toxicology and Human Health: Environmental Exposures and Biomarkers 9819921929, 9789819921928

Table of contents :
Foreword
Preface
Acknowledgments
Contents
Editors and Contributors
About the Editors
Contributors
Abbreviations
Part I: Environmental Exposure to Contaminants and Assessment
1: Environmental Contaminants and Their Impact on Wildlife
1.1 Introduction
1.2 Classification of Environmental Contaminants
1.3 Pesticides
1.4 Industrial Chemicals
1.5 Fossil and Mineral Fuels
1.6 Pharmaceuticals (Human and Veterinary)
1.7 Personal Care Products
1.8 Metals
1.9 Fertilizers
1.10 Impact of Environmental Contaminants on Wildlife
1.11 Pesticides
1.12 Industrial Chemicals
1.13 Fossil and Mineral Fuels
1.14 Pharmaceuticals (Human and Veterinary)
1.15 Personal Care Products
1.16 Metals
1.17 Impact of Fertilizers
1.18 Conclusion
References
2: Heavy Metal Pollution in Water from Anthropogenic and Natural Activities and the Remediation Strategies
2.1 Introduction
2.2 Chemical Nature of Heavy Metals
2.3 Sources of Heavy Metal Pollution
2.4 Heavy Metals and Their Dangerous Impacts
2.4.1 Copper
2.4.2 Iron
2.4.3 Lead
2.4.4 Cadmium
2.4.5 Zinc
2.4.6 Nickel
2.4.7 Chromium
2.4.8 Arsenic
2.5 Characteristics of Common Heavy Metals
2.6 Heavy Metals Removal Technologies
2.7 Heavy Metals Removal from Water
2.8 Conventional Methods
2.9 Non-Conventional Methods
2.10 Nanotechnology
2.11 Phytoremediation of Heavy Metals
2.12 Biological Approach by Using Diatoms
2.13 Endophytes Isolation and Characterization
2.14 Uses of Endophytic Microbes in Real Contaminants
2.15 Future Predictions
2.16 Conclusion
References
3: Cement Dust Pollution and Environment
3.1 Introduction
3.2 Chapter Aims
3.3 Influence of Cement Dust on the Characteristics and Population of the Environment
3.3.1 Cement Dust Pollution and Atmosphere
3.3.2 Cement Dust Pollution and Water
3.3.3 Cement Dust Pollution and Soil
3.3.4 Cement Dust Pollution and Human Health
3.3.5 Cement Dust Pollution and Plant Health
3.4 Conclusion
References
4: Microplastics: An Overview
4.1 Introduction
4.2 Types of Plastics
4.2.1 Megaplastics
4.2.2 Macroplastics
4.2.3 Mesoplastics
4.2.4 Microplastics
4.2.5 Nanoplastics
4.3 Sources
4.4 Biological Interaction
4.5 Conclusion
References
5: Aquaculture Fish Responses Towards Temperature Stress: A Critical Review
5.1 Introduction
5.2 Materials and Methods
5.3 Fish Responses to Temperature Stress
5.4 Neuroendocrine Response to Temperature Stress
5.5 Antioxidant Responses to Temperature Stress
5.6 Immunity Status Under Temperature Stress
5.7 Haematological Responses to Temperature Stress
5.8 Growth and Metabolic Responses to Temperature Stress
5.9 Biochemical Response to Temperature Stress
5.10 Response of Ionic Balance to Temperature Stress
5.11 Reproductive Responses to Temperature Stress
5.12 Effects of Temperature on Sex Determination and Differentiation
5.13 Thermal Imprinting in Fish
5.14 Mitigation Measures to Temperature Stress
5.15 Levans
5.16 Proteins and Amino Acids
5.17 Tryptophan
5.18 Phenylalanine and Tyrosine
5.19 Methionine
5.20 Arginine
5.21 Branched-Chain Amino Acids
5.22 Glutamine
5.23 Tyrosine, Glycine, and Phosphatidylserine
5.24 Essential Fatty Acids and Phospholipids
5.25 Vitamins
5.26 Vitamin C
5.27 Vitamin E
5.28 Vitamin A
5.29 B Group Vitamins: Vitamins B2 and B3
5.30 Vitamins B9 and B12
5.31 Vitamins B5 and B7
5.32 Minerals
5.33 Nucleotides
5.34 Methyl Donors
5.35 Conclusion and Future Perspective
References
Part II: Biomarkers of Human Health
6: Thrombophilia and Its Markers: A Comprehensive Insight
6.1 Thrombosis
6.2 Coagulation Cascade
6.3 Epidemiology
6.4 Specific Genetic Types of Inherited Thrombophilia
6.4.1 Factor V Leiden
6.4.2 Prothrombin Genetic Mutation
6.4.3 Methylenetetrahydrofolate Reductase (MTHFR) Mutation
6.4.4 Protein C Deficiency
6.4.5 Protein S Deficiency
6.4.6 Antithrombin Deficiency
6.5 Thrombophilia in Pregnancy
6.6 Portal Vein Thrombosis
6.7 Cerebral Venous Thrombosis (CVT)
6.8 Coronary Heart Disease
6.9 Conclusion
References
7: Role of Salivary Markers for Diagnosis of Systemic Diseases
7.1 Introduction
7.2 Salivary Diagnostics for Systemic Diseases
7.2.1 Cardiovascular Diseases
7.2.2 Cardiac Enzymes
7.2.2.1 Pro-inflammatory Salivary Markers
7.2.2.2 Soluble Cell Adhesion Markers
7.2.3 Diabetes
7.2.4 Renal Diseases
7.2.5 Malignancy
7.2.6 Brain Diseases
7.2.7 Infectious Diseases
7.2.8 Bacterial Diseases
7.2.9 Viral Diseases
7.3 Salivary Diagnosis of Corona Virus Disease-19 (COVID-19)
7.3.1 Autoimmune Disorders
7.3.2 Psychological Research
7.3.3 Hereditary Diseases
7.3.4 Respiratory Disease
7.3.5 Forensic Evidence
7.4 Saliva in Hormone Level Monitoring
7.4.1 Aldosterone
7.4.2 Progesterone
7.4.3 Insulin
7.5 Conclusion
References
8: Role of Biomarkers in Cancer Prevention and Therapy
8.1 Introduction
8.2 History of Cancer Biomarkers Discovery
8.3 Limitations of Cancer Therapies and Need for Cancer Biomarker Discovery
8.4 Cancer Biomarkers and Their Clinical Applications
8.5 Some Commonly Used Cancer Biomarkers in Clinical Practices
8.6 Sources of Cancer Biomarker Detection
8.6.1 Circulating Tumor Nucleic Acids
8.6.2 Circulating Tumor Cells
8.6.3 Exosomes
8.7 Stages of Cancer Biomarker Development
8.8 Biomarkers Used in Some Common Cancers
8.9 Targeted Therapies Based on Cancer Biomarkers
8.10 Techniques Used for Biomarker Discovery
8.11 Conclusion
References
9: Polycystic Ovary Syndrome (PCOS): Clinical Features, Risk Factors, Biomarkers, Treatment, and Therapeutic Strategies
9.1 Introduction
9.2 Multifaceted Disease
9.3 Diagnosis
9.4 Hyperandrogenism
9.5 Menstrual Abnormalities
9.6 Ultrasonography Documentation of Polycystic Ovaries
9.7 Common Manifestations in PCOS
9.7.1 Obesity
9.7.2 Insulin Resistance
9.7.3 Diabetes Mellitus
9.7.4 Cardiovascular Disease
9.7.5 Infertility
9.7.6 Cancers
9.8 Biomarkers of PCOS
9.8.1 Inflammatory Markers
9.8.2 Oxidative Stress Markers
9.8.3 Adipose Markers
9.8.4 miRNA as Biomarkers in PCOS
9.9 Treatment Strategies
9.10 Conclusion
References
10: Impact of Environmental Stress on Gene Modification, Cancer, and Chemoresistance
10.1 Introduction
10.2 Environmental Pollutant Exposure and Genome Instability
10.3 A Brief Overview of the Mode of Action of Some Common Chemotherapeutic Drugs
10.4 Target Sites for Developing Chemoresistance and its Molecular Mechanism
10.5 Pathological Remodeling of Extracellular Matrix
10.6 Increase in the Number of Cancer Stem Cell Populations
10.7 Overexpression of Genes Coding for CYP450 Isozymes
10.8 The Ability of Cancer Cells to Repair DNA Damage
10.9 Induction of Oncogenic Signaling
10.10 Common Organic Pollutants Interfering with Chemotherapeutic Drugs
10.11 Particulate Matter
10.12 Aluminum Chloride
10.13 Benzo [a] Pyrene
10.14 Persistent Organic Pollutants
10.15 Conclusion
References
Part III: Human Health Risk Assessment
11: Human Health Risk Assessment (HHRA) for Environmental Exposure: A Brief Account
11.1 Introduction
11.2 Basic Steps in HHRA
11.3 Utilization of HHRA
11.4 HHRA for Exposure to Polluted Air
11.5 HHRA for Exposure to Polluted Water
11.6 HHRA for Exposure to Polluted Soil
11.7 Conclusion
References
12: Human Health Risk Assessment Due to the Consumption of Heavy Metals
12.1 Introduction
12.2 Materials and Methods
12.2.1 Health Risk Assessment for Fish Consumption
12.2.1.1 Calculation of EDI and THQ
12.2.1.2 HI
12.2.1.3 TR
12.3 Results and Discussion
12.3.1 EDI, THQ, and HI
12.3.2 Target Cancer Risk (TR)
12.4 Conclusion
References

Citation preview

Md. Irshad Ahmad Mohammad Mahamood Mehjbeen Javed Saleh S. Alhewairini   Editors

Toxicology and Human Health Environmental Exposures and Biomarkers

Toxicology and Human Health

Md. Irshad Ahmad  •  Mohammad Mahamood  •  Mehjbeen Javed  •  Saleh S. Alhewairini Editors

Toxicology and Human Health Environmental Exposures and Biomarkers

Editors Md. Irshad Ahmad Department of Biophysics All India Institute of Medical Sciences New Delhi, India Mehjbeen Javed Department of Science T.R. Kanya Mahavidyalaya Aligarh, India

Mohammad Mahamood Department of Biology Qassim University Buraydah, Saudi Arabia Saleh S. Alhewairini College of Agriculture and Veterinary Medicine Qassim University Buraydah, Saudi Arabia

ISBN 978-981-99-2192-8    ISBN 978-981-99-2193-5 (eBook) https://doi.org/10.1007/978-981-99-2193-5 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

To the parents

Foreword

It is a pleasure to write a foreword for the book entitled, Toxicology and Human Health edited by Dr. Md. Irshad Ahmad, Dr. Mohammad Mahamood, Dr. Mehjbeen Javed, and Dr. Saleh S. Alhewairini. The presence of toxic substances in water, air, soil, and in the food we eat is continuously on an increase. Toxic substances affect the lives of plants and animals alike, even the wildlives in remote forests and Polar Regions are not spared. Several chemicals and wastes are added to our ecosystems on a daily basis. These pollutants may be in the form of dust, gases, pollens, microplastics, chemicals, liquids, several compounds, etc. The physical and mental health of a population is directly affected by the environment where they live and the foods and drinks they consume. A good knowledge of toxic substances and their impact on human health is essential for sustainable development. Identifying a disease at an early stage with the help of biomarkers reduces the fatality of the disease. This work covers the risk assessment of a variety of toxic substances that are released in the milieu through anthropogenic activities, microplastics, cement dust, heavy metals, etc. which directly affect our health. It also discusses different biomarkers of human diseases ranging from systemic ones to cancer and hormonal disorders to environmental stress. The contents of the book are of great scientific value, and it would be of interest to students and established researchers alike. The knowledge embodied in this book will further help in the decision-making processes of industries, government, as well as non-governmental agencies and it, may even strongly influence the direction of future research. Division of Plant Quarantine ICAR-National Bureau of Plant Genetic Resources, New Delhi, India

Zakaullah Khan

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Preface

Environmental pollution is one of the greatest threats to the health of our planet. Day by day, there is an increase in the range of chemicals from different industries, agricultural runoffs, medicines, and many other sources which continuously contribute to the earth’s chemical load. Almost all countries are facing great difficulties in responding to the crucial and immediate need for effective management. As a result, the science of toxicology/ecotoxicology involving the use of biomarkers has been developed. It provides a broad conceptual framework for evaluating the effects of chemicals/xenobiotics on human health as well as in natural ecosystems. Moreover, this edited book titled, Toxicology and Human Health subtitled “Environmental Exposures and Biomarkers” is an extensive single-source coverage of toxicology, biomonitors, and biomarkers used in different disciplines of ecology, ecotoxicology, environmental sciences, risk assessment, and human health. Furthermore, the realization of new biomarkers for disease and their rapid assessment at an early stage will be a boon for disease diagnosis. The monitoring of human health, onset of disease, prognosis, and therapy outcomes using noninvasive techniques are the most preferable healthcare delivery aims. This interdisciplinary book emphasizes understanding the exposure and effects of environmental contamination on organisms including human beings. The scope of the book covers the following main themes—Environmental exposure to contaminants and assessment, Biomarkers of human health, and finally, Human health risk assessment completes the book. New Delhi, India Buraydah, Saudi Arabia  Aligarh, India  Buraydah, Saudi Arabia 

Md. Irshad Ahmad Mohammad Mahamood Mehjbeen Javed Saleh S. Alhewairini

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Acknowledgments

We thank all the contributing authors for their support, patience, and trust on us. We also extend our thanks to those who provided critical reviews of the chapters in this book.

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Contents

Part I Environmental Exposure to Contaminants and Assessment 1

 Environmental Contaminants and Their Impact on Wildlife����������������   3 Sharad Kumar

2

 Heavy Metal Pollution in Water from Anthropogenic and Natural Activities and the Remediation Strategies ����������������������������������������������  27 Ahmad Manan Mustafa Chatha, Saima Naz, Shabana Naz, Rifat Ullah Khan, and Amna Nawaz

3

 Cement Dust Pollution and Environment������������������������������������������������  55 Abdulmajeed Bashir Mlitan

4

Microplastics: An Overview����������������������������������������������������������������������  75 Hina Javed

5

Aquaculture Fish Responses Towards Temperature Stress: A Critical Review ��������������������������������������������������������������������������������������  83 Saima Naz, Saba Iqbal, Rifat Ullah Khan, Ahmad Manan Mustafa Chatha, and Shabana Naz

Part II Biomarkers of Human Health 6

 Thrombophilia and Its Markers: A Comprehensive Insight ���������������� 135 Humira Jeelani, Qudsia Fatima, Shuja Abass, Khalid Bashir Dar, Muzamil Farooq, Nahida Tabasum, and Fouzia Rashid

7

 Role of Salivary Markers for Diagnosis of Systemic Diseases �������������� 159 Syed Amaan Ali, Safia Habib, Asif Ali, Moinuddin, and Ekramul Haque

8

 Role of Biomarkers in Cancer Prevention and Therapy������������������������ 179 Sujata Pathak and Asrar Alam

9

Polycystic Ovary Syndrome (PCOS): Clinical Features, Risk Factors, Biomarkers, Treatment, and Therapeutic Strategies�������� 197 Qudsia Fatima, Humira Jeelani, Shuja Abass, Muzamil Farooq, and Fouzia Rashid xiii

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Contents

10 Impact  of Environmental Stress on Gene Modification, Cancer, and Chemoresistance �������������������������������������������������������������������������������� 231 Shamila Fatima, Moinuddin, Asif Ali, and Safia Habib Part III Human Health Risk Assessment 11 Human  Health Risk Assessment (HHRA) for Environmental Exposure: A Brief Account������������������������������������������������������������������������ 251 Partha Sarathi Singha and Debosree Ghosh 12 Human  Health Risk Assessment Due to the Consumption of Heavy Metals���������������������������������������������������������������������������������������������������������� 263 Mehjbeen Javed and Nazura Usmani

Editors and Contributors

About the Editors Md. Irshad Ahmad  currently works as Research Associate (Structural biologist), Crystallography & Drug Designing Lab, in the Department of Biophysics, All India Institute of Medical Sciences, New Delhi. Dr. Ahmad received his M.  Tech. (Bioinformatics) and Ph.D. in Biochemistry from the University of Hyderabad in 2011 and Aligarh Muslim University (AMU) in 2018, respectively. He has broad research interests ranging from inhibitors and drug designing to cytotoxicity and genotoxicity on rats and fish models through to drugs and pesticides biochemistry. He has supervised many M.Sc. students during his Ph.D. at AMU. He has authored over 24 publications in refereed journals and 2 book chapters on environmental study, bioremediation, and biodegradation. He has been a strong advocate of toxicology public outreach and has organized events at various venues to enhance the public’s understanding of the role of toxicology in society and people’s lives. Mohammad Mahamood  is a doctorate from Aligarh Muslim University, India. Besides serving the Qassim University in Saudi Arabia, Dr. Mahamood also serves the Institute of Applied Ecology, Chinese Academy of Sciences, China, as a Visiting Professor. His has nearly two decades of experience in teaching and research. He has been a recipient of several fellowships. He is an author and also an editor. His authored book was published by Academic Press while he also edited two books for IntechOpen. Dr. Mahamood is also a well-acclaimed researcher who has published several research papers in journals of high standards having high impact factor. Mehjbeen Javed  has graduated from the Department of Zoology, Aligarh Muslim University, India. She has been a recipient of prestigious national fellowships and awards. She has many studies on the toxicity of heavy metals and pesticides with special reference to biomarkers. Her area of expertise includes aquatic toxicology, heavy metal and pesticide toxicity, risk assessment, and interaction studies. She is an author of several good quality and high-impact publications in international journals of repute. Saleh  S.  Alhewairini,  an alumnus of the University of Nottingham, UK, is an eminent researcher in Qassim University, Saudi Arabia. His experience as an active researcher and as a mentor spans more than a decade. He has extensively worked on xv

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Editors and Contributors

the management of insect pests of various crops grown in Qassim region by using biocontrol and chemical management techniques. He is the recipient of the prestigious Abdulrahman Al-Sudairy Cultural Center Award for Olive Research in Al-Jouf for the year 2019. His approaches to manage the population of red palm weevil and other nemic and insect pests of vegetables and fruits are highly appreciated by farmers in the region. He is a very popular scientific content writer of local and national monthly magazines in the kingdom. He has published a large number of scientific research papers in the leading journals of Science. He is also actively involved in several important government and scientific policy-making, advisory, and controlling organizations.

Contributors Shuja  Abass  Department of Clinical Biochemistry, SKIMS, Soura, Srinagar, Jammu and Kashmir, India Asrar  Alam  Preventive Oncology, Dr. B.R.  Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India Asif Ali  Faculty of Medicine, Department of Biochemistry, JN Medical College, Aligarh Muslim University, Aligarh, India Syed Amaan Ali  Faculty of Medicine, Department of Periodontics and Community Dentistry, ZA Dental College, Aligarh Muslim University, Aligarh, India Ahmad  Manan  Mustafa  Chatha  Department of Entomology, Faculty of Agriculture and Environment, Islamia University of Bahawalpur, Bahawalpur, Pakistan Khalid Bashir Dar  Department of Clinical Biochemistry, University of Kashmir, Hazratbal, Srinagar, Jammu and Kashmir, India Muzamil Farooq  Department of Advanced Centre for Human Genetics, SKIMS, Soura, Srinagar, Jammu and Kashmir, India Qudsia  Fatima  Department of Clinical Biochemistry, University of Kashmir, Hazratbal, Srinagar, Jammu and Kashmir, India Shamila Fatima  Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, India Debosree Ghosh  Department of Physiology, Government General Degree College, Kharagpur II, Madpur, West Bengal, India Safia  Habib  Faculty of Medicine, Department of Biochemistry, JN Medical College, Aligarh Muslim University, Aligarh, India Ekramul Haque  Faculty of Medicine, Department of Periodontics and Community Dentistry, ZA Dental College, Aligarh Muslim University, Aligarh, India

Editors and Contributors

xvii

Saba Iqbal  Department of Zoology, Government Sadiq College Women University, Bahawalpur, Pakistan Hina  Javed  Department of Chemistry, Aligarh Muslim University, Aligarh, UP, India Mehjbeen  Javed  Department of Medical Elementology and Toxicology, Jamia Hamdard, New Delhi, India Humira  Jeelani  Department of Clinical Biochemistry, University of Kashmir, Hazratbal, Srinagar, Jammu and Kashmir, India Rifat Ullah Khan  College of Veterinary Sciences, Faculty of Animal Husbandry & Veterinary Sciences, The University of Agriculture, Peshawar, Pakistan Sharad  Kumar  Department of Wildlife Sciences, Aligarh Muslim University, Aligarh, UP, India Abdulmajeed Bashir Mlitan  Department of Environmental Sciences, Faculty of Environmental Sciences and Natural Resource Development, University of Misurata, Misrata, Libya Moinuddin Faculty of Medicine, Department of Biochemistry, JN Medical College, Aligarh Muslim University, Aligarh, India Amna  Nawaz Department of Zoology, Government Sadiq College University, Bahawalpur, Pakistan Saima Naz  Department of Zoology, Government Sadiq College Women University, Bahawalpur, Pakistan Shabana Naz  Department of Zoology, Government College University, Faisalabad, Pakistan Sujata Pathak  Preventive Oncology, Dr. B.R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India Fouzia  Rashid Department of Clinical Biochemistry, University of Kashmir, Hazratbal, Srinagar, Jammu and Kashmir, India Partha  Sarathi  Singha  Department of Chemistry, Government General Degree College, Kharagpur II, Madpur, West Bengal, India Nahida  Tabasum  Department of Pharmaceutical Sciences, Pharmacology Division, University of Kashmir, Hazratbal, Srinagar, Jammu and Kashmir, India Nazura  Usmani  Aquatic Toxicology Research Laboratory, Department of Zoology, Aligarh Muslim University, Aligarh, UP, India

Abbreviations

11-Hsd1 and 11-Hydroxysteroid dehydrogenase 1 17-OHP 17-Hydroxyprogesterone 3-BC 3-Brominated compound 4-MBC 4-Methylbenzylcathinone ABCG2 ATP binding cassette subfamily member 2 ABCT ATP binding cassette transporter ACH50 Alternative complement pathway AChE Acetylcholine esterase ACS Acute coronary syndrome ACTH Adrenocorticotropic hormone AD Alzheimer’s disease ADA American Dental Association AE Androgen excess AFP Alpha fetoprotein AGEs Advanced glycation end products AKT Ak strain transforming Al Aluminum AlCl3 Aluminum chloride AMI Acute myocardial infarction AMPK AMP activated protein kinase ANA Antinuclear antibodies Anti-ds-DNA Antibodies against Double-Stranded Deoxyribonucleic Acid Anti-ss-DNA Antibodies against Single-Stranded Deoxyribonucleic Acid APC Activated protein C APCR Activated protein C resistance AP-HRA Air pollution health risk assessment APLN Apelin APTT Activated partial thromboplastin clotting time Arg Arginine ARS Acute Respiratory Syndrome As Arsenic AT Antithrombin ATM Ataxia telangiectasia mutated ATn Average time for non-carcinogens xix

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Abbreviations

ATR Ataxia telangiectasia rad3 Aβ42 Amyloid β 42 B Blood b2-M Beta-2 microglobulin BaP Benzo[a]pyrene BAX Bcl-2 associated X protein BC Before Christ Bcl-2 B-cell leukemia/lymphoma-2 BCL-XL B-cell lymphoma-extra large BHA Beta hydroxy acid BHT Butylated hydroxy toluene BMD Benchmark dose BMI Body mass index BNP Brain natriuretic peptide BP Benzo [a] pyrene BP-3 Benzophenone-3 BPA Bisphenol A BPDE Benzo [a] pyrene-7,8-diol-9,10-epoxide BR Benchmark response BRCA 1 &2 BReast CAncer gene 1 & 2 BRCA3 Breast cancer gene 3 BTA Bladder tumor antigen Bw Body weight CA 125 Cancer antigen 125 CA 19-9 Cancer antigen 19-9 CA15-3 Cancer antigen 15-3 CAL 27 Tongue epithelial cells CARDIUS Cardiac Arrest Rapid Diagnostic Information Using Saliva CASP 3,7,9 Caspase 3,7,9 CAT Catalase CCL3 Chemokine ligand 3 CCN1 Cellular communication network factor 1 CD 44 Cell surface adhesion receptor Cd Cadmium CD40 Cluster of differentiation 40 CDH1 Cadherin-1 CDKNIA Cyclin-dependent kinase inhibitor 1A CDKs Cyclin-dependent kinases CEA Carcinoembryonic antigen c-erB2 Human epidermal growth factor receptor 2 cfDNA Cell-free DNA CFTR Cystic fibrosis transmembrane conductance CGRP Calcitonin gene-related peptide CHD Coronary heart disease CHK2 Check point kinase

Abbreviations

CK-MB Creatine kinase-MB CMKLR1 Chemokine-like receptor 1 CMV Cytomegalovirus Cmyc Master regulator of cell cycle entry CNS Central nervous system Co Cobalt COC Combined oral contraceptive COPD Chronic obstructive pulmonary disease COVID-19 Corona Virus Disease-19 COX Cyclooxygenase CPK Creatine phosphokinase CPSo Carcinogenic potency slope for oral dose Cr Chromium CRP C-reactive protein CSF Cerebrospinal fluid CT Computerized tomography CTCs Circulating tumor cells CtDNA Circulating tumor DNA CTGF Connective tissue growth factor CtIP Gene with multiple roles in DNA repair cTn Cardiac troponin complex cTnI Cardiac troponin inhibitory Cu Copper CVD Cardiovascular disease CVST Cerebral venous sagittal thrombosis CVT Cerebral venous thrombosis CWC Central water commission CWs Constructed wetlands CXCL12 C-X-C Motif chemokine ligand CYP 450 Cytochrome P 450 CYP Cytochrome P CYP1A Cytochrome P1A DA Dopamine DDE Dichlorodiphenyl dichloro ethylene DDT Dichloro-diphenyl-trichloroethane DEA Diethanolamine DHA Docosahexaenoic acid DHEA Dehydroepiandrosterone DHT Dihydrotestosterone DNA Deoxyribonucleic acid DVT Deep venous thrombosis E2 Estradiol-17 ECA Erythrocytic cellular abnormality ECD Extracellular domain ECG Electrocardiogram

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ECM Extra cellular matrix ED Exposure duration EDI Estimated daily intake EE2 Ethinyl estradiol EF Exposure frequency EGF Epidermal growth factor EGFR Epidermal growth factor receptor ELISA Enzyme-linked immunosorbent assay EMEA European medicines agency ENA Erythrocytic nuclear abnormality EPA Eicosapentaenoic acid EPA Environmental Protection Agency EPAR European public assessment report EPA-US Environmental Protection Agency-United States ER α Estrogen receptor α ER Estrogen receptor ER+ Estrogen receptor positive ERBB2 Erythroblastic oncogene B2 ERK Extracellular signal-regulated kinase ERK1/2 Extracellular signal-regulated kinases ESRD End-stage renal disease EU European Union F Adult human female FAI Free androgen index FAO Food and Agriculture Organization FCR Feed conversion ratio FDA Food and Drug Administration Fe Iron FGF Fibroblast growth factor FGF19 Fibroblast growth factor 19 FGFR-1 Fibroblast growth factor receptor-1 FISH Fluorescent in situ hybridization FOBT Fecal occult blood testing FRS2 Fibroblast growth factor receptor substrate-2 FSH Follicle-stimulating hormone FV Factor V FW Freshwater G Gills G6Pase Glucose 6 phosphatase GABA Gamma-aminobutyric acid GCF Gingival crevicular fluid GFR Glomerular filtration rate Gln Glutamine GLOBOCAN Global Cancer Observatory GLUT Glucose transporter

Abbreviations

Abbreviations

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GMP Guanine monophosphate GNIH Gonadotrophin-inhibitory hormone GnRH Gonadotropin-releasing hormone GNRH Gonadotropin-releasing hormone receptor GO Gene ontology GPER G protein-coupled estrogen receptor GPx Glutathione peroxidase GR Glutathione reductase GREB1 Growth-regulating estrogen receptor binding protein-1 Gro-a Growth-related protein-a GSK 3-β Glycogen synthase kinase 3-β GST Glutathione-S-transferase Hb Hemoglobin HBCD Hexabromocyclododecane HCC Hepatocellular carcinoma HDL High-density lipoprotein HE4 Human Epididymis Protein 4 HELLP Hemolysis, elevated liver enzymes, and low platelets syndrome HepG2 Human hepatoma cells HER2 Human epidermal growth factor receptor 2 Hg Mercury HHRA Human Health Risk Assessment HI Hazard index HIV Human immunodeficiency virus HME1 Human mammary epithelium HMG High mobility group HOMA-IR Homeostasis model assessment estimated insulin resistance HPA Hypothalamic-pituitary adrenal axis HPI Hypothalamus-pituitary-interrenal axis HPV Human papillomavirus HSP Heat shock protein HSPs Heat shock proteins HSV-1 Herpes simplex virus Type 1 I Intestine IAA Indole-3-acetic acid ICAM Intercellular adhesion molecule IgA Immunoglobulin A IGFBP-1 Insulin-like growth factor-binding protein IgG Immunoglobulin G IgM Immunoglobulin M IKKb Inhibitor of kappa light polypeptide gene enhancer in B-cells IL Interleukin IL-1 Interleukin-1 IL1β Interleukin 1β IL6 Interleukin 6

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Abbreviations

IL8 Interleukin 8 IL-β Interleukin-β IPBES Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services IPCC Intergovernmental Panel on Climate Change IR Ingestion rate IRS Insulin receptor substrate ISIRI Institute of Standards and Industrial Research of Iran IUGR Intrauterine growth restriction IVF In vitro fertilization JAK Janus Kinase K Kidney KEGG Kyoto encyclopedia of genes and genomes KLF4 Kruppel-like factor 4 L Liver LC-PUFAs Long-chain polyunsaturated fatty acids LDCT Low-dose computerized tomography LDH Lactate dehydrogenase LDL Low-density lipoprotein LDL-C Low-density lipoprotein cholesterol LH Luteinizing hormone lncRNA Long non-coding RNA LOD Laparoscopic ovarian drilling LPO Lipid peroxidation LSZ Lysozyme M Adult human male M Muscle MAPK Mitogen-activated protein kinase MAPK/ERK Mitogen-activated protein kinases/Extracellular signal-­ regulated kinases Mc Metal concentration MCF-7 Breast cancer epithelial cell line MCP Macrophage chemoattractant protein MDA Malate dehydrogenase MDA Malondialdehyde MDM4 Mouse double minute 4, human homolog of P53-binding protein MFCs Microbial fuel cells Mg Magnesium MGMT O-6 methyl DNA methyltransferase MHC Major histocompatibility class MHPG 3-methoxy-4-hydroxyphenylglycol MI Myocardial infarction MIP Macrophage inflammatory protein miRNA microRNA MMP Matrix metalloproteinases

Abbreviations

MMP-2 Matrix Metallopeptidase 2 MMP-9 Matrix Metalloprotease-9 Mn Manganese MPO Myeloperoxidase MPQ Maximum permissible quotients MPs Microplastics MRI Magnetic resonance imaging mRNA Messenger ribonucleic acid MRP2 Multidrug resistance protein-2 MTH Methylene tetrahydrofolate MTHFR Methylene tetrahydrofolate reductase MUC16 Mucin 16 MYO Myoglobin NAC N-acetyl cysteine NCI National Cancer Institute ND Not detected NER Nucleotide excision repair NF-Κb Nuclear factor kappa NGOs Non-governmental organizations NGS Next-generation sequencing Ni Nickel NIH National Institute of Health NKCC Na+-K+-Cl cotransporter NMFS National marine fisheries service NMP-22 Nuclear matrix protein-22 NMR Nuclear magnetic resonance NO Nitric oxide NPK Nitrogen, Phosphorus, and Potassium NRF2-ARE Nuclear factor erythroid 2-related factor NSAID Non-steroidal anti-inflammatory drug NSCLC Non-small cell lung cancer NYSDOH New York State Department of Health OAZ1 Ornithine decarboxylase antizyme 1 OC Organochlorine OCP Oral contraceptive pills ODA-1 Ornithine decarboxylase antizyme-1 OHSS Ovarian hyper stimulation syndrome P Plasma PA Primary aldosteronism PAHs Polyaromatic hydrocarbons PAI Plasminogen activator inhibitor Pb Lead P-B Peptide B PBDEs Polybrominated diphenyl ethers PC Protein C

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Abbreviations

P-C Peptide C PC Protein carbonyl PCa Prostate cancer PCB-1254 Polychlorinated biphenyl-1254 PCBs Polychlorinated biphenyls PCDDs Polychlorinated dibenzo-p-dioxins PCDFs Polychlorinated dibenzofurans PCNA Proliferating cell nuclear antigen PCOS Polycystic ovary syndrome PCPs Personal care products PCR Polymerase chain reaction PCRWR Pakistan Council of Research in Water Resources PDC Pancreatic ductal carcinoma PD-L1 Programmed death-ligand 1 PFOs Perfluoro octane sulfonate PGB Plant growth-promoting bacteria PGC1 α Peroxisome proliferator-activated receptor-gamma coactivator α PGPE Plant growth-promoting endophytes pH Hydrogen ion concentration PHI Prostate health index PI3K/AKT Phosphoinositide-3-kinase protein kinase/AK strain transforming PM Particulate matter POC Point-of-care POPs Persistent organic pollutants PPAR Peroxisome proliferator-activated receptor PR Progesterone receptor PRKDC Protein kinase DNA-activated catalytic subunit PRL Prolactin PROS1 Protein S1 PROS2 Protein S2 PS Phosphatidylserine PSA Prostate-specific antigen Pss Primary Sjogren’s syndrome PTE Pulmonary thromboembolism PTX Pentraxin PUFA Polyunsaturated fatty acid PV Portal vein PVT Portal vein thrombosis QPCR Quantitative polymerase chain reaction qRT-PCR Real-time quantitative reverse transcription RAD50/51 A DNA repair protein RAGE Receptor for advanced glycation end products RAS Rat sarcoma virus RB Respiratory burst RBC Red blood cells

Abbreviations

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RF Rheumatoid factor RfD Reference dose RNA Ribonucleic acid ROS Reactive oxygen species SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 SAT Spermine N-1 acetyltransferase SCC 9 Squamous cell line 9 Se Selenium SEM Standard error mean SGR Specific growth rate SH Thiol group SHBG Sex hormone-binding globulin S-ICAM Soluble intercellular cell adhesion molecule SIK1 Salt inducible kinase 1 SMC1A Structural maintenance of chromosomes SOD Superoxide dismutase SOPs Standard operating procedures SOX2 Sex-determining region Y box 2 SRC Sarcoma gene in humans SREBF Sterol regulatory element-binding protein STAT3 Signal transducer and activator of transcription S-VCAM Soluble vascular cell adhesion molecule SW Saltwater SYT Synaptotagmin T3 Triiodothyronine T4 Thyroxine TAFI Tissue activable fibrinolytic inhibitor TAM Tamoxifen TC Total cholesterol TDS Total dissolved solids TF Tissue factor Tg Thyroglobulin TG Triglycerides TGF Transforming growth factor THQ Target hazard quotient TIMP1 Tissue inhibitor metalloprotease 1 TiO2 Titanium dioxide TLR Toll-like receptors TLS Translesion synthesis TMEFF2 Transmembrane protein with EGF-like and two follistatin-like domains 2 TNF Tumor/Tissue necrosis factor TNF-1 Tumor necrosis factor-1 TNF-α Tumor necrosis factor-α TNF-β Tumor necrotic factor-β

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Abbreviations

TnI Troponin inhibitory TPA Tissue plasminogen activator TPMT Thiopurine methyl transferase TR Target cancer risk TSGs Tumor suppressor genes TUNEL assay Terminal deoxynucleotidyl transferase nick end labeling TVU Transvaginal ultrasound UK United Kingdom UNECOSOC United Nations Economic and Social Council USA United States of America USEPA United States Environmental Protection Agency USG Ultrasonography UTR Untranslated region VCAM Vascular cell adhesion molecule VCR Vincristine VIM Vimentin VIN Vinblastine VLDL Very low-density lipoprotein VLDL-C Very low-density lipoprotein cholesterol VTE Venous thromboembolism WBC White blood cell WFDC2 Wap four-disulfide core domain protein 2 WHO World Health Organization WWTPs Waste water treatment plants XRCC6 X-ray Repair Cross-Complementing Zn Zinc ZnO Zinc oxide ZnPic Zinc picolinate

Part I Environmental Exposure to Contaminants and Assessment

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Environmental Contaminants and Their Impact on Wildlife Sharad Kumar

1.1 Introduction The harmful effects of environmental contaminants are one of the foremost reasons behind the continuous decrease in the abundance of wild animals worldwide. The drastic decline in the vulture population in Asia due to diclofenac is the most striking example of the ill effects of environmental contaminants on wild animals. DDT had a heavy toll on wildlife in many parts of the world, which led to a ban by many countries on the utilization of this insecticide. However, many countries still use deadly chemicals that threaten wildlife conservation. Contamination is the presence of an elevated concentration of substances in the environment above the natural level for the area and the organisms. Environmental contaminants are chemicals introduced intentionally or accidentally in our environments and have harmful impacts on biological systems. Environmental contaminants are defined as any substance or matter (physical, chemical, biological, or radiological) that has adverse impacts on components of the atmosphere or living beings and is introduced into the environment through natural processes or human activities. Since environmental contaminants have harmful impacts on wildlife, for the conservation of wildlife, it is imperative to study the effects of environmental contaminants on wildlife. The study of the harmful effects of environmental contaminants on wildlife (amphibians, reptiles, birds, and mammals) is known as Wildlife Toxicology. Generally, the adverse effects of environmental contaminants on fish and aquatic invertebrates are not studied under wildlife toxicology as they are covered under a separate branch of science Aquatic Toxicology (Hoffman 2003). The problem of environmental contaminants began receiving the attention of scientists in the late nineteenth century. The unusual increase in the death of fallow deer (Dama dama) due to the negative effects of arsenic in the areas close to S. Kumar (*) Department of Wildlife Sciences, Aligarh Muslim University, Aligarh, UP, India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 M. I. Ahmad et al. (eds.), Toxicology and Human Health, https://doi.org/10.1007/978-981-99-2193-5_1

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industries processing metal ores in Freiberg, Germany in 1887 is the first published record of the harmful impact of toxic agents introduced because of anthropogenic activity (Newman 1979). After this, many studies put light on the harmful impacts of toxic agents such as hydrogen sulfide and led on waterfowl (Calvert 1876; Grinell 1894; Wetmore 1919; Phillips and Lincoln 1930; Gallagher 1918; Whitehead 1934). With industrialization, intensification of agriculture, and increase in human population and consumerism, the level of environmental contaminants is increased manifold and in turn their impact on wildlife habitats and wildlife. A wide variety of environmental contaminants having harmful impacts on wildlife have been detected in the environment. This range of environmental contaminants includes pesticides, insecticides, chemicals released from industries, fuels (fossil and minerals), pharmaceuticals, beauty products, metals, and fertilizers (Grim et  al. 2012). These contaminants enter into the environment from various sources such as the leaching of toxic organochlorine solvent residues in water sources from waste dumps and fertilizers and pesticides reaching water bodies with runoff water, etc.

1.2 Classification of Environmental Contaminants Most environmental contaminants having direct and indirect adverse effects on wildlife can be categorized into seven classes—pesticides, industrial chemicals, fossil and mineral fuels, pharmaceuticals (human and veterinary), personal care products, metals, and fertilizers (Grim et al. 2012). Table 1.1 presented the data on the impact of environmental contaminants on wild animals.

1.3 Pesticides Pesticides are the chemical products utilized to kill, deter, or regulate the abundance of pest species. These are the products utilized by humans to guard themselves against the various insects that act as the carrier of disease-causing pathogens, control the abundance of unwanted plants (weeds) in agriculture fields to reduce the competition with crops, and defend crops and livestock from diseases and attacks from various organisms such as the fungi, insects, mites, and rodents. It includes various herbicides, molluscicides, avicides, fungicides, nematicides, rodenticides, algaecides, insecticides, and chemicals utilized to control the population of various plants and animals causing loss to humans. Pesticides such as aromatic hydrocarbon hexachloride, calcium cyanide, Bromo chloropropane, endrin, ethyl mercury chloride, aldrin, heptachloride, menazone, nitrogen, paraquat dimethyl sulfate, chlordane, copper acetoarsenite, pentachloronitrobenzene, pentachlorophenol, phenylmercury acetate, sodium methane arsenate, tetradfone, toxafen, dichlorodiphenyl trichloroethane (DDT), dieldrin, diazinon, parathione, aldicarb, atrazine, paraquat, and glyphosate are some of the most harmful pesticides used by humans to kill and control the population of pests.

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Table 1.1  General classification of environmental contaminants having negative impacts on wild animals (Adapted from Grim et al. 2012) Chemical class Pesticides

Industrial chemicals

Fossil and mineral fuels

Pharmaceuticals (Human and Veterinary)

Personal care products

Metals

Types of contaminants included Insecticides/nematicides/molluscicides Avicides/rodenticides, herbicides/ fungicides/algaecides Growth regulators (plant and insect) Volatiles (e.g., household products such as wood preservatives, paints, paint strippers, aerosol sprays, cleansers and disinfectants, moth repellents, air fresheners, stored fuels, automotive products, hobby supplies, and dry-cleaned clothing) Semi-volatiles (e.g., industrial plasticizers (phthalates), byproducts of incomplete combustion of fossil fuels (benzo(a)pyrene), dioxins, PCBs, brominated flame retardants, and lubricants) Solvents (e.g., acetone, ethanol, hexane, carbon tetrachloride, and ether) and surfactants Nanomaterials Explosives and energetic compounds Oil/ petroleum, coal, natural gas, nuclear fuels Naturally occurring energetic compounds (e.g., perchlorate) Hormone agonists/antagonists (e.g., birth control pills, thyroid medications, cholesterol synthesis blockers, both synthetic, and natural) Antimicrobials (e.g., antibiotics, antiparasitics, antifungals, and antivirals) Analgesics/neuroleptics/Anesthetics Antidepressants/antianxiety medications Controlled substances (illicit) Antihypertensives Nutraceuticals (e.g., herbal) Food additives (e.g., caffeine) Fragrances, cosmetics, soaps, and daily use items Heavy and/or inorganic metals Metalloids (e.g., zinc, lead, mercury, and selenium) and organotins

Unifying characteristics Designed to kill, repel, control, or alter physiological mechanisms in target organisms Most vast class of synthetic chemicals with no clear common characteristics. Used in households, in work areas, and in industrial processes

Natural resources that primarily consist of carbon and hydrogen are burned to produce energy or are used to develop consumer items (e.g., plastics) Designed to be biologically active and often reach in environment at steady rates through sewage treatment plants, concentrated animal feeding operations, and widespread biosolid dispersal

Individual consumer use is introduced into the environment at steady rates primarily through sewage and water treatment plants Cannot decompose into less harmful components and can biomagnified, non-biodegradable (continued)

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Table 1.1 (continued) Chemical class Fertilizers

Types of contaminants included Natural (vermicompost, manure, water treatment sludge) Chemical fertilizers

Unifying characteristics Chemicals and manure used to improve agriculture productivity

Because of the mechanization of agriculture and lack of awareness about the harmful impacts of pesticides, farmers, especially in developing countries, are utilizing these chemicals more than their prescribed limits, which leads to a high concentration of pesticides in the environment. There is a steep increase in the utilization of pesticides in India and their utilization increased 20 times in 40 years (1958–1998) from 5000 metric tons to 102,240 metric tons (Sabra and Mehana 2015). The effect of large-scale unsustainable use of pesticides is not only restricted to target species but also harms various taxa of wildlife and our environment and is considered one of the grave threats to the long-term conservation of wildlife. The utilization of pesticides is not just a modern practice and possibly they are first time used by Egyptians around 1550  BC to repel away the fleas from their homes (Hayes 1991). However, pesticide use has been much more extensive and prevalent in modern times. By 1990, more than 3000 pesticides were in use by human society including around 300 insecticides 290 herbicides, and 165 fungicides (Hayes 1991).

1.4 Industrial Chemicals Chemicals that trace their immediate source to industrial practices come under industrial chemicals. Industrial chemicals include the various volatile compounds found in household products (e.g., insect repellents, room fresheners, paints, paint strippers, preservatives used in wood, cleansers and disinfectants, aerosol sprays, stored fuels, automotive products, hobby supplies, and dry-cleaned clothing), semi-­ volatiles, byproducts produced due to the incomplete combustion of fossil fuels (benzo(a)pyrene), dioxins, (polychlorinated biphenyls) PCBs, brominated flame retardants, lubricants), solvents (e.g., acetone, ethanol, hexane, carbon tetrachloride, and ether), surfactants, nanomaterials, energetic compounds and explosives and energetic compounds. Since the advent of the industrial revolution, the intensity of contamination of the environment with industrial chemicals has been continuously increasing and has emerged as one of the greatest threats to the conservation of wildlife and the environment.

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1.5 Fossil and Mineral Fuels Modern human society is heavily dependent on fossil and mineral fuels, and we cannot imagine our life without fossil and mineral fuels. Fossil and mineral fuels include petroleum and its products, coal, natural gas, polycyclic aromatic hydrocarbons, energetic compounds occurring in nature (e.g., perchlorate), and other associated chemicals. Exploration and extraction of fossil and mineral fuels have a negative impacts on wildlife and the environment. The exploration of fossil and mineral fuels affects wildlife through habitat conversion, habitat degradation, habitat fragmentation, loss of habitat, pollution, disturbances, physiological impacts, and alteration of species’ behavior (Harfoot et al. 2018). The burning of fuels (mineral and fossil) also increases greenhouse gas emissions, which intensify the problem of climate change (IPCC 2014) and climate change poses a threat to many wildlife species. Furthermore, the demand for fossil and mineral fuels is continuously increasing, intensifying these problems. The negative impacts of fossil and mineral fuels are posing a challenge to the conservation of both terrestrial and marine wildlife.

1.6 Pharmaceuticals (Human and Veterinary) Pharmaceuticals are considered the potentially potent group of chemical contaminants that negatively impact wildlife (Arnold et  al. 2013). The class of Pharmaceuticals covers various hormonal agonists or antagonists (e.g., birth control pills, natural and synthetic cholesterol synthesis blockers, and thyroid medications), antimicrobials products (e.g., antifungals, antibiotics, antivirals, and antiparasitic), analgesics or Neuroleptics or Anesthetics, Antidepressants or Antianxiety medications, Controlled substances (illicit), Antihypertensives. With the increase in the human population and more focus on health, there is escalating demand for human and veterinary pharmaceuticals. Once reached in the environment, pharmaceuticals will be spread into the soil, air, water, and sediments and therefore have the potential to impact various wildlife species. Pharmaceuticals and their biotransformation products exist in various wildlife areas and have catastrophic negative impacts on wildlife. There are clear evidences of pharmaceuticals such as diclofenac, other non-steroidal anti-inflammatory drugs (NSAIDs, synthetic estrogen 17α-ethinyloestradiol (EE2), and 17β-oestradiol (E2) having adverse impacts on wildlife all over the world (Jobling et al. 2006; Cuthbert et al. 2011).

1.7 Personal Care Products Personal care products include various beauty products that are used by humans to improve the quality of daily life of themselves and their pets. Their contamination of the environment leads to adverse effects on humans and wildlife. Personal care products can be divided into two categories: leave-on and rinse-off products (Juliano

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and Magrini 2017). The toxic effects of products like beauty care products, soaps, fragrances, nutraceuticals, food additives (e.g., caffeine), and other daily use items are now well known to science. Chemicals like P-phenylenediamine, beta hydroxy acid (BHA) and butylated hydroxytoluene (BHT), dioxane, triclosan, and diethanolamine (DEA) are found in various personal care products, and when these chemicals are introduced to the environment, they are detrimental to multiple taxa of wildlife. In addition to this, the high demand for personal care products also puts pressure on the wildlife habitat. With the increase in the purchasing capacity of humans, the contamination of our environment by these chemicals is increasing continuously. The chemicals coming to the environment from personal care products are poisoning both aquatic and terrestrial habitats and killing wildlife habitats and their inhabitants. Their ecological impact is greater than pharmaceuticals as they are utilized in large quantities and throughout their entire life and being of their external application, reach an environment unaltered without any metabolic transformation through washing, swimming, showering, or bathing (Ternes et al. 2004).

1.8 Metals Chemically, metals can be defined as elements that have a metallic luster, have electric conductivity, form cations, are malleable and ductile, and have basic oxides (Atkins and Jones 1997). Metals occur naturally in small amounts in the environment. But the introduction of these metals in the environment beyond a specific level has detrimental effects on the functioning of the environment and wildlife. The presence of heavy metals, inorganic metals, metalloids, and organotin in the environment has the potential to pose a risk to wildlife. The high quantity of metals like lead, mercury, arsenic, cadmium, copper, zinc, and nickel harms wildlife. Heavy metals have remained in nature for a long time and from the environment; they enter the creatures and accumulate in the tissues of organisms. The quantity of uptake of heavy metals and their bioaccumulation in the body of creatures depend on several factors, and it varies from species to species.

1.9 Fertilizers Fertilizers are the chemical substances used to provide the necessary elements to plants and increase the plants’ productivity. Natural (e.g., manure, vermicompost, and sludge from water treatment processes) and chemical fertilizers (Urea, DAP) have several nutrients and pollutants that have detrimental effects on wildlife if not managed effectively. Nutrients and chemicals associated with manure and fertilizers enter the environment through soil erosion and runoff water. The entering of harmful substances associated with fertilizers and manures in water bodies lead to various problems such as oxygen depletion, excess weed growth, algae blooms, ammonia toxicity, the introduction of various pathogens found in the manure, and high level of nitrates. The problem of eutrophication is the result of the

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accumulation of nutrients in the water bodies, which leads to the death of several aquatic faunas. The ill effects of natural and inorganic fertilizers shoot up with the intensification of agriculture to sustain the ever-increasing human population. Intensification of agriculture leads to high environmental costs, including the disappearance of biodiversity values and ecosystem services provided by biodiversity (Foley et al. 2011; Kleijn et al. 2009; Green et al. 2005). Currently, it has become one of the most significant concerns for the people working for wildlife conservation.

1.10 Impact of Environmental Contaminants on Wildlife The environmental contaminants reach wildlife habitats through various sources. There is a great variation in the adverse impact of various contaminants on wildlife. It depends on various factors like the biological properties of the contaminant, its concentration in wildlife habitat, and the species’ ability to tolerate the contaminant, etc. The adverse effects of contaminants can be categorized into four categories-­ acute, chronic, secondary, and indirect effects. In acute effects, contaminants lead to death or significant impact on the health of wild animals after short exposure to environmental contaminants. It includes cases like the death of vultures after feeding on livestock contaminated with diclofenac or the death of many fishes and waterfowl after contamination of the aquatic ecosystem by pesticides and heavy metals. These impacts can be determined by analyzing the tissue of impacted wild animals or investigating the biochemical processes. Chronic effects have an adverse impact on wild animals after the exposure of wildlife over an extended period of time to contaminant levels not immediately lethal to species. For example, the adverse impacts of various pesticides such as DDT, dieldrin, and endrin lead to bird mortality, etc. This leads to bird mortality and a negative impact on the diverse fauna of aquatic habitats. Secondary impacts include the toxicity of animals when they consume food resources having residues of contaminants. For example, the ill effects of environmental contaminants on birds of prey when they consume the animals died because of acute poising to contamination and accumulation and transportation of harmful chemicals in the food chain. Through the process of bioaccumulation, when they reach high trophic levels, they become lethal to wild animals. Indirect effects of environmental contaminants may have adverse impacts on populations of wild animals through modification of the availability of necessary resources in wildlife habitats and turn reduce the physical fitness and reproductive success of the species. For example, herbicides can kill many non-target herbs and reduce food availability, cover, and shelter for insects, birds, and mammalian species. Similarly, the application of insecticides leads to a decline in insect populations and, in turn, reduces the supply of food for fish, amphibians, reptiles, and birds fed on.

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There is quite a variation in the impacts of various classes of environmental contaminants on wild animals. Therefore, the impacts of each class of contaminants will be discussed separately.

1.11 Pesticides Pesticides are used to kill insects, weeds, and other unwanted organisms, but when used in an unsustainable manner, numerous non-target species such as beneficial insects, fishes, amphibians, reptiles, birds, and mammals are negatively affected by pesticides. Utilization of pesticides leads to the indiscriminate killing of all the wildlife species sharing habitat with pest species and they kill many non-target organisms that are not pests. While using broad-spectrum pesticides, we should take utmost care at the time of spraying them over large areas, such as colonies, cities, and entire agricultural fields. But due to the lack of awareness and coordination between the various department, they are used indiscriminately over large areas. Many non-pest wildlife values are exposed to these sorts of applications, in addition to the planned target of pests. Based on the type of pesticide and susceptibility of the non-pest wildlife values to the pesticide, the exposure of non-target species can result in a considerable, unintentional, but unavoidable loss of the wildlife values. Pesticides have long been identified as a potential threat to wildlife beyond their intended targets, and many broad-spectrum pesticides having an adverse impact on wildlife are no longer in widespread use. In India alone, 145 pesticides are registered to use in agriculture (Arya et al. 2019). Pesticides have an array of negative impacts on wildlife. The effects of pesticides can be acute, chronic, secondary, or indirect. There is great variation in the direct impact of pesticides on wildlife (Moore 1967). Pesticide, in general, has adverse effects on wildlife in two ways: through direct toxicity or through modification of habitat and/or supply of food resources. Wildlife toxicity due to pesticides depends on the potency of the pesticide to species and other aspects such as the amount applied, rate, timing and method of spraying, weather, vegetation structure, and soil type (Isenring 2010). Different species of wildlife have different responses to the toxicity of pesticides. Research by Grolleau and Gibban (1996) has found that closely related partridge species, red-legged, pheasant, and bantam have a similar response to BHC while they respond in a different way to heptachlor. Agriculture pesticides decrease the number of weeds and insects that form the important food resources for many wildlife species. The decline in food availability has a serious impact on the wildlife population. The low availability of food reduced the reproductive success of the wildlife species and negatively impacted the conservation of wildlife. The utilization of insecticides within the 20 days of egg hatching leads to a reduction in the number of chicks of the yellow hammer, a decrease in the mean weight of chicks of skylark, and an increase in mortality in corn bunting (Boatman et al. 2004). The various herbicides used by the farmers lead to changes in wildlife habitat through the alteration of vegetation structure which in turn leads to a decline in the population of wildlife (Isenring 2010). The alteration of wildlife

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habitat has a negative impact on wildlife as the habitat becomes less suitable to fulfill the requirement of the wildlife species. The intensity of the problem can be judged from the data presented in a review compiled by Isenring in 2010. As per the reports, in western Europe, the abundance of farmland birds is now half that of 1980, even of those species which are formerly common species. The report also pointed out that while there is a 10% decline in all common and forest birds, the population of farmland birds declined by 48% between 1980 and 2006. Organophosphate insecticides such as diazinon, fenthion, disulfoton, and parathion are shown high toxicity to birds. They frequently poisoned birds feeding in the agriculture fields (Mineau et al. 1999). DDT is responsible for the eggshell thing and depressed reproduction in many raptor species (Cooke 1975; Risebrough et al. 1986). Raptors are more prone to ill effects of pesticides because they are at the top of the food chain and they are more sensitive to pesticides in comparison to other groups of birds (Olsen et al. 1993). A study in Australia recorded the thinning of eggshells due to the DDT and dichlorodiphenyl dichloro ethylene (DDE) in falcon species, and these pesticides are responsible for the decline of falcon populations (Olsen et al. 1993). Egg thinning and reproductive failures due to DDT are responsible for the disappearance of the Peregrine falcon from many parts of its former range (Ratcliffe 1967). Therefore, it can be concluded that DDT is responsible for the decline of many raptor species worldwide. On the other hand, the population of many raptors species all over the world recovered after the ban on DDT, broad-­ spectrum pesticides, and other pesticides. Neonicotinoid insecticides, a new class of insecticides, negatively impact the numbers of insect species and adversely affect the bird species feeding on invertebrate food. A study in Europe concluded that the high concentration of neonicotinoid insecticides is accountable for the decline in the population of several widespread bird species (Hallmann et al. 2014). Among mammals, bats and rodents are the most affected groups negatively affected by pesticides, and around 38% of species of bats and rodents are affected by pesticides (Harris et al. 1995). Carnivore mammals and bird raptors are negatively affected by secondary poisoning of pesticides by preying on rodents poisoned by rodenticides. Berny et al. (1997) reported cases of toxicity of foxes and buzzards by the residues of bromadiolone in prey tissue in France through secondary poisoning. In the UK, bank voles, wood mice, and field voles were reduced drastically after rat control through the application of rodenticides (Brakes and Smith 2005). The utilization of wide-spectrum insecticides such as organophosphates and pyrethroids leads to the population decline of beneficial insects such as honey bees, spiders, or beetles. A number of studies found that the diversity and abundance of beneficial insects are less in agriculture fields treated with pesticides than the farms practicing organic farming. Amphibians having permeable skin are more prone to the indirect effects of pesticides by coming in contact with runoff water from land treated with pesticides and soil contaminated with pesticides. Atrazine suppresses the immune system of many amphibians like frogs and salamanders. The suppression of the immune system leads to a frog being more prone to certain fungal diseases such as Batrachochytrium

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dendrobatidis. This fungal disease, commonly known as chytrid fungus, is responsible for the decrease in the population of amphibian species all over the world. The salamanders exposed to atrazine are more prone to infection by pathogenic viruses (Forson and Storfer 2006). Research in Germany found that two pesticides Pyraclostrobin and Dimethoate, commonly used in orchards and on grains, led to 100% mortality when frogs were exposed to doses recommended on the label. Researchers from the University of Pittsburgh found that the utilization of the pesticide Roundup (have glyphosate) leads to changes in the physiological shape of two species of amphibians by interfering with the hormones of tadpoles. The presence of herbicides in the water increases the abundance of trematodes and nematode parasites in the water, which intensifies the infection of amphibians from these parasites. The insecticides chlorpyrifos and endosulfan can have significant negative impacts on amphibians at concentrations present in the environment under normal conditions of utilization (Sparling and Feller 2009). Like amphibians, negative impacts of pesticides such as organochlorine (OC) insecticides such as DDT, dieldrin, heptachlor, and toxaphene have adverse effects on reptiles and further research needs to be initiated. Pesticides affect fish fauna through oxidative damage, diminishing of metabolism, inhibition of Acetylcholinesterase activity, histopathological changes, developmental changes, mutagenesis, and carcinogenicity, and sometimes also lead to the mortality of fish fauna (Sabra and Mehana 2015). The exposure of fish larvae to pesticides leads to swimming abnormalities, resulting in a decrease in the survival rate of the fish. In addition to this exposure to pesticides also negatively impacts enzymes and delays the growth of many species (Sabra and Mehana 2015). According to a report prepared by National Marine Fisheries Service (NMFS), USA, three herbicides (pendimethalin, oryzalin, and trifluralin) are posing a significant threat to roughly 50% of endangered Puget Sound steelhead and Pacific salmon species. It also adversely affects the habitat of these fishes. The pesticides are also detrimental to non-target plant species and lead to the decline of common plant species. The large-scale utilization of herbicides like sulfonylurea, Triazine herbicides sulfonamides, and imidazolinones is a grave threat to ecosystem functioning and plant species found in terrestrial and aquatic habitats.

1.12 Industrial Chemicals Contamination of the environment by industrial chemicals is through the various types of industrial processes and improper waste disposal practices. The contamination from industries has a severe impact on wildlife species. The effects of industrial contamination include immediate and long-term impacts on wildlife. But scanty information is available on the harmful impacts of industrial chemicals on wildlife. Industries, which are using a large amount of water for processing, pollute the aquatic habitats through the discharge of water into the natural aquatic habitat by runoff or seepage of the stored chemical (Mathubala et al. 2015). The discharge of

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water from the industries also leads to changes in the chemistry of aquatic habitats, which adversely affect the various life stages of aquatic flora and fauna of natural water bodies. The industrial chemicals dumped in wildlife habitats lead to the death of wild animals. When harmful chemicals are dumped in the terrestrial habitat, they are absorbed by the plants and they become part of the food chain and have a negative impact on all the species found in a particular habitat. Industrial chemicals like toxaphene and other organochlorine pesticides found their path in wild animals’ tissue through bioaccumulation over a long period of time. Industrial chemicals like polychlorinated, polybrominated, and polybrominated diphenyl ethers were known to have toxic effects on wildlife. They also lead to reproductive dysfunction in wild animals. The pulp and paper industries are the most polluting industry. Every year, large amounts of harmful chemicals are added to wildlife habitats by the industry. A review on the impact of paper and pulp effluent on fish by Dey et al. (2013), reported that effluent from the pulp and paper industry leads to the mortality of fishes, negative impacts on growth and development, immune system, and enzymes activity. Exposure to effluents from the pulp and paper industry also leads to increased biochemical alterations and genotoxicity, reproduction dysfunction, skin and gill disruption, Malpighian corpuscles alterations, excessive mucous secretion, epidermal lesions, degenerative changes in the ovary and damage to the liver (Dey et al. 2013). Chemicals like Bisphenol A and phthalates used in plastics and nonylphenols used in detergents have been banned in Europe and the USA because they act as endocrine disruptors in wild animals (Grim et al. 2012). The ill effects of plastic on wildlife lead to a significant decrease in the population of many species, especially aquatic species. Plastic litter in marine habitats is considered one of the biggest problems by many conservationists. A large amount of plastic is reaching our aquatic habitats from industries. Tiny plastic pellets and granules, used to manufacture plastic products, reached the marine environments through accidental spillage and become a potential threat to marine biota (Derraik 2002). Plastics that contain additives such as bisphenol and phthalates can have endocrine-disruptive properties and these plastics can have many toxic effects on wildlife (Grim et al. 2012). When reached in aquatic habitats, the plastic debris from the finished products has an adverse impact on wildlife values by entanglement and by ingestion (Derraik 2002). Marine debris has a negative impact on 26 species found in marine habitats worldwide, including 44% of sea birds, 86% of marine turtles, and 43% of marine mammals (Laist 1997). The ingestion of plastic by wild animals reduces the storage capacity of the stomach and feeding stimulus. This in turn reduces the fitness of the species and the reproductive success of the species. Feeding on plastic debris also reduces fat deposition among the animals, which negatively impacts the migratory capabilities of many fishes, marine turtles, and birds. Reduction in the migratory capabilities of wild animals has significant effects on the reproductive success of migratory species. The ingestion of plastic by wildlife also leads to reduced feeding stimulus, dropped steroid hormone levels, blockage of gastric enzyme secretion, delayed ovulation, and reproductive failure (Azzarello and Van-Vleet 1987).

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Nanoparticles are particles whose sizes range between 1 and 100 nm. They are emerging industrial chemicals used in various products such as sunscreens, electronics, and fabric coatings. The engineered nanoparticles reach our environment through intentional releases or unintentional releases (atmospheric emission and solid or liquid waste into natural water bodies from industries). The abundance of engineered nanoparticles in the environment is increasing continuously, and they are posing a significant threat to wildlife (Grim et al. 2012). The nanoparticles have adverse effects on the respiratory system, immune system, gills, cell cycle, and liver of wild animals.

1.13 Fossil and Mineral Fuels Fossil and mineral fuels contaminated wildlife habitats through mining practices (runoff in natural water bodies and dumping of unwanted rocks and soil in water), transportation of fuels, and further processing of fossil and mineral fuels. The oil spills and leaks during the extraction or transportation of fossil fuels have attracted considerable attention from the media and conservationists and pose a severe threat to wildlife, especially marine biota. The contamination of petroleum in water bodies decreases the insulating properties of fur and feathers of aquatic bird species and which in turn leads to hypothermia and death of the aquatic birds (Grim et al. 2012). The contamination of fossil and mineral fuels leads to increased temperature and carbon dioxide concentration, internal nutrients loading, decreased oxygen concentration, and alteration of the physical properties of aquatic habitats. This alteration of physical and chemical properties of the aquatic habitats has an adverse impact on the reproductive success of species, species composition, and abundance of wildlife species and increases the mortality of species. The combined effects of all these impacts increase the risk of extinction of species. In addition, the degraded habitats are more susceptible to other negative consequences and combined effects lead to the extirpation of many species from the face of the earth. The retention ponds, wastewater discharges, and liquid waste generated by thermal power plants become the death trap for migratory birds as they are highly toxic to migratory birds. In the year 2008 in the USA, approximately 1600 ducks died due to landing in a tar sands tailings pond (Gosselin et al. 2010). The mining of fossil fuels like coal also leads to mercury contamination, methyl-­ mercury, cyanide, and arsenic in the environment. The coal ash from the industries contains a high level of selenium, mercury, and arsenic, leading to contamination of water bodies located near the coal-powered plants, which results in malformations in larval bullfrogs (Rana catesbeiana) found in contaminated sites. Malformations have negative impacts on the survival of larvae and in turn, lead to a decline in amphibians’ population (Hopkins et al. 2000). The contamination of mercury into freshwater bodies is known all over the world. This contamination affects the fish fauna and fish-eating birds while damaging their neurological and respiratory systems (Science for Environment Policy 2017). Wetlands that provide refuge to a large number of wildlife species are badly affected by methyl-mercury poisoning.

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Biomagnification of mercury leads to the high concentration of mercury in the bodies of wildlife species that depend on the wetlands. The high concentration of mercury in Rusty blackbirds, Saltmarsh, and Saltmarsh sparrows have a negative impact on their physical fitness (Cristol et al. 2011). Energetic compounds such as perchlorate have negative effects on the functioning of thyroid glands (York et al. 2001). Nitroaromatic munitions are mostly found in military installations or in areas where explosives devices have been detonated and they are reported to be mildly toxic to bird and amphibian species (Talmage et al. 1999). The contamination of nuclear fuels also has a severe impact on wildlife. Under the acute impacts, radiation leads to mass mortality of plant species, which also negatively impacts the survival of wild animals. At contamination sites, the radiation level in the animals is quite high, which leads to the mortality of the wild animals. The impact of radiation is more pronounced in mammals in comparison to the lower invertebrates. For example, after the accident at Chernobyl Nuclear Power Plant, Ukraine in 1986, a 30-fold decrease in the abundance of invertebrates was reported in a periphery of 3–7 km from the site (Beresford and Copplestone 2011). The long-term chronic impacts of contamination of nuclear fuels include impaired reproductive success, decrease in diversity and abundance of species, germline mutations, chromosome aberration, increased sperm deformities, albinistic or deformed feathers, reduced egg viability, and reduced survival success.

1.14 Pharmaceuticals (Human and Veterinary) Pharmaceuticals reach our environment from sewage treatment plants, improper disposal, leaching from landfills, drain water, industries, and dispersal of biosolid and concentrated animal feeding operations. Pharmaceuticals differ from other bioactive chemical contaminants of the environment like pesticides. Except for a few exceptions (anthelmintics, antibiotics, and fungicides), they aim to kill or regulate the population of organisms (Arnold et al. 2013). After reaching the wildlife habitats, both human and veterinary pharmaceuticals become a potential threat to wild animals as they are designed for their bioactive properties. Several studies have shown exposure of freshwater taxa to pharmaceuticals while there are few studies on terrestrial and marine species (Arnold et al. 2013). Few large-scale catastrophes related to wild animals due to the adverse effects of pharmaceuticals on wildlife have been recorded. One of the cases of the impact of pharmaceuticals having population-level effects is the crash of the vulture population in Indian subcontinents due to the NSAID diclofenac, which is used to treat livestock (Shultz et al. 2004; Prakash et al. 2007). The drug causes toxicity to the kidneys of Gyps vultures (Oaks et al. 2004; Swan et  al. 2006) and contamination of the drug led to a 95% decline in the vultures’ population in the Indian subcontinent. The vultures were exposed to a sufficient level of the drug when they feed on the carcasses of livestock treated with the drug shortly before the death of the livestock. Considering the severity of the problem,

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the manufacturing of veterinary formulations of diclofenac was banned by the government of India, Nepal, and Pakistan in 2006 and by the Government of Bangladesh in 2010 (Galligan et  al. 2020). Recent studies have discovered that many new NSAID drugs such as Nimesulide, Ketoprofen, Aceclofenac, and Flunixin have toxicity to vultures and other raptor species (Cuthbert et al. 2016; Taggart et al. 2009; Galligan et al. 2016). Another well-documented case of the adverse impact of pharmaceuticals on wildlife is male fish feminization due to the exposure of fishes to effluent contaminated with synthetic estrogen EE2 released by wastewater treatment plants (WWTPs) (Corcoran et al. 2010). The compound accumulates in the fish tissue and leads to the induction of vitellogenin and in turn feminization of wild fish in the rivers of the UK (Gibson et al. 2005). The effects of feminization vary from the presence of developing oocytes and/or oviducts in the testes of male fishes to the vitellogenin in blood plasma (Arnold et al. 2014). In addition, the high concentration of EE2 leads to the crash of the population of fathead minnows (Pimephales promelas) (Kidd et al. 2007). Intersex frogs have been recorded in urban ponds having contamination of pharmaceuticals and experiments conducted in the laboratories by various researchers on other taxa suggest that the exposure of amphibians to synthetic hormones like estrogens and progestogens can lead to the impairment of the reproductive functions of the amphibians. This can be done through their effect on vitellogenesis and reproductive functions (Arnold et al. 2014). Ivermectin, a veterinary drug used to kill parasites on livestock, has adverse effects on wildlife. A major part of the drug is excreted in the feces, and due to its insecticidal properties, residues of ivermectin in livestock dung have a negative impact on the density and diversity of non-target insect species. The residues of the drug also have a negative impact on the larvae of some flies, and it inhibits larval development and/or stops pupation. This also reduces the availability of food for birds that depend on invertebrate food found in the dung of livestock (Lyons 2014). Avermectins (the class of antiparasitics which includes ivermectin) has the potential to adversely affect the population of birds and bats due to their role in dropping the amount of food available (McCracken 1993). Many studies (Gunnarsson et al. 2009; Beijer et al. 2013) demonstrated that fish exposed to pharmaceutical effluents have significant physiological impacts in terms of the activity of cytochrome P450 1A, global gene expression, and levels of plasma phosphate. A preliminary study on river otters in the UK has pointed out the possibility of nephrotoxicity to otters due to the exposure of otters to NSAIDs (Richards et al. 2011). In addition to severe direct impacts on wild animals, pharmaceuticals also have several indirect adverse effects on wild animals. They can negatively impact foraging efficiency, antipredator abilities, and abilities to attract prey species. Although these effects are subtle, they can severely impact the wildlife population in the long run. For example, the laboratory experiment on wild starlings showed that exposure to endocrine-active chemicals leads to immune depression, and change in behavior and brain structure (Markman et al. 2008; Markman et al. 2011).

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1.15 Personal Care Products In the last decades, personal care products (PCPs) have raised considerable concern as an important class of emerging contaminants of the environment as they have severe adverse impacts on aquatic environments (water, sediments, and biota). These contaminants enter into the water bodies mainly through sewage effluents, wash-off from the skin (through recreational activities like washing of face, bathing, swimming), water runoff, and incomplete and efficient removal of these chemicals. Around 64 compounds are recorded in wastewater plants as compared to 43 in surface water and 23 in groundwater, which is evidence of the role of human activities in the contamination of water with PCPs. Most PCPs contain toxic chemicals. After reaching into the environment, they are destroying natural habitats and wildlife. The accumulation of PCPs in the aquatic environment is toxic for various aquatic wildlife such as crustaceans, phytoplanktons, protozoa, and microalgae (Sanchez-­ Quiles and Tovar-Sanchez 2015). The ingredients of sunscreen (like 3-BC, 4-MBC, BP-3, and nano-TiO2) have a negative impact on endocrine activity, reproduction, development, and behavior of the species, and compounds like nano-ZnO are extremely toxic to zebrafish, marine algae, sea urchins, and other marine organisms (Juliano and Magrini 2017). Oxybenzone (Benzonphenone) contamination, a common ingredient of sunscreen and an emerging contaminant of concern in marine habitats, leads to the bleaching of the coral reefs (Danovaro et  al. 2008; Downs et al. 2016). Plastic microbeads, present in the PCPs as abrasive scrubbers, also act as a potential threat to marine biota. After reaching the aquatic habitats, microbeads made of high-density plastics (Polyvinyl chloride and polyester) settle down and deposit on sediments, whereas the low-density plastics (polystyrene and polythene) cover the surface of aquatic habitats (Subedi et  al. 2011). These microplastics reached the body of aquatic animals and lead to reduced growth, starvation or blockage of the intestine tract, and impairment of reproduction and feeding abilities (Juliano and Magrini 2017). Microplastic can accumulate at the higher food chain through bioaccumulation. Another negative impact related to the potential of PCPs is to aid the delivery of persistent organic pollutants (polycyclic aromatic hydrocarbons, polychlorinated biphenyls, organochlorine pesticides, etc.) mixed at the time manufacturing of plastics or absorbed after coming in contact with water of natural water bodies and then they can be moved along the food chain and have a negative impact on fish and other aquatic organisms (Juliano and Magrini 2017).

1.16 Metals Heavy metals like arsenic, cadmium, molybdenum, mercury, aluminum, chromium, cobalt, nickel, selenium, copper, iron, lead, silver, tin, and zinc have toxic effects on wildlife. Although metals are naturally found in small quantities in the environment and not harmful to living organisms. But human activities lead to the concentration of metal beyond the critical points and the present level of these metals is a potential

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risk to living organisms. Now there is increasing awareness among people and scientists about the impact of metals on the environment. The heavy metals reach the environment from mining, metal refineries, foundries, smelters, burning fossil fuels, agricultural, pharmaceuticals, domestic effluents, and atmospheric sources. Industries and vehicles release huge quantities of toxic metals into the atmosphere. Later on, they settle down on the ground. After the rain, these toxic metals find their way into natural water bodies with the runoff water. In urban areas, this is one of the most substantial sources of contamination of the environment with toxic metals. The mixing of lead in gasoline as an anti-knock agent leads to the shoot-up release of lead in the environment through automobile exhaust. It is also widely used in paints. Lead has an adverse impact on multiple organ systems, inducing anemia, neurological impairment, and nephrotoxicity (Goyer 1995). The intensification of agriculture worldwide leads to the release of toxic metals (like selenium) into the environment via agricultural practices as many fertilizers and insecticides have metals as their ingredients (Alengebawy et al. 2021). Mining processes are the greatest source of contamination of our environment with toxic metals. It leads to the exposure of deposits of ore and rocks’ waste to the weathering process, resulting in the release of toxic metals into water bodies. The most striking example of this is the contamination of the Sacramento River near Redding by Iron Mountain Mine. Although the mine is closed, the degraded area that drains into the river brings a huge quantity of toxic metals into the aquatic habitat of the river which threatened and endangered the aquatic fauna (Druschel et al. 2004). In addition to these sources, various products used by modern society also have many toxic metals, and eventually, they reach the wildlife habitat through improper disposal practices and sewage. The household products such as laundry detergents, bleaches, and bathroom cleansers have measurable quantities of toxic metals. Through sewage water, they reach the aquatic ecosystem. The exposure of wildlife to heavy metals increased exponentially because of the intensive utilization of heavy metals in various domestic, industrial, agricultural, and technological applications. Some parts of these toxic metals are suspended in the upper layer of the atmosphere and spread over a large area far away from their sources. This results in a high concentration of toxic metals in the lake sediments and glaciers located in remote areas far away from the sources. Roads pass through most of the terrestrial wildlife habitats and wild animals existing in close proximity to roads have been shown to accumulate a high level of lead concentrations (Clark and Karr 1979), which is highly toxic to wild animals. The heavy metals reach the body of wild animals directly from the abiotic environment (soil, water, and sediments) or from the food eaten by them. One of the most striking examples of the negative effects of heavy metals on wildlife is the selenium poisoning of Kesterson Reservoir in California’s San Joaquin Valley. The reservoir was created to increase the wetlands habitat in the area by utilizing agriculture drainage in the 1960s. The coastal mountains, located on the western boundary of the San Joaquin Valley, comprise rocks that have a high concentration of selenium. This leads to a high level of selenium in the agriculture drainage of the poorly drained soil of the area and finally, this selenium reaches the

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Kesterson reservoir. The concentration of selenium is quite high in biota found in the Kesterson reservoir’s aquatic ecosystem and has an adverse impact on them (Ohlendorf 2002). For example, mosquitofish collected from Kesterson reservoir has 100 times higher concentration of selenium than fishes collected from the nearby wetlands that did not receive the agricultural drainage (Tanji et al. 1986). The death of large numbers of birds due to the toxicity of selenium is in the media in the 1980s. The high level of selenium in birds leads to impaired reproductive success, reduced body fitness, muscle atrophy, liver degeneration, severe emaciation, and abnormal loss of feathers (Ohlendorf 2002; Ohlendorf et al. 1990). Several studies indicated that ingestion of lead fragments such as lots of fishing sinkers and tackle and spent shots and bullets by wild animals (reptiles, birds, and mammals) causes various adverse effects (molecular and behavioral) that historically may have resulted in the decline in the population of various wildlife species such as raptors, waterfowls, and condors (Grim et al. 2012). The adverse impacts of lead on waterfowls are one the earliest reported evidences of the effects of toxic metals on wild animals, and it leads to the restrictions by many countries on the utilization of lead ammunition for hunting of waterfowl and to a lesser extent, on fishing tackle (Rattner et al. 2011). As per the media reports, in the USA, lead poisoning is responsible for the death of around 2 million ducks and geese each year. In some counties like Mexico, lead shots are still in practice and pose a risk to migratory waterfowl during the annual migrations. Mercury is another serious heavy metal having an adverse impact on wild animals. The high concentration of mercury has an adverse impact on fishes, birds, amphibians, reptiles, mammals, and toxicological effects, including reproductive failure, histopathological lesions, overt neurotoxicity, and mortality (Grim et  al. 2012). The high concentration of mercury in fishes leads to death and adverse effects on reproduction (decrease in spawning and increase in mortality) and development processes (Friedmann et  al. 1996; Drevnick and Sandheinrich 2003; Friedmann et al. 2002). In birds high concentration of mercury leads to immediate death, lower reproductive success (low clutch size, decrease in clutch size, lower hatching success, altered chick behavior, lower survival rates, and decreased nest attendance by parents), behavioral abnormalities (change in time allocation to different activities), physiological problems (Bouton et  al. 1999; Evers et  al. 2003; Facemire and Chlebowski 1991; Frederick et  al. 2004; Schwarzbach et  al. 2006; Heath and Frederick 2005; Spalding et al. 2000). High levels of mercury contaminants in mammals result in outright mortality and physiological and reproductive problems (Wobeser and Swift 1976; Wren 1985; Facemire et al. 1995; Mierle et al. 2000; Basu et al. 2005a, 2005b).

1.17 Impact of Fertilizers The excessive and improper utilization of fertilizers in agriculture is an emerging threat and has several negative impacts on wildlife. As per the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES), the

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runoff from agriculture fields laced with various chemical fertilizers negatively affects terrestrial and aquatic ecosystems. These effects can be direct impacts (high concentrations of nitrogen can be toxic to wild animals that absorb elements directly from the environment) and indirect impacts by promoting various factors such as soil or water acidification, nutrient enrichment, oxygen depletion in water bodies, or intensifying the impact of other stressors such as invasive species, pathogens, and climate change (Erisman et al. 2013). The utilization of chemical fertilizers is responsible for the population decline of many microorganisms found in the agriculture fields. The decline in the population of earthworm species because of the application of nitrogen, phosphorus, potassium (NPK) is well known to science and many studies documented the fact. Urea, a widely used NPK fertilizer caused mortality in adult earthworms 100% if they come in contact with urea (Shruthi et al. 2017). The runoff of NPK fertilizers into the water bodies results in the disturbance of the nitrogen cycle. This results in an increase in the amount of nitrogen in water bodies, which leads to eutrophication. This, in turn, results in the deterioration of the local ecosystems and has negative effects on biota. Out of the 63 large marine ecosystems, assessed under the Transboundary Waters Assessment Programme, 16% of the ecosystems fall under the “high” or “highest” risk categories for coastal eutrophication due to nutrient runoff (UN ECOSOC 2017). The availability of excessive nutrients in marine habitats leads to algal blooms (some algae grow more extensively than the usual normal conditions). Blooming algae releases harmful toxins and also reduces the availability of oxygen for other organisms. This oxygen reduction suffocates the other marine animals. Sometimes the impact of algae and its toxin is so severe that the whole area becomes unsuitable to other marine creatures. Amphibians are greatly affected by the contamination of fertilizers in aquatic habitats as their skin is permeable. The high concentration of urea, nitrate, ammonia, ammonium nitrate, etc. had an adverse impact on the embryonic development, larvae development, and physiological processes of amphibians. It leads to abnormalities in animals and also decreases the efficiency of fertilization of eggs. A high concentration of ammonia in the body of amphibians can be very toxic. High concentration of ammonia leads to a significant decrease in the hatching success of Rana aurora and Ambystoma gracile (De Solla et al. 2002).

1.18 Conclusion Impacts of environmental contaminants can be mild like reducing the population of species by reducing the availability of food or lethal like causing direct toxicity to species (drastic decline in vulture population due to diclofenac. They have severe adverse impacts on wildlife in every part of the globe and emerged as a serious threat to the long-term conservation of wildlife. Therefore, there is a need of having a holistic approach to minimize the impacts of environmental contaminants on wildlife. While making laws for the regulation and control of environmental

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contaminants is important and many countries already have many laws to regulate and control environmental contaminants, the implementation of these laws on the ground is of prime importance. Many counties, especially developing counties, are not able to implement these laws on the ground efficiently. To implement laws and regulations on the ground effectively, it is essential to have coordination among the various government agencies working for the production, use, and regulation of various environmental contaminants. Generally, it is noted that agencies like the agriculture department, promote the utilization of various pesticides, insecticides, and inorganic fertilizers without considering their negative impacts. In addition to this, there is the utmost need to create awareness among the people about the harmful impacts of various environmental contaminants on wildlife and the environment. At present, a major part of the human population lacks awareness about the ill effects of environmental contaminants and they are not adopting measures designed to curb the introduction of harmful substances in the environment. Lack of awareness also leads to unsustainable utilization of resources which further increases the problem. So, to create awareness among the public it is required that all commercial substances should have clear information about the harmful impacts of the chemical. The problem of environmental contaminants is a complex problem and to deal it with, it is imperative that various agencies work in coordination with each other with the involvement of the public. Until and unless, all sections of society actively work toward implementing the measures to stop the contamination of the environment, they will pose challenges to the long-term conservation of wildlife. Therefore, to ensure the long-term conservation of wildlife, it is crucial to frame holistic policies for the regulation of environmental contaminants and implement them on the ground with the support of the public. Acknowledgments  I would like to express my sincere gratitude to Dr. Jamal Ahmad Khan, Chairman, Department of Wildlife Sciences, Aligarh Muslim University, Aligarh for providing permission to submit the chapter. I wish to place my sincere thanks to Dr. Naveen Pandey, Deputy Director, The Corbett Foundation for going through the manuscript of the chapter.

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Mineau P, Flectcher MR, Glaser LC et al (1999) Poisoning of raptors with organophosphorus and carbamate pesticides with emphasis on Canada, U.S. and U.K. J Raptor Res 33:1–37. http:// elibrary.unm.edu/sora/jrr/v033n01/p00001-­p00037.pdf Moore NW (1967) Effects of pesticides on wildlife. Proc R Soc Lond B167:128–133. https://doi. org/10.1098/rspb.1967.0017 Newman JR (1979) Effects of industrial air pollution on wildlife. Biol Conserv 15:181–190 Oaks JL, Gilbert M, Virani MZ et al (2004) Diclofenac residues as the cause of population decline of vultures in Pakistan. Nature 427:630–633 Ohlendorf HM (2002) The birds of Kesterson reservoir: a historical perspective. Aquat Toxicol 57:1–10. https://doi.org/10.1016/S0166-­445X(01)00266-­1 Ohlendorf HM, Hothem RL, Bunck CM et  al (1990) Bioaccumulation of selenium in Birds at Kesterson Reservoir, California. Arch Environ Contam Toxicol 19:495–507 Olsen P, Fuller P, Marples TG (1993) Pesticide-related eggshell thinning in Australian Raptors. EMU 93:1–11 Phillips JC, Lincoln FC (1930) American waterfowl, their present situation and the outlook for their future. Houghton Mifflin, New York, p 312 Prakash V, Green RE, Pain DJ et al (2007) Recent changes in populations of resident Gyps vultures in India. J Bombay Nat Hist Soc 104:129–135 Ratcliffe DA (1967) Decrease in eggshell weight in certain birds of prey. Nature 215:208–210 Rattner BA, Scheuhammer AM, Ellott JE (2011) History of wildlife toxicology and the interpretation of contaminant concentrations in tissues. In: Beyer WN, Meador JP (eds) Environmental contaminants in biota: interpreting tissue concentrations, 2nd edn. CRC Press, Boca Raton Richards NL, Cook G, Simpson V et al (2011) Qualitative detection of the NSAIDs diclofenac and ibuprofen in the hair of Eurasian otters (Lutra lutra) occupying UK waterways with GC-MS. Eur J Wildlife Res 57:1107–1114. https://doi.org/10.1007/s10344-­011-­0513-­2 Risebrough RW, Jarman WM, Springer AM et  al (1986) A metabolic derivation of DDE from Kelthane. Environ Toxicol Chem 5:13–19 Sabra FS, Mehana E-SE-D (2015) Pesticides toxicity in fish with particular reference to insecticides. Asian J Agric Sci 3(1). https://www.ajouronline.com/index.php/AJAFS/article/ view/2156 Sanchez-Quiles D, Tovar-Sanchez A (2015) Are sunscreens a new environmental risk associated with coastal tourism. Environ Int 83:158–170 Schwarzbach SE, Albertson JD, Thomas CM (2006) Effects of predation, flooding, and contamination on reproductive success of California clapper rails (Rallus longirostris obsoletus) in San Francisco Bay. Auk 123:45–60 Science for Environment Policy (2017) Tackling mercury pollution in the EU and worldwide. In-depth report 15 produced for the European Commission, DG Environment by the Science Communication Unit, UWE, Bristol. http://ec.europa.eu/science-­environment-­policy Shruthi N, Biradar AP, Muzammil S (2017) Toxic effect of inorganic fertilizers to earthworms (Eudrilus eugeniae). J Entomol Zool Stud 5(6):1135–1137 Shultz S, Baral HS, Charman S et al (2004) Diclofenac poisoning is widespread in declining vulture populations across the Indian subcontinent. Proc R Soc Lond B 271:S458–S460. https:// doi.org/10.1098/rsbl.2004.0223 Spalding MG, Frederick PC, McGill HC et al (2000) Histologic, neurologic, and immunologic effects of methylmercury in captive great egrets. J Wildl Dis 36:423–435 Sparling DW, Feller GM (2009) Toxicity of two insecticides to California, USA, anurans and its relevance to declining amphibian populations. Environ Toxicol Chem 28(8):1696–1703. http:// www.allenpress.com/pdf/ENTC_28.8_1696_1703.pdf Subedi B, Mottaleb MA, Chambliss CK et al (2011) Simultaneous analysis of select pharmaceuticals and personal care products in fish tissue using pressurized liquid extraction combined with silica gel cleanup. J Chromatogr A 1218:6278–6284 Swan GE, Cuthbert R, Quevedo M et al (2006) Toxicity of diclofenac to Gyps vultures. Biol Lett 2:279–282

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Taggart MA, Senacha KR, Green RE et al (2009) Analysis of nine NSAIDs in ungulates tissues available to critically endangered vultures in India. Environ Sci Technol 43:4561–4566 Talmage SS, Opresko DM, Maxwell CJ et al (1999) Nitroaromatic munition compounds: environmental effects and screening values. In: Ware GW (ed) Reviews of environmental contamination and toxicology, vol 161. Springer, New York, NY. https://doi.org/10.1007/978-­1-­4757-­6427-­7_1 Tanji K, Läuchli A, Meyer J (1986) Selenium in the San Joaquin Valley. Environ Sci Policy Sust Develop 28(6):6–39. https://doi.org/10.1080/00139157.1986.9929919 Ternes TA, Joss A, Siegrist H (2004) Scrutinizing pharmaceuticals and personal cares products in wastewater treatment. Environ Sci Technol 38:392A–399A UN ECOSOC (2017) Progress towards the sustainable development goals. Report of the Secretary-­ General E/2017/66. UN Economic and Social Council. http://www.un.org/ga/search/view_doc. asp?symbol=E/2017/66&Lang=E Wetmore A (1919) Lead poisoning in waterfowl. U.S.  Department of Agriculture, Bulletin 793, p 12 Whitehead FE (1934) The effect of arsenic, as used in poisoning grasshoppers, upon birds. Oklahoma Agricultural and Mechanical College Agriculture Experiment Station. Exp Station Bull Number 218, p 54 Wobeser GA, Swift M (1976) Mercury poisoning in a wild mink. J Wildl Dis 12:335–340 Wren CD (1985) Probable case of mercury poisoning in a wild otter (Lutra canadensis) in northwestern Ontario. Can Field-Nat 99:112–114 York RG, Brown WR, Girard MF et al (2001) Two-generation reproduction study of ammonium perchlorate in drinking water in rats evaluates thyroid toxicity. Int J Toxicol 20:183–197. https://doi.org/10.1080/109158101750408019

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Heavy Metal Pollution in Water from Anthropogenic and Natural Activities and the Remediation Strategies Ahmad Manan Mustafa Chatha, Saima Naz, Shabana Naz, Rifat Ullah Khan, and Amna Nawaz

2.1 Introduction Water is the essential element for all biotic factors to exist on Earth (Bytyçi et al. 2018). More precisely, it is the fundamental natural resource upon which our social and economic growth relies greatly (Pobi et al. 2019; Proshad et al. 2021). Generally, we are globally facing the issue of water shortage. About 40% of the worldwide food supply runs through the irrigation system. Also, industries depend on water to produce various products. Though it is a basic need of life, it is being contaminated by human activity leading to water pollution, a disturbing food chain, and aquatic decline (Halder and Islam 2015). Microbial degradation, metal contamination, and pesticides are the major causes of pollution, and at a few locations, fluorides, and nitrates are the primary reasons for water decline (Azizullah et al. 2011). Modernization too lowers the standards of A. M. M. Chatha Department of Entomology, Faculty of Agriculture and Environment, Islamia University of Bahawalpur, Bahawalpur, Pakistan e-mail: [email protected] S. Naz · A. Nawaz Department of Zoology, Government Sadiq College University, Bahawalpur, Pakistan e-mail: [email protected] S. Naz Department of Zoology, Government College University, Faisalabad, Pakistan e-mail: [email protected] R. U. Khan (*) College of Veterinary Sciences, Faculty of Animal Husbandry & Veterinary Sciences, The University of Agriculture, Peshawar, Pakistan e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 M. I. Ahmad et al. (eds.), Toxicology and Human Health, https://doi.org/10.1007/978-981-99-2193-5_2

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water from run-off to basin. In cities, rainfall washes off the contaminants gathered on the surface. Residue from the commercial, residential, and industrial areas gives rise to a faint smell, particularly in the garbage and other pollutants. The rainfall system contaminates rivers even more (Afroz and Rahman 2017). Generally, modernization, agriculture, disposal of polluted waste material by industries, residential areas, and agriculture contribute a considerable quantity of pollutants like most heavy metals (Saha and Zaman 2013) which are further fed by the primary producers (Malik et  al. 2010). Hence, they are passed on to human beings via the food chain with devastating health effects on seafood consumers (Agusa et al. 2007). Heavy metals are severely harmful to sea animals even if they are present in minor concentrations (Effah et al. 2021). However, most water pollution is driven by household, industrial, and agricultural activities (Yılmaz et  al. 2007; Ayanda et al. 2019). The most significant environmental involvement is the heavy metals because of the direct poisonous impact on living organisms and the indirect impact of making food contaminated (Gbogbo et al. 2018). Excess in heavy metal quantities like cadmium (Cd), nickel (Ni), zinc (Zn), copper (Cu), lead (Pb), iron (Fe), chromium (Cr), and arsenic (As) can decline the water standards such as the excess of Cd give rise to blood deficiency, harm to the olfactory nerve, tarnished teeth, nasal septum ulcer, rhinitis, and loss of smell to the water bodies (Maurya et  al. 2019; Malik et  al. 2020). A few heavy metals such as Zn, Cu, and Fe are needed for an average human body to function at a particular limit. However, an elevated range of these elements can make them poisonous for normal functioning (Tongesayi et al. 2013). The health of the entire aquatic environment as well as that of humans is being negatively impacted by heavy metal poisoning. Since heavy metals reduce productivity owing to the risk posed by biomagnification and bioaccumulation inside the food chain, they can change the physiological and biochemical characteristics of aquatic species (Kobielska et al. 2018; Marella et al. 2020). Commonly found heavy metals in an aquatic ecosystem include Cu, Cd, Pb, Zn, mercury (Hg), and Cr. Cadmium-derived compounds are frequently used in the plastic industry as coloring and anticorrosive coating agents for electrical batteries and batteries. In metal ores and natural deposits, it also appears spontaneously. Fish that eat filters may readily absorb Cd, which can cause biomagnification along the food chain (Rizwan et al. 2019). Cd can seriously harm human kidneys and lead to osteoporosis (Rebelo and Caldas 2016). Cd may also penetrate the environment from Zn, Pb, or Cu ore. It can enter freshwater by dumping industrial and domestic waste. The rate of marine species' reproduction may also be affected by exposure to heavy metals, which can cause generations of these organisms to slowly disappear in contaminated environments (Chary et al. 2008). For instance, Cd and Hg injure the kidney and transmit indications of usual poisoning, which include defective duplication and retarded kidney processing, stone formation, hypertension, and hepatic dysfunction (Mansour and Sidky 2002). Heavy metals have a profound impact on marine life. They are highly chronic and tend to disrupt life processes by entering the food caravan (Islam et al. 2015). Due to their direct effects on the functioning of marine life and human life, the

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accurate evaluation and identification of water pollution are essential (Saha et al. 2017). Pb and Hg are non-decaying metals that allow the accumulation in the food chain despite their toxicity even at low concentrations (Kumar et  al. 2020). The impact of heavy metals on marine life is determined by their capacity to bioconcentrate and bio-proliferate, which is therefore dependent on people (Georgescu et al. 2017). The presence of genotoxic pollutants in marine ecosystems and fishes is the finest example (Walia et al. 2015; Aich et al. 2015; Sharma et al. 2018) since these water bodies are vulnerable to even a minor amount of metals within the water. Also, they are found in abundance and live in unique habitats (Malik et al. 2020). Livings beings consuming fishes contaminated with poisonous metals or from other sources can result in general health disorders. Parkinson's disease, Cancer, multiple sclerosis, and Alzheimer's disease are just a few of the devastating illnesses that can develop from prolonged exposure to heavy metals (Mishra et al. 2010). The literature is replete with such documentation detailing the worst effects of heavy metals on man, including liver destruction, kidney injury, heart-related diseases, and frequent death (Saha and Paul 2019). These effects also include some cognitive, physiological, musculoskeletal, and neurologic issues (Liu et  al. 2020). Moreover, the water contamination issue is getting more lethal, with increasing documents showing a downward trend year after year (Zhang et al. 2015). Therefore, the suitable detection of water quality containing the contamination of heavy metals is of supreme importance to save the ecosystem and living beings’ health (Tchounwou et  al. 2012). A number of approaches have been prepared to get rid of a load of contaminants. Water containing heavy metals as pollutants includes chemisorption, ion exchange, and electrolytic removal as examples of conventional treatment methods. Moreover, the problems can be related to the significant technical need for processing, installing, and maintaining, leading to inappropriate processes. Generally, such techniques are helpful in decentralized setups and developing countries. As a result, the requirement to make practical yet environmentally acceptable alternatives that may include an adsorbent system entails biopolymers, organic, or nano-techniques (Bethke et al. 2018; Lee et al. 2019; Wani et al. 2020; Kumar et al. 2021; Tavker et al. 2021). The evaluation work covers the underlying heavy metal contamination, the crucial problems associated with their contamination in freshwater, and the health and well-being consequences on living organisms. We are also covering the technologies used to identify these toxins, the variables that influence how they are treated, and potential therapies for these toxins that would have a low by-product count and a high level of effectiveness. Below is a detailed discussion of the leading treatment technologies.

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2.2 Chemical Nature of Heavy Metals Natural soil and freshwater depositions are diverse, resulting in varying degrees of heavy metals and other hazardous element interaction. Variation in their connection for toxic substances, particularly permeability elements, can result in the deposition of metallic carbonates and hydroxides, as well as other physicochemical properties of the heavy metal, such as electron affinity, charge density, and hydrolysis regularity. Given below are the measurements of molecular weight, oxidation state, and Van der Waals radius representing chemical properties of a few heavy metals (Appel et al. 2008) (Table 2.1).

2.3 Sources of Heavy Metal Pollution Due to their great persistence and ability to detect in many tissues of living things in the food chain, freshwater ecosystems are seriously threatened by harmful metals (Islam et  al. 2015). The constant release of many degraded chemical sources is another cause of contamination, which increases metal interaction in water and has hugely detrimental effects on aquatic systems. As a result, the real disruption of conventional ecosystem processing may be seen (Islam et al. 2015; Raknuzzaman et  al. 2016; Kumar et  al. 2019). Furthermore, these poisonous metals can penetrate the bloodstream through filthy water, sea critters, and cutaneous contact (Saha and Paul 2019). Exposure to these contaminated pollutants might result in physical, mental, and emotional retardation (Saha and Paul 2019). As, Cr, Cd, Pb, Cu, Ni, Mg, Zn, Fe, and Al are generally noticed as toxic metals in industrial contaminants. These heavy metal origins can be divided into two groups: • Point source pollution (industrial waste, sewage treatment plants, and animal farms) • Non-point source pollution (farming actions, consistent run-off) (Fig. 2.1)

Table 2.1  Chemical properties of the studied heavy metals Heavy metal Arsenic Cadmium Chromium Copper Lead Nickel Zinc

Molecular weight (g mol−1) 74.9 112.4 52.0 63.5 207.2 58.7 65.4

Oxidation state (s) −3, +3, +5 +2 −2 to +6 0, +1, +2, +3 0, +2, +4 −1, 0, +2, +3, +4 0, +2

Van der Waals radius (10−12 m) 185 158 200 140 202 163 139

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2.4 Heavy Metals and Their Dangerous Impacts As a result of living organisms’ actions, the sudden and disturbing growth of industries worldwide is believed to be the primary source of international water contamination, notably in urban river system habitats where harmful byproducts discharged

Fig. 2.1  Types of anthropogenic water pollution sources

Wastes from: Agriculture, Mines, Residential, transportation, Industries

Liquid wastes

Solid waste

Water resources polluted

Soil Pollution, which affects:

Gaseous waste Accumulates in air and becomes part of rain

Microbial activity Soil health Crop productivity Organic Pollutants Biodegradation

Inorganic Pollutants Alterations of metabolic activities in plants and animals

Bioaccumulation

Fig. 2.2  Flowchart represents effects of heavy metal contamination

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by businesses end up in waterways (Pandey and Singh 2019; Kumar et al. 2020). It reveals the lack of proper checks and balances witnessing the deficiency of law enforcement. Therefore, most industries dump polluted industrial waste into the environment or the water bodies, which then degrades the standard of water by bringing several water contaminants. Heavy metals, for example, are highly hazardous in several ways, in all mediums (Edokpayi et al. 2017) (Fig. 2.2).

2.4.1 Copper Generally, Cu is a common element found in the environment and is utilized too much by human beings. The resources of this metal in streamlets are Cu mining and smelting. Moreover, chemical resistance, steel making, technical enterprises, agribusiness, and stitchery sludge. Several kidneys collapse in children disclosed to high Cu concentration (Orr and Bridges 2017). Copper is crucial for building hemoglobin and some enzymes in living beings; however, elevated infusions can harm the liver and kidneys. Increased Cu contamination in drinkable water can lead to a bad taste. However, a small amount of Cu is essential to human life (De Namor et al. 2012), but its great attention is fatal for humans. Copper usually penetrates drinkable water via pollution by the Cu water transfer pipe commonly used to transfer water for domestic purposes (WHO 2011). Maximum Permissible Quotients (MPQ) The maximum permissible limits for Cu are 2.00 mg/L, 0.05 mg/L, 2.00 mg/L, and 1.00 mg/L by the World Health Organization (WHO), Environmental Protection Agency-United States (EPA-US), European Union (EU), and Pakistan Council of Research in Water Resources (PCRWR), respectively (Table 2.1).

2.4.2 Iron Iron is one of the elements present in abundance in the environment. Also, the most widely found toxic metal. Available in the environment as Fe++ or Fe+++. It is an essential element required for living organisms’ growth and development. It is a vital part of cytochromes, porphyrins, and metalloenzymes. The intake of a high amount of iron produces a hemochromatosis situation. Also, in alcoholism, tissue destruction in a few cases occur with a large quantity of Fe ingestion from alcoholic drinks (CWC 2014). A higher intake of Fe can lead to digestion problems, diarrhea, gastrointestinal injury, metabolic acidosis, shock, mental issues, tachycardia, cardiovascular collapse, coagulation, deficiencies, hepatic necrosis, and in case maybe death (Saboor et al. 2015). MPQ The Maximum permissible limits for Iron are 3.00 mg/L, 0.3 mg/L, 0.2 mg/L, and 0.3 mg/L by WHO, EPA-US, EU, and PCRWR, respectively (Table 2.1).

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2.4.3 Lead Lead is an unnecessary element assumed to be a burden to living organisms. It is an excellent threat to biotic factors of life that causes destruction even if present in small quantities. It does not generally use living processes or biochemical processes. The poisonous nature of lead is well known for the severe challenges leading to athletic, skeletal, anxious, immune, and disturbed reproductive systems. Furthermore, it can significantly affect intelligence quotients and impede children's development (Jaihan et al. 2022). Pregnant and older women are more vulnerable to the impacts of lead. Lead is one of the most common pollutants in the environment, and so it is found naturally in rocks, the earth, and the oceans. It is quickly swallowed by fishes once released into the marine environments, and it is collected in the muscle tissue, bones, organs, and scales 41. Lead is classified as a primarily dangerous and damaging factor to biological elements of life by the United States Environmental Conservation Agency (USEPA 2012). Lead is assumed to be a brain toxin that induces constant behavioral deficiencies in fish and reduces life chances, growth rates, maturation, and metabolism. MPQ The Maximum permissible limits for Lead are 0.015 mg/L, 0.015 mg/L, 0.01 mg/L, and 0.01 mg/L by WHO, EPA-US, EU, and PCRWR, respectively (Table 2.1).

2.4.4 Cadmium Like Pb, Cd is also a toxic element with general carcinogenic impacts on living beings. By disrupting calcium control in biological systems in humans, fishes, or other living things, Cd causes chronic kidney damage, including cell death and injury (Rafati et al. 2017). Moreover, if cadmium onetime amasses in the liver, it is not manageable to evacuate. Cd, in great concentration, can cause high blood pressure, and renal collapse and can ruin tissues of the testicles and the erythrocytes (Hyder et al. 2013). Cd even generates demineralization of the bones, lung operation destruction, and lung cancer susceptibility (Wang et al. 2021). Industrial wastes have polluted drinking waters, plating, plants manufacturing cadmium dyes, fabric processes, toxins from sound sewer systems, metal polymers, or nickel–cadmium binders (Rani et al. 2014). Cd is a hefty metal in fish. It can cause blood deficiency and vertebral ruptures, osmoregulatory issues, reduced digestive efficiency, hematological and biochemical outcomes, development deficiencies, irregular swimming, and mortality. The harmful effect of Cd is worsened by a long natural half-life and retention for long periods in organisms after accumulating in them (Genchi et al. 2020a). MPQ The Maximum permissible limits for Cd are 0.003 mg/L, 0.005 mg/L, 0.005 mg/L, and 0.003 mg/L by WHO, EPA-US, EU, and PCRWR, respectively (Table 2.1).

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2.4.5 Zinc Zn is an essential metal that recreates a vital part of living organisms' metabolic courses. Its deficiency can induce loss of hunger, retarded maturation, skin transformations, and destruction of the immune system (Prasad 2013). Zn is a required element for biotic factors of life. Zn is involved in the replication and interpretation of genetic information, including enzyme systems. When ingested by mouth, Zn is thought to become a nontoxic metal, but an excessive amount might induce system disruption, resulting in slowed life processes. Vomiting, trots, bloodstained urine, and icterus (yellow phlegm membrane) are some of the common symptoms (Plum et al. 2010). Zn is a cofactor in various enzyme reactions, including carbonic anhydrase, which is found in RBCs. Because the toxic nature of Zn is reduced by salts of alkaline earth elements, being acidulated with Zn is uncommon. The toxic effects of Zn elevate are the temperature elevates, and the oxygen level in water concentration declines. Long-term exposure to high levels of Zn can cause significant health problems, like tiredness, dizziness, or neutropenia (Zamora-Ledezma et al. 2021). MPQ The Maximum permissible limits for copper are 3.00 mg/L, 5.00 mg/L, and 15 mg/L by WHO, EPA-US, and PCRWR, respectively (Table 2.1).

2.4.6 Nickel Like many other heavy metals, Ni is a vital metal for various wild species, micro-­ species, and plants. The poisonous nature may also lead to a small and large amount of nickel being received (Genchi et  al. 2020b). The Ni attention is elevated in a specific area by living organisms' actions such as urbanization, extracting, smelting emissions, coal or oil combustion, pesticide, and antifungal usage. Ni is a ubiquitous metal that has been linked to skin allergies and responses and is one of the most found reasons for allergic references to dermatitis (Genchi et al. 2020a). Nickel is extensively used in the Fe and Ni composite materials industries, which can have potentially harmful effects on individuals (Boustani et al. 2012). MPQ The Maximum permissible limits for Ni are 0.02 mg/L, 0.1 mg/L, and 0.02 mg/L by WHO, EPA-US, and EU, respectively (Table 2.1).

2.4.7 Chromium Cr is used to serve as a metal having two surfaces, mainly depending on its concentration and oxidation state, it can be beneficial or harmful to living beings and other creatures. Electrodeposition, dye and colorants manufacture, textile manufacturer, fertilizer, and tannery are a few industries that use chromium (Ganguli and Tripathi

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2002). Chromium is produced by a variety of businesses and appears in various oxidation states, the most important of which are Cr3 and Cr4. Chromium is a poisonous, mutagenesis, and cancerous in an influential way (Lee et al. 2008). The origin of Cr could be attributed to farming run-off, paints employed in boats, and leaching from rocks in the analysis area (Chen et al. 2022). Cr is discharged into the sea by effluent from tanning, electroplating, pigments manufacturing, resistive techniques (De Namor et al. 2012), ferrochrome synthesis, and other processes. MPQ The maximum permissible limits for Cu are 0.05 mg/L, 0.1 mg/L, 0.05 mg/L, and 0.05 mg/L by WHO, EPA-US, EU, and PCRWR, respectively (Table 2.1).

2.4.8 Arsenic Arsenic is a cosmopolitan element that may be rare yet highly distributed in the environmental ground, stones, natural water reservoirs, and living beings. Even though acute poisoning yields such as pesticides and fertilizers have tremendously declined in recent years, their use for wood safeguarding is still known. It is listed in the environment by various environmental methodologies such as physiological activities (Kapaj et al. 2006). Erosional responses and geological events, and various human sources over the last few years. The impact of acute poisoning substances on the ecosystem will last for several years (Jayaraj et al. 2016). Inorganic (elemental, trivalent, and pentavalent arsenic) and organic (trivalent and pentavalent arsenic) forms of As are seen. Because of the quick elimination of potent toxins inside the human body, it does not persist for long. MPQ The Maximum permissible limits for Arsenic are 0.01 mg/L, 0.01 mg/L, 0.01 mg/L, and 0.01 mg/L by WHO, EPA-US, EU, and PCRWR, respectively (Table 2.2).

Table 2.2  Heavy metals and their maximum permissible limits by WHO, EPA-US, EU, and PCRWR Metal Cu Fe Pb Cd Zn Ni Cr As

WHO (mg/L) 2.00* 3.00* 0.015* 0.003* 3* 0.02* 0.05* 0.01*

EPA-US 0.05^ 0.3^ 0.015^ 0.005^ 5^ 0.1^^ 0.1^ 0.01^

EU 2.00 0.2 0.01 0.005 NA 0.02 0.05 0.01

PCRWR 1.00 0.3 0.01 0.003 15 NA 0.05 0.01

WHO World Health Organization; EPA-US Environmental Protection Agency-United States; EU European Union; PCRWR Pakistan Council of Research in Water Resources

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2.5 Characteristics of Common Heavy Metals Dietary orientation to different heavy metals has been recognized as a health hazard to humans through the consumption of infected food. Many heavy metals attach to the sulfur present in enzymes, disrupting their process (Jairoun et  al. 2020). The presence of toxic pollution in aquatic ecosystems is of special interest due to the potential threats to public health upon consumption. Heavy metal concentrations in tissue can result in chronic sickness and overall harm (Briffa et al. 2020). Prolonged exposure to heavy metals above the acceptable limits in people and animals has negative consequences, including cognitive issues, headaches, and organ disease. Concentrations of heavy metals in marine creatures’ tissue are increased due to repeated exposures via water and diet (Tchounwou et al. 2012). It is well-­recognized that sea animals absorb environmental contaminants and deposit toxins. Do not add the much-elevated amount in these organs than that of the external environment (Table 2.3). Due to the well-documented effects of heavy metals on people's well-being, numerous scientists have carried out extensive analyses on metal pollution of water source materials, in particular, third-world countries, including China, Pakistan, Iran, and India. An extensive portion of the study has been carried out on these to express toxic metals from freshwater resources, municipal sewage, sewage sludge, and other waterways (Table 2.4).

Table 2.3  Characteristics of common heavy metals Heavy metals Copper (Cu) Iron (Fe) Lead (Pb) Cadmium (Cd) Zinc (Zn) Nickel (Ni) Chromium (Cr) Arsenic (As)

Common health effects Gastrointestinal issues Liver or kidney damage Gastrointestinal disorders, Cardiovascular diseases Kidney damage Reduced neural development Kidney damage Carcinogenic System dysfunctions, neutropenia Cardiovascular, immunological effects Allergic dermatitis, Diarrhea, nausea, vomiting Skin damage Circulatory system issues

Common sources Naturally occurring Household plumbing systems Naturally occurring Lead-based products Household plumbing systems Naturally occurring Various chemical industries Naturally occurring Naturally occurring Mining and smelters Naturally occurring Steel manufacturing Naturally occurring Electronics production

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Table 2.4  An overview of heavy metal pollution in different geographical regions including Pakistan, India, and Afghanistan

Metal Copper (Cu)

Location River Nile at El-kanater, El-khyria MIS of Taruma Micro-basins Ismailia Canal Egypt San Francisco, Argentina Uttar Pradesh India Rupsa-river Bangladesh

Iron (Fe)

Lead (Pb)

Durgapur, west Bengal, India Swan River, Islamabad, Pakistan River Nile at El-kanater, El-khyria MIS of Taruma Micro-basins

No. of samples/ sites Not available 6

4 4 28 20

40 12

Not available 6

Nile River Rahaway Drain

Not available

Durgapur, west Bengal, India Changchun, China Surulere, Nigeria

40

Ismailia Canal, Egypt San Francisco, Argentina Amritsar, India Uttar Pradesh, India

197 29

4 4 Not available 28

Mean value 13.86 ± 1.60 ug/L 0.016 ± 0.007 mg/L 47.35 ± 1.71 ug/L 10.7 ug/g 2.54 ± 0.68 mg/L 5.45 ± 0.441 mg/L 0.021 mg/L 15.89 ug/g 690.76 ± 249.81 ug/L 3.698 ± 0.285 mg/L 927.76 ± 61.48 ug/L 0.991 mg/L 0.03 mg/L 0.001– 0.024 mg/L 7.03 ± 0.68 ug/L 7.2 ug/g 2.3 ± 0.02 ug/L 0.85 ± 0.08 mg/L

MPLa 9.0 ug/g (USEPA)

References Gaber et al. (2013)

2.000 mg/L (WHO)

Viana et al. (2018)

– 0.8 ug/g (MPQ) 1.5 mg/L (WHO) 0.5 mg/L (WHO)

Ismail et al. (2017) Fernando et al. (2007) Maurya et al. (2019) Proshad et al. (2021)

1.3 mg/L (ATSRD) 140 ug/g (EU)

Saha and Paul (2019) Perveen et al. (2017)

1000 ug/L (USEPA)

Gaber et al. (2013)

0.300 mg/L (WHO)

Viana et al. (2018)

1000 ug/L (USEPA)

Gaber et al. (2013)

0.3 mg/L (ATSRD) 0.3 mg/L (NSAC) 0.01 mg/L (WHO)

Saha and Paul (2019) Sprague and Vermaire (2018) Momodu and Anyakora (2010)

–

Ismail et al. (2017) Fernando et al. (2007) Kaur and Dua (2015) Maurya et al. (2019)

2.0 ug/g (MPQ) 0.1 ug/L (EPAR) 0.01 mg/L (WHO)

(continued)

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Table 2.4 (continued)

Metal

Cadmium (Cd)

Zinc (Zn)

Nickel (Ni)

Location Rupsa-river Bangladesh Durgapur, west Bengal, India Swan River, Islamabad, Pakistan MIS of Taruma Micro-basins

No. of samples/ sites 20

40 12

6

Surulere, Nigeria

19

River Korotoa, Bangladesh Ismailia Canal, Egypt Amritsar, India

10 4 Not available

Rupsa-river Bangladesh

20

Swan River, Islamabad, Pakistan Mashavera River Georgia MIS of Taruma Micro-basins

12

San Francisco SF1 Swat River, Pakistan Swan River, Islamabad, Pakistan MIS of Taruma Micro-basins Amritsar, India

17 6

Not available 9 12

6

Not available

Mean value 0.975 ± 0.106 mg/L 0.014 mg/L 15.48 ug/g

MPLa 0.5 mg/L (WHO)

References Proshad et al. (2021)

0.015 mg/L (ATSRD) 300 ug/g (EU)

Saha and Paul (2019) Perveen et al. (2017)

0.003 mg/L (WHO)

Viana et al. (2018)

0.003 mg/L (WHO)

Momodu and Anyakora (2010)

3 g/L (WHO) – 2.0 ug/L (EPAR)

Islam et al. (2015) Ismail et al. (2017) Kaur and Dua (2015)

0.005 mg/L (WHO)

Proshad et al. (2021)

3.0 ug/g (EU)

Perveen et al. (2017)

458.9 mg/ kg 1.158 ± 0.254 mg/L 92.8

150 mg/kg (WHO) 3.000 mg/L (WHO)

Withanachchi et al. (2018). Viana et al. (2018)

30.0 (MPQ)

0.0692 ug/g 60.32 ug/g

123 ug/g (WHO) 300 ug/g (EU)

Fernando et al. (2007) Liu et al. (2020) Perveen et al. (2017)

0.090 ± 0.020 mg/L 3.01 ± 0.03 ug/L

0.070 mg/L (WHO)

Viana et al. (2018)

3.0 ug/L (EPAR)

Kaur and Dua (2015)

0.007 ± 0.001 mg/L 0.001– 0.098 mg/L 11 ± 8 g/L 4.67 ± 0.17 ug/L 0.193 ± 0.002 ug/L 3.85 ± 0.694 mg/L 2.79 ug/g

(continued)

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Table 2.4 (continued)

Metal

Chromium (Cr)

Arsenic (As)

Location Swat River, Pakistan Mashavera River Georgia Rupsa-river Bangladesh Swan River, Islamabad, Pakistan Uttar Pradesh, India Swat River, Pakistan Mashvera River, Georgia River Korotoa, Bangladesh Rupsa-river Bangladesh

No. of samples/ sites 9 17 20

12

Ontario, Canada

29

0.36 ± 0.07 mg/L 0.0096 ug/g 26.4 mg/ kg 83 ± 27 g/L 7.20 ± 0.613 mg/L 46 ± 27 g/L 0.0333 ug/g 5.36 ± 0.471 mg/L 4.3 mg/L

Sistan and Baluchestan, Iran

493

1.5 mg/L

River Korotoa, Bangladesh Swat River, Pakistan Rupsa-river Bangladesh

28

Mean value 0.0304 ug/g 22.3 mg/ kg 7.09 ± 0.904 mg/L 20.43 ug/g

9 17 10 20

10 9 20

MPLa 20 ug/g (WHO) 20.9 mg/kg (WHO) 0.2 mg/L (WHO)

Withanachchi et al. (2018) Proshad et al. (2021)

75 ug/g (EU)

Perveen et al. (2017)

0.05 mg/L (WHO) 25 (WHO)

Maurya et al. (2019) Liu et al. (2020)

81 mg/kg (WHO) 5 g/L (WHO) 0.5 mg/L (WHO)

Withanachchi et al. (2018) Islam et al. (2015) Proshad et al. (2021)

50 g/L (WHO) –

Islam et al. (2015) Liu et al. (2020)

0.04 mg/L (WHO)

Proshad et al. (2021)

0.05 mg/L (CCME) 0.01 mg/l (ISIRI)

Adeyeye et al. (2020) Radfard et al. (2019)

References Liu et al. (2020)

MPL Maximum permissible limit

a

2.6 Heavy Metals Removal Technologies Toxic substances have been removed from water using a variety of methods. Chemisorption, ozonation, and electrical reduction are examples of traditional methods with several drawbacks like partial removal, high energy demands, and the creation of excess construction, administration, and upkeep, which might lead to an insufficient deployment of these innovations, especially in decentralized settings and third world countries.

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Fig. 2.3  Represents all the conventional and non-conventional methods used to remove heavy metals from polluted water

As a result, the need to implement better and ecologically friendly alternatives, such as polymer-based absorption methods, physiological ways, or nanoscale strategies (Bethke et  al. 2018; Lee et  al. 2019; Wani et  al. 2020; Tavker et  al. 2021) (Fig. 2.3).

2.7 Heavy Metals Removal from Water There are three types of wastewater management processes. The method used in the first treatment is to remove organic debris and dissolved materials from sewage water. Nanofiltration, biochemical filtration, aggregation, and coalescence are the more significant fundamental procedures in handling toxic metals (Yenkie 2019). The second process (anaerobic or aerobic) depends on natural microbes that transform organic and inorganic pollutants into more straightforward and safer compounds allowing greater extraction efficiency. The efficiency of microbes in removing metals is still being researched, although preliminary findings revealed a high clearance percentage. The oxidation process, electrochemical precipitate, crystallization, evaporation, photocatalytic degradation, adsorption, barrier technologies, and ion exchange technique are examples of the third treatment. More than 90% of elimination efficiency can be obtained when the third method is combined with the first and second methods (Hopkins et al. 2001).

2.8 Conventional Methods 1. Chemical precipitation Chemical precipitation is mainly regarded as an effective method to eliminate toxic metals, generally from textile businesses and electroplating enterprises.

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2.

3.

4.

5.

41

During this method, chemical precipitants like lime, salt, Fe, alum, and a few other polymers react with heavy metals present in sewage water, giving rise to insoluble precipitates (Verma and Balomajumder 2020). Coagulation/flocculation It is a scientific approach to eliminating quite effective contaminants, small particulates, and colloid clumps together to form bigger particles, reducing turbulence, and other discharged contaminants. Coagulation applied to water induces the coalescence of suspended particles into tiny clumps, termed flocculation. In the primary stage Ferric sulfate Poly aluminum chloride, aluminum sulfate, polymeric ferric sulfate, and polyacrylamide are the most commonly used coagulation factors (Pang et  al. 2009; Hargreaves et  al. 2018). The flocs agglomeration with mild staring is included in the second phase, settled down, and dumped off as sludge. This procedure’s flexibility is employed as pre, post, or primary sewage methods (Hopkins et al. 2001). Ion exchange This method involves interacting or sharing ions between the mobile and immobile phases. More precisely, an insoluble material that eliminates ions from electrolytic solution and gives away ions of the same charge in equal chemical percentages (Kurniawan et al. 2006). Synthetic organic resins are the most used materials (Ahmad and Sharma 2019) and synthetic inorganic tri-matrices (Bashir et al. 2019). Membrane technologies Membrane technologies refer to the action of a membrane as a partition that permits some chemicals to flow along while preventing others from doing so. The exclusion measurement, steric retardation process, the Donnan charge to charge repulsive forces, and the adsorption potential of specific contaminants all play their part in this technique's management (Abdullah et al. 2019). Suspended ordinary solids and natural contaminants are eliminated by this treatment (Gunatilake 2015). Generally, the membranes are categorized as natural (made of a natural-synthetic polymer such as cellulose acetate and polyethylene) or ordinary (made with inorganic material including metals, zeolites, silica, or ceramic materials) depending upon the reactant material used in the process of making them (Ezugbe and Rathilal 2020). Electrochemical technologies This is an influential process to eliminate metal ions from freshwater reservoirs. It is based on metals restoring to their basic state (Fu and Wang 2011) by utilizing electrochemical cells for anode and cathode ways reactions (Vardhan et al. 2019). In addition, it contains electric storage, electric coagulation, or electric flotation (Maarof et al. 2017).

2.9 Non-Conventional Methods 1. Adsorption It is thought to be the most delicate process to reduce water pollutants, like toxic metals. when counting the benefits of an elevated elimination potential

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level at a relatively minor amount of energy wastage, systematic needs for process, and the probability of avoiding higher secondary contamination (Burakov et  al. 2018). There are several characteristics that absorbents must possess, including a high surface-to-volume ratio, solid mechanical stability, and excellent thermal conductivity. Endurance, stabilized physiology, and functioning of life processes in a sound and sustainable atmosphere. Good adsorption potential and capability, picking, affordability, and reusing ability should all translate into high performance. Some of the most utilized adsorbents involve activated carbon, polymer compounds, biomaterials, magnetic materials, and agro-industrial wastes. 2. Microbial fuel cells Microbial fuel cells (MFCs) are regarded as the best techniques in which electricity is generated using organic matter in sewage water with the help of biocatalysts like microbes. In this technique, the biocatalyst gives rise to positive and negative ions in the anode cell (anaerobic). The positive ion is sent via a positive ion exchange membrane. On the other hand, the negative ions are sent via the outer circuit to the cathode cell (aerobic). Because they employ biocatalysts like bacteria to make power from organic materials found in wastewater, MFCs are a promising technological advancement. In MFCs, the bacteria create electrons and protons on the anode cell (which is anaerobic), which then transmits the electrons through an external circuit and the protons through a proton exchange membrane to the cathode cell (aerobic). Oxygen closes the loop at the cathode and drops to water due to its large reduction potential (Jayakumar et al. 2020; Vélez-Pérez et  al. 2020). Additionally, harmful metals may be immediately removed and received in the cathode compartments using MFCS, although they have a greater reduction potential than anode electrodes (Bagchi and Behera 2020). MFCs have also been used in rivers for in situ cleanups; results indicate 97.3% Hg2+, 87.7% Cu2+, and 98.5% Agl+ reductions after 2 months of processing. Additionally, MFCs increased the rate of inorganic material's biodegradation, produced electricity, and offered a different way to effectively remove heavy metals pollution and simultaneously recover bioenergy (Wu et al. 2020).

2.10 Nanotechnology Nanotechnology refers to nanoparticles that have attracted substantial interest recently due to their elevated ground ratios and superior electrical, visual, and magnetic capabilities, which are used in nanotech solutions (Gehrke et  al. 2015; Upadhyay et al. 2020). Microfiltration is among the most widely utilized nanotechnology procedures to remove heavy metals. Chemisorption structures, usually on alumina nanoparticles, are incredibly efficient at eliminating soluble toxic metals. Reduced structures such as nanocarbon, solitary or multiple metal oxides, magnetic nanoparticles, non-metals oxides, and elimination, metals oxides, magnetic nanoparticles, and elimination (Kang et al. 2019; Borji et al. 2020; Vázquez-Núñez et  al. 2020). Each of these nanoparticles possesses huge surface expanses and is

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chemically active, and many of these are available in nature or can be made cheaply. In sewage treatment, micro, nanoplates, nanoparticles with graphene, and hierarchy ZnO nano-rods have all been employed. However, understanding is deficient regarding the toxicological, atmospheric, and adverse hazards of nanoparticles, which limits their maximum potential (Wołowiec et  al. 2019). The toxicological, atmospheric, and adverse hazards of nanoparticles, which limits their maximum potential (Wołowiec et al. 2019).

2.11 Phytoremediation of Heavy Metals Phytoremediation is among the most extensively employed approaches for removing pollutants from ecologies or surroundings. To reduce the damaging impact of contaminants, it utilizes genetically altered species of plants (Schück and Greger 2020). To rectify polluted ecologies, plants are cultivated, and merged with other living organisms such as algae, biofilms, fungi, bacteria, and plants. Exterior procedures suggest thermal, biological electronic, or physiological input processes containing green manure, macro-micro nutrients, essential minerals, fertilizers, foliar, nanomaterials, natural polymers, sandy clay, water, ventilation, etc. (Zubair et al. 2016; Ojuederie and Babalola 2017; Haldar and Ghosh 2020). To increase this technology’s productivity and fix its current flaws, several new supplemental systems and procedures are being created. On the other hand, Phytoremediation effectiveness is influenced by logistics infrastructures, time, and expenses, about technological considerations.

2.12 Biological Approach by Using Diatoms Toxic metal bioremediation involves two simple steps: biosorption of the toxic metal to several metal-binding agents on the cell surface and then progress to bioaccumulation. This process occurs outside of the cell and the cell's machinery, including the ordinary molecules and related enzymes (Diep et al. 2018). Bioaccumulation happens more quickly in which most heavy metals are bonded to the surface. Certain metal ions are transported into the body and utilized for medicinal ISM purposes depending on the metal needed for intracellular metabolic processes. Regarding the effects of various metal ions on diatom algae and their cell- and molecular-level reactions to metal toxicity, diatom algae are one of the most researched species (Table 2.2). However, when contrasted to green and blue, green algae. There is a shortage of studies on diatoms for heavy metal removal (Chugh et  al. 2022). The assimilation of toxic substances into the outer membrane was caused by a succession of events in the proposed action. 1. Detoxification of metal ions at the extracellular level via comparison by both extracellular polysaccharides and phyto-chelates.

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2. The input of toxic substances into the cell is regulated by power and floods. The system at the outer membrane controls their entry through an intensity mechanism in which external metallic, ionic strength regulates intracellular ingestion. 3. Enzymatic activity additionally modifies internal metallic ions by modifying the oxidation state. Heavy metals are more easily exploited for sale when vaporized into a volatile molecule. Metal ion exposure to sensitive intracellular reaction sites is reduced when methylated metals. 4. Binding compounds, particularly polyphosphates and polychaetes, transport metal ions intracellularly, further deactivating metal toxicity. 5. The metals and ligands combination attaches to the cellular membranes and organelles. 6. Organelles such as mitochondria use toxic metals for a variety of metabolic functions. Diatoms control their enzymatic actions, letting them detoxify the metals by dehydrogenation and nitrogen denitrification (Xiong et  al. 2018; Kumar et al. 2015).

2.13 Endophytes Isolation and Characterization Hyperaccumulators of heavy metals especially those found in polluted environments are plant species that can take far more metal compounds than other plants. Endophytic microorganisms inhabit the interior tissues of hyperaccumulators and create a variety of symbiotic, mutualistic, and trophobiotic partnerships with the host plant without producing illness. Exploitation of hyperaccumulating endophytic microorganisms as a bioremediation method for heavy metals. Plants sustain the microbial population in such a plant–bacteria combination, and microbes boost plant development and pollutant detoxification in return. As a result, when compared to other microorganisms, these hyperaccumulator endophytes have better heavy metal tolerance and accumulating ability (Jan et al. 2019). Endophytes from extensively polluted locations contaminated with radionuclides and other hazardous heavy metals might be valuable bioresources for heavy metal decontamination. Endophytic microorganisms can be used as an efficient bioremediation technique. Previously, a bacterium strain was isolated from the root of the Solanum nigrum L. (Cd hyperaccumulator) capable of binding Cd and Zn effectively in both singleand multi-ion systems in its developing microbial cells (Luo et al. 2010). Inoculating S. nigrum L. with an endophyte isolated from its host plant (Pseudomonas sp. Lk9), boosted phytoextraction rates of all metals from multi-metal polluted soils (17.4%, 48.6%, and 104.6%, respectively) (Chen et al. 2014). About 14 bacterial endophytes were isolated from Alnus firma roots and tested for Pb tolerance, with Bacillus sp. being identified as isolate MN3–4 (Shin et al. 2011). Bacillus MN3–4 might also create siderophores and indoleacetic acid, which could change the form of lead in soils or enhance plant Pb accumulation. Endophytes that promote plant development Plant growth-promoting endophytes (PGPE), which have been discovered as valuable bioresources in phytoremediation, increase plant growth and heavy metal absorption through a variety of processes

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(Ma et  al. 2015). Four Cd-resistant endophytic strains aided their hosts' toxicity stress responses. They generated indole-3-acetic acid (IAA), phosphate solubilizing activity, 1-aminocyclopropane-1-carboxylic deaminase, and siderophores, all of which have been recognized as plant growth promoters (Sarkar et  al. 2018). To boost phytoremediation efficacy, several heavy metal-resistant (Cd, Zn, Pb, and Cu) PGPE from root nodules of Robinia pseudoacacia in a mining region were chosen. The symbiotic bacteria Mesorhizobium loti HZ76 and Agrobacterium radiobacter HZ6 have the best heavy metal resistance and PGP characteristics (Fan et al. 2018). Endophytic fungi have been studied for their stress-relieving properties in addition to bacteria. Penicillium funiculosum LHL06, isolated from soybean roots, may aid in the modulation of molecular, physio-chemical, and proteomic responses to various heavy metal toxicities (Ni, Cu, Pb, Cr, and Al). In comparison to non-fungi-­ inoculated plants, fungus LHL06 can upregulate Gibberellins, IAA biosynthesis, and downregulate heavy metal ATPase genes in its host plants.

2.14 Uses of Endophytic Microbes in Real Contaminants Three different endophytic bacteria were used as bioaugmentation in a plant–bacterial system with constructed wetlands (CWs) for the efficient treatment of tannery effluent (Ashraf et al. 2018). The outcomes showed that the removal of heavy metals (Cr, Fe, Mn, Ni, Pb, Ba, Cd, and Co) from wastewater by plants and endophytes was superior to that of plants alone, as indicated in Table 2.1. The study's key finding was the use of the Cr-resistant endophytes Prosopis juliflora (bacteria from another plant) with the salt-tolerant plant Leptochloa fusca for the treatment of tannery effluent. Another vertical flow constructed wetlands system at pilot size was employed for a year to handle dye-rich textile effluent. Significant heavy metal removal was achieved by endophyte-assisted constructed wetlands (CWs) (Cr 97%, Fe 89%, Ni 88%, and Cd 72%), as well as decreases in chemical and biochemical oxygen demands, color (74%), nitrogen (84%), and phosphorus (79%) (Hussain et al. 2018). Future field-scale and time-efficient bioremediation of actual industrial wastewater comprising organic and inorganic contaminants may employ the aforementioned study's findings. An endophyte-assisted phytoremediation experiment was performed using plants infected with various consortia in a metal-contaminated mine soil (Burges et al. 2016). By increasing the amount of chlorophyll and carotenoids in the plants, endophyte inoculation enhanced their physiological condition. Additionally, plant growth-promoting bacteria (PGB) properties including increased levels of acid phosphatase activity and microbial community variety were mirrored in the favorable effects of plant growth and endophyte inoculation on soil parameters. Through endophyte inoculation, the microecosystems of the rhizosphere and endosphere were affected, increasing the phytoremediation of vanadium-­ contaminated soil.

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2.15 Future Predictions Legislation and requirements worldwide are growing through quantitative, analytical, and phenomenology research (Shoushtarian and Negahban-Azar 2020). Organizations with low financial inclusion ability without complete technology, infrastructure, social, and human potential have had to build their legislation regarding international legislation, randomly adopting, or adjusting various criteria. Implementing and administering those guidelines, which are sometimes unrelated to the geological, environmental, ecosystem, and socio-economic realities of the country or region where legislations are developed might cause serious health concerns. In this framework, laws, legislation, guidelines, industry standards, and methods for monitoring and controlling the number of toxic metal pollutants in the air and mitigating their negative consequences broadly are critical. Among other things, this efficient model should: • When considering the specific aspects of the human basis, these metals add to the elimination of the number of toxic contaminants produced. • They encourage the employment of methodologies and techniques that allow for precise and straightforward investigation and monitoring of pollutants, attention in various ecosystems, ideally in situ. • Encouraging water restoration and cleanup materials and processors that are both echo sound and premium.

2.16 Conclusion Water resource control and safety from harmful chemical contamination due to anthropogenic actions are paramount to scientists, administration and non-­ administration communities, and the general public. Facts from the literature analyzed have typically shown the usefulness in remediating heavy metals from various sources. Heavy metals from water reservoirs are continuously practiced. However, the reduction speeds are mixed and primarily governed by the physicochemical possessions of the water, pollutants, plant, and the practical framework. Despite the reasonable efforts so far, there are still restrictions in particular areas restricting the damage provoked by heavy metals.

References Abdullah N, Yusof N, Lau W et  al (2019) Recent trends of heavy metal removal from water/ wastewater by membrane technologies. J Ind Engg Chem 76:17–38. https://doi.org/10.1016/j. jiec.2019.03.029 Adeyeye O, Xiao C, Zhang Z et al (2020) State, source and triggering mechanism of iron and manganese pollution in groundwater of Changchun, Northeastern China. Environ Monit Assess 192:1–15. https://doi.org/10.1007/s10661-­020-­08571-­0

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Cement Dust Pollution and Environment Abdulmajeed Bashir Mlitan

3.1 Introduction The environment of an organism includes air, water, and soil. It is considered polluted when there is an imbalance in the natural composition (Mlitan et al. 2013). Air pollution has the rapid growth of the ecosystems such as thermal power stations, steel and coal industries, steel and iron industries, automobile fuels, and cement factories. Many types of air pollutants do not stay in the air but are deposited on soil or water and this precipitation will cover plants, microorganisms, animals, and humans. This results in environmental pollution, which has become a serious problem that has warranted careful attention in the world. Environmental pollutants are substances that cause harmful environmental changes in addition to those related to natural background variation. A wide range of industries emits chemicals into the environment that can be harmful to humans, plants, animals, other organisms, air, water, and soil (Ade-Ademilua and Obalola 2008). Some substances can be toxic even at very low concentrations (Pandey and Pandey 2008), particularly to plants (Wolf 1986), or to humans (Mlitan 2010). As rehearses know, major pollutants include nitrogen dioxide, sulfur dioxide, oxides of carbon and volatile organic compounds, hydrogen sulfide, and cement dust. These pollutants are harmful to organisms, including humans, and cause environmental problems such as global warming and acid rain (Anwer and Maaz 2021). An important source of environmental imbalances is the cement industry, which plays a significant role in these imbalances, particularly through air pollution (El-Soul et  al. 2019). According to the Indian Central Pollution Control Board, the cement industry is one of the 17 most polluting industries (Subramanian et al. 2011). Cement is the main component that A. B. Mlitan (*) Department of Environmental Sciences, Faculty of Environmental Sciences and Natural Resource Development, University of Misurata, Misrata, Libya e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 M. I. Ahmad et al. (eds.), Toxicology and Human Health, https://doi.org/10.1007/978-981-99-2193-5_3

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goes into building construction in most countries. The term “cement” is used for “powdered materials which have strong adhesive qualities when combined with water.” It is used to bond other materials together and especially as a binder in concrete. The first modern Portland cement was manufactured in 1800. There are many kinds of cement, with different compositions and uses (Mindess et al. 2002). Cement products pass through different steps. The manufacturing process involves quarrying, mixing, grinding, burning, and milling. Cement is a heterogeneous substance whose constituents vary among locations and with time (Bechu and Ambasht 1980). Ghosh (2002) and El-Soul et al. (2019) listed Portland cement contents as oxides of calcium, silicon, aluminum, iron(III), magnesium, potassium, sodium, and sulfur, together with calcium carbonate, carbon dioxide, and water; the percentages for them were reported to be 44.4, 14.3, 3.0, 0.59, 0.52, 0.13, 0.07, and 79.3, respectively. Similarly, an investigation of the chemical composition of cement kiln dust using X-ray analysis showed that oxides of aluminum, silicon, calcium, iron (III), potassium, magnesium, sodium, and titanium were major chemical constituents (El-Awady and Sami 1997). Other analysis using X-ray diffraction found that cement dust consisted of “mainly of calcium hydroxide, calcium carbonate, calcium di-silicate, sodium chloride, potassium chloride, and quartz” (El Sherbiny et  al. 2004). Cement factory gases such as nitrogen oxides, carbon monoxide, and sulfur dioxide have been discovered in cement plants and polluted air (Mehraj et al. 2013; Rovira et al. 2011; Zhao et al. 2017). Table 3.1 outlines cement composition.

3.2 Chapter Aims In view of the rising emissions of dust, metals, and gases from cement plants into the environment, this chapter aims to investigate how cement dust affects soil, air, and water and their living and nonliving constituents.

Table 3.1  The chemical components of cement grain (reproduced from Mlitan 2010) Cement compound Tricalcium silicate Dicalcium silicate Tricalcium aluminate Tetracalcium aluminoferrite Gypsum Magnesium oxide Calcium oxide

Shorthand notation C3S C2S C3A C4AF CSH2 MgO CaO

Chemical formula Ca3SiO5 or 3CaO.SiO2 Ca2SiO4 or 2CaO.SiO2 Ca3Al2O6 or 3CaO.Al2O3 Ca4Al2Fe2O10 or 4CaO.Al2O3.Fe2O3 CaSO4.2H2O MgO CaO

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3.3 Influence of Cement Dust on the Characteristics and Population of the Environment The increasing global population has led to increasing demand for cement (Adeniran et al. 2018) and an increase in the construction of cement factories (Arfala et al. 2018; Shen et al. 2017; Ogunbileje et al. 2013). In Nigeria, for example, cement production increased from 2.4 million tonnes in 2004 to 23 million tonnes in 2014 (Anyakwu and Yunisa 2019). How cement dust influences the environment is a large topic; therefore, the discussion here will concentrate on its effects on air and water. However, additional data will be shown concerning its effects on soil, both characteristics and population, because the dust lands on the soil after it is emitted from the factories. The cement industry has been a priority for industries with a negative nature on the environment organizations dealing with the environment (Qadar et al. 2017). Notably, air pollution from cement plants has led to complaints from local residents (Mlitan, 2010; Kim et al. 2015; Lee et al. 2016; El-Soul et al. 2019).

3.3.1 Cement Dust Pollution and Atmosphere It has been estimated that air pollution causes the deaths of 7 million people every year. The effects have been particularly serious in Asia and Africa (Adeyanju and Okeke 2019). According to the Indian Central Pollution Control Board, there are 17 categories of major polluting industries. Raw materials, fuel, and chemical additives are the most required to produce cement, and these decrease environmental quality. Cement factory emissions include gases such as carbon dioxide, methane, and nitrous oxide as well as particulates (Rosyid et al. 2020). Cement plants are categorized as sources of pollution for their possible influence on the atmosphere (Hindy et al. 1990). Cement factories emit a large number of pollutants as well as consume energy and natural resources (Konstantin and Metin 2002). An example is Egypt, where the annual release of cement dust into the air is approximately 2.4 million tons. The problems that the dust causes are related to the small size (1–10 μm) and high pH (11.5) of the particles (El Haggar 2005). Production of cement has been recognized as the biggest source of Particulate Matter Emissions (Francisco et al. 2015; Hua et al. 2016). A number of studies have shown the toxic effects that cement dust has on the environment (Takatsuka 1978). In Libya, a cement factory emitted a large amount of dust and this absolutely polluted air and precipitated on the soil (Fig. 3.1). In Egypt, when a cement plant chimney emits dust, also it throws out manganese, cobalt, nickel, zinc, iron, and cadmium (Hindy et al. 1990). Different oxides and sulfur compounds are emitted during cement manufacturing with cement dust in Egypt (Bagy 1992). The cement industry emits a large amount of carbon dioxide (Adeyanju and Okeke 2019). Cement manufacturing and the iron and steel industry are sources of mercury. These industries emit this element from the combustion of fossil fuels in Japan (Fukuzaki et al. 1986). Cement manufacturing plants in Pakistan emitted potentially toxic substances such as fluoride, several metal elements, and acids (Iqbal and Shafig 2001).

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Fig. 3.1  Cement dust polluted air (photographed by the writer—cement factory in Libya)

Compared to higher organisms, bacteria and fungi can respond quickly to environmental stress, because of their close relations with their surroundings (Kara and Bolat 2007). There are several known morphological and physiological effects of air pollution on microorganisms, including subtly altered or radically transformed properties. In fungi, these include changes in pigmentation and suppression of aerial hyphae, sporulation, spore germination, and formation of fruiting bodies (Babich 1974). These changes are related to the gases and dust emitted from different factories including cement plants (Mlitan 2000). In a study investigating fungal populations in the air near a cement plant in Egypt, Aspergillus niger and Cladosporium herbarum were the most tolerant fungi in this air contaminated by cement, whereas Aspergillus flavus was sensitive to this pollution (Abdel-Rahman et al. 1989). The authors suggested that A. flavus should be used as a biological index for the removal of metals from the contaminated area. In similar work, Mlitan et al. (2013) isolated fungi from the area around a cement factory and other factories in Libya. They stated that the cement factory probably disturbed airborne fungi. Alternaria and Aspergillus were the most fungi isolated from the air of cement factories in Libya (Mlitan 2000). Results from laboratory investigations have shown that air pollution could affect microbial interactions in different ways (Babich 1974). For example, sulfur trioxide which comes from cement can lead to the emission of sulfur dioxide, which is toxic to the spores of Botrytis cinerea and Alternaria species (Couey 1965). Also, sulfur dioxide is generated from exhaust gases in the production of cement. It is considered one of the

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most toxic compounds to fungi (Saunders 2007). Several activities of bacteria, fungi, algae, and lichens are influenced by sulfur dioxide; lichens are extremely sensitive to this gas (Babich 1974). This may be because sulfur dioxide dissolves readily in water, and easily exists in different ionic forms depending on the pH of the solution (Frankland et al. 1994). On the other hand, numerous researchers have described stimulation or inhibition of microbial activity after exposure to different air pollutants (Babich 1974).

3.3.2 Cement Dust Pollution and Water Cement dust affects water in indirect ways through biogeochemical cycling and directly when it contacts them (Mishra 1990). It should be noted that one of the main causes of water contamination is water conduit contamination, as water may leach cement paste. The outcomes of this pollution are increases in the pH and calcium carbonate content of water. Cement contact with water increased its pH to 10 or more (Douglas et al. 1996). Water plays a very important role in cement concrete, the cement pH changes as a result of interactions with surrounding rock, particularly carbonate forms found in cement (Akomah and Jackson 2020). The European Union is attempting to address this problem (Neville 2001). The leaching of trace elements from cement increased when water was chlorinated. Prolonged exposure led to a large relative increase in Zn (217%), and smaller increases in boron (19%), and gallium (12%), whereas increases for other tested elements, were less than 10% (Sowski et al. 2019). Cement constituents such as aluminum, cadmium, and chromium can leach from cement mortars in soft water for at least 2 years (Conroy et al. 1993). Some cement plants use high-alumina cement instead of Portland cement. This increases the aluminum concentration in water (Conroy 1991). 0.2 mgl-1 aluminum could be leached from high-alumina cement and be present in water for up to 8 weeks. In addition, long-term water contamination by high-alumina cement can cause its pH to stay above 9.5 for several years. A major concern in cement application is chromium toxicity. Hexavalent chromium can leach from concrete structures, leading to the contamination of groundwater (Potgieter et al. 2003). El Ghandour et al. (1983) reported that large amounts of water-soluble and insoluble substances such as calcium carbonate are emitted from cement plants. Water samples collected from cement plant areas exhibit poor water quality of water associated with elevated levels of electrical conductivity, turbidity due to sulfate, total hardness, and calcium. Lamare and Singh (2016) found that in Meghalaya, India, water quality was lower near cement plants than near where limestone for cement production was mined.

3.3.3 Cement Dust Pollution and Soil It is important to monitor the contamination of soil by pollutants, including cement dust, because they may adversely affect crop production and leach into groundwater. Contamination by cement dust can change the physicochemical properties of

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soil, particularly by increasing pH and total calcium content (Saralabai and Vivekanandan 1995). The uptake of metal ions from cement by soil and then plants affect biological functions (Mlitan 2010). Cement dust changes soil physically and chemically (Al-Faifi and El-Shabasy 2021). Soil properties (clay minerals, organic matter, pH, temperature, redox potential, and interrelationships between heavy metals) can influence how soil microorganisms interact with heavy metals (Wainwright 1999). When cement dust contacts the soil surface, reactions involving its metal ions alter the properties of the soil (Ibanga et al. 2008). The high carbonate content makes cement dust highly alkaline, which raises soil pH. Treatment with cement raw materials also affects water content and electrical conductivity (Khan and Khan 1996). Around cement plants in Meghalaya, India, soil electrical conductivity and bulk density were higher, and water holding capacity, soil moisture content, organic carbon, and total nitrogen content were lower than at control sites (Lamare and Singh 2020). The industrial revolution resulted in soil pollution which has accelerated dramatically. The influences of metal contamination, including heavy metals, on soil microbial communities have been the center of attention of several studies over the last decades. In general, metallic elements in soil may be found in silicate minerals, as free ions in various forms, and in or as insoluble compounds (Leyval et al. 1997). Utgikar et al. (2003) mentioned that the values of the metals are generally higher at the depths as recorded in their result and this may be attributed to no production activities in the cement factory over a long period and hence factors such as surface run-off, leaching, sedimentation, and bioaccumulation of these metals by some plants come into play thereby making them less available on the topsoil. As several metals are found in cement and it is a chemical substance with distinct physical characteristics, it is considered to be one of the many pollution sources that can affect soil properties in general. Minerals, dead organic matter, air, water, and living organisms are the main components of the soil environment (Biyik et  al. 2005). These contents can change their characteristics as a result of any stress. Soil ecosystems are changing at unprecedented rates, linked to global climate change (Ali 2008) or directly to human activities. Cement dust is very dusty. This dust can influence soil characteristics. It can readily cover the soil surface, especially in wet weather, and then the deposits on the surface will leach into deeper horizons. An investigation of the properties of soil exposed to cement dust was carried out in Nigeria by Khan and Khan (1996), who found that there was a strong effect on soil such as some physiochemical parameters. Nigeria, 21 elements have been determined from soil contaminated by cement. Calcium, potassium, sulfur, chromium, nickel, copper, and zinc were the most abundant in these samples of soil (Asubiojo et al. 1991). The pH was found to be higher in soil contaminated by cement than in control samples (Hasenekoglu and Sulun 1991; Hemida 2005). In a study in Libya, soil samples were collected around the Alhewary cement factory in Benghazi. Again, the main changes in soil properties were increases in total calcium content and soil pH. Concentrations of sodium and lead were also high compared to unpolluted soil (Mlitan et al. 2018).

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Ade-Ademilua and Obalola (2008) investigated how cement dust pollution affected Celosia argentea (Lagos spinach). They found significant amounts of iron, calcium, magnesium, aluminum, silicon, and sulfur in Lagos spinach leaves and soil contaminated by cement dust. Mercury emitted into the atmosphere from a cement factory can be recognized in humus and surface soil around the cement plant. High rates of calcium carbonates and soil high pH were found in an area (Alkomos Libya) exposed to cement dust compared to sites far from pollution (Mlitan et al. 2018). This decreased as the distance from the cement plant increased. Accumulation of cement dust over a number of years led to the formation of a layer of cement that kept water on the surface (Mlitan et al. 2018). The calcium content in soil from polluted areas near a cement factory was significantly greater (P  sulfur dioxide > ammonia, and stated that cement dust is the most effective factor against Alternaria solani. However, this area (exposed to cement dust) studied had higher fungal and bacterial populations in comparison with the control. The authors suggested that the direct influence on Alternaria solani was affected by large numbers of saprophytes and A. solani was found less in the site containing higher numbers of other fungi and bacteria (cement dust site). Similarly, the incidence and severity of leaf spot disease in rice decreased because of cement dust contamination (Singh and Rai 1990). On the other hand, more fungal leaf spots were found in grape leaves with moderate cement dust deposits compared to the control. Cement kiln dust has been

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found to increase leaf spot disease caused by Cercospora beticola in sugar beet leaves (Rai 1987). In addition, the numbers of bacteria and fungi but not kinds greatly increased compared to leaves without cement dust (Manning 1971). Many fungi synthesize melanins, dark brown or black pigments with a high molecular mass (Vidal-Cros et al. 1994). Some mutants cannot synthesize melanin. Melanins can absorb metal ions and are important for reducing levels of toxic metal ions outside fungal cells, improving growth in the presence of such ions. There have been not enough published reports on the effects of cement dust on fungal pigmentation. Mlitan (2010) mentioned that the fungal pigment has been changed. However, the effects of different cement constituents have been individually investigated by his research. He stated that in conclusion, cement components do not completely explain the complex effects of cement on fungal growth, but the evidence indicates that calcium, silicate, and copper together with pH are probably significant contributors. In addition, however, at the highest cement concentrations, morphological differences appeared in some species. In general, it was observed that as cement concentration increased, significant modifications in color (from yellow-green to white) and texture (from cottony to hairy) of the mycelia occurred, mainly in Aspergillus nidulans wild type 00, and in strain G0248 the color changed from white to yellow to green at almost all cement concentrations. Moreover, the morphology of Aspergillus nidulans wild type 00 was more affected than that of strain G0248. The appearance of the mycelia of the latter at all concentrations was close to that of the control for the wild type. The involvement of constituents of cement in these effects, in particular, calcium, silicon, and aluminum, was investigated using Aspergillus nidulans (model fungus) and Aspergillus niger¸ which is more resistant to cement dust than A. nidulans. Calcium chloride at concentrations up to approximately 1 gl−1 stimulated growth and calcium silicate at concentrations above approximately 5 gl−1 inhibited growth and spore formation. Aluminum oxide had relatively little effect on the growth and number of spores. The copper concentration did not individually affect the growth of Aspergillus nidulans wild type 00, but these concentrations, combined with calcium silicate, inhibited growth and spore formation. Significant modifications in color were produced but no clear changes in the texture of the mycelia. In general, contaminated air can affect microbial pigmentation. For example, the pigmentation of the bacterium Serratia marcescens increased when it was exposed to nitrogen dioxide (Babich 1974). Pigments of Fusarium solani were also inhibited by metals examined (lead, copper, and cadmium) (Kowshik and Nazareth 2000). Penicillium expansum spores were changed to white from their original color when exposed to 1–2 mg l−1 O3 (Babich 1974). There was a link between resistance to higher concentrations of metals (lead, copper, and cadmium) by fungi and the production of pigment (Nazareth and Marbaniang 2008).

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3.4 Conclusion In conclusion, infrastructure for housing, industry, and recreational projects is essential for human and economic development and depends on cement. The physicochemical properties of soils in the most polluted areas indicate a strong effect of cement dust that settles on the soil around cement factories. Therefore, a balance is needed to allow legitimate developments without compromising environmental sustainability. Almost all researchers have improved knowledge of how the environment deals with cement dust as a pollutant and the factors that influence the growth of all organisms and microorganisms under cement stress. It has provided information about conditions necessary for microbiological experiments with cement. In general, the results of most experiments related to the fieldwork seemed to correlate well with the experimental results from laboratory studies of the effects of cement in relation to low diversity and absence of some microorganisms species which were inhibited by high cement concentrations added to the growth medium. In general, environments and their living and nonliving contents were suffering and changing from continuing cement dust pollution. Acknowledgments  My sincere special deepest gratitude thanks to my parents, my wife (Enas), and my children (Fatima, Maria, Sereen, Rahaf, Hala, and Ahmed) for their support and help during this writing and I would never have been as successful without their efforts. Also, My Thanks to Dr. Hack from the University of Newcastle upon Tyne for all his efforts regarding this chapter.

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Hindy K, AbdelShafy H, Farag S (1990) The role of the cement industry in the contamination of air, water, soil and plant with vanadium in Cairo. Environ Pollut 66:195–205. https://doi. org/10.1016/0269-­7491(90)90001-­s Hua S, Hezhong T, Kun W et al (2016) Atmospheric emission inventory of hazardous air pollutants from China’s cement plants: temporal trends, spatial variation characteristics and scenario projections. Atmos Environ 128:1–9. https://doi.org/10.1016/j.atmosenv.2015.12.056 Ibanga IJ, Umoh N, Iren O (2008) Effects of cement dust on soil chemical properties in the Calabar environment, southeastern Nigeria. Commun Soil Sci Plant Anal 39:551–558. https://doi. org/10.1080/00103620701826829 Iqbal M, Shafig M (2001) Periodical effect of cement dust pollution on the growth of some plant species. Turk J Botany 25:19–24. https://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1. 1.868.2907&rep=rep1&type=pdf Kamaludin NH, Jalaludin J, Mohd Tamrin SB et al (2020) Exposure to silica, arsenic, and chromium (VI) in cement workers: a probability health risk assessment. Aerosol Air Qual Res 20:2347–2370. https://doi.org/10.4209/aaqr.2019.12.0656 Kamran SN, Wenchun M, Gulshan A et al (2020) Chronic cement dust load induce novel damages in foliage and buds of Malus domestica. Sci Rep 10:12186. https://doi.org/10.1038/ s41598-­020-­68902-­6 Kara O, Bolat I (2007) Impact of alkaline dust pollution on soil microbial biomass carbon. Turk J Agr Forest 31:181–187. https://hdl.handle.net/20.500.12628/711 Khan M, Khan M (1996) The effect of fly ash on plant growth and yield of tomato. Environ Pollut 92:105–111. https://doi.org/10.1016/0269-­7491(95)00098-­4 Khrbish Y, Abugassa I, Benfaid N et  al (2007) Instrumental neutron activation analysis for the elemental analysis of cement. J Radioanal Nucl Chem 271:63–69. https://doi.org/10.1007/ s10967-­007-­0107-­3 Kim SH, Lee CG, Song HS et al (2015) Ventilation impairment of residents around a cement plant. Ann Occup Environ Med 27:3. https://doi.org/10.1186/s40557-­014-­0048-­6 Konstantin S, Metin A (2002) High volume mineral additive for ECO-cement. Am Ceram Soc Bull 81:39 Kortesharju J, Savonen K, Saynatkari T (1990) Element contents of raw humus, forest moss and reindeer lichens around a cement works in northern Finland. Ann Bot Fenn 27:221–230. https:// www.jstor.org/stable/23725360 Kowshik M, Nazareth S (2000) Metal tolerance of Fusarium solani. Ecol Environ Conserv 6:391–395 Kumar S, Singh N, Kumar V et al (2008) Impact of dust emission on plant vegetation in the vicinity of cement plant. Environ Eng Manag J 7:31–35 Lamare R, Singh O (2016) Application of CCME water quality index in evaluating the water quality status in limestone mining area of Meghalaya, India. Ecoscan 10(1&2):149–154. https:// www.researchgate.net/publication/308801145 Lamare R, Singh O (2020) Effect of cement dust on soil physico-chemical properties around cement plants in Jaintia Hills, Meghalaya. Environ Eng Res 25(3):409–417. https://doi. org/10.4491/eer.2019.099 Lawgali MY (2002) Effects of cement dust on straw yield and ear yield of barley (Hordeum vulgare cv Wadi El-kouf) under controlled conditions. International Herbage Seed Group, Australia Lee HS, Lee CG, Kim DH et al (2016) Emphysema prevalence related air pollution caused by a cement plant. Ann Occup Environ Med 28:4–11. https://doi.org/10.1186/s40557-­016-­0101-­8 Leyval C, Turnau K, Haselwandter K (1997) Effect of heavy metal pollution on mycorrhizal colonization and function: physiological, ecological and applied aspects. Mycorrhiza 7:139–153. https://doi.org/10.1007/s005720050174 Liblik V, Pensa M, Ratsep A (2003) Air pollution zones and harmful pollution levels of alkaline dust for plants. Water Air Soil Pollut 3(5):199–209. https://doi.org/10.1023/A:1026061330172 Mandre M, Kloseiko J, Ots K et  al (1999) Changes in phytomass and nutrient partitioning in young conifers in extreme alkaline growth conditions. Environ Pollut 105:209–220. https://doi. org/10.1016/S0269-­7491(98)00220-­6

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Parthasarathy S, Arunachalam N, Natarajan K (1975) Effect of cement dust pollution on certain physical parameters of maize crop and soils. Indian J Environ Health 17:114–120. https://www. osti.gov/etdeweb/biblio/5195922 Pascal M, Pascal L, Bidondo ML et al (2013) A review of the epidemiological methods used to investigate the health impacts of air pollution around major industrial areas. J Environ Public Health 2013:737926. https://doi.org/10.1155/2013/737926 Phenrat T, Marhaba TF, Rachakornkij M (2005) A SEM and X-ray study for investigation of solidified/stabilized arsenic-iron hydroxide sludge. J Hazard Mater 118:185–195. https://doi. org/10.1016/j.jhazmat.2004.10.019 Potgieter S, Panichev N, Potgieter J et al (2003) Determination of hexavalent chromium in South African cements and cement-related materials with electrothermal atomic absorption spectrometry. Cem Concr Res 33:1589–1593. http://worldcat.org/issn/00088846 Prajapati SK, Pandey SK, Tripathi BD (2006) Monitoring of vehicles derived particulates using magnetic properties of leaves. Environ Monit Assess 120(1–3):169–175. https://link.springer. com/article/10.1007/s10661-­005-­9055-­y Prakash J, Mishra RM (2003) Effect of cement dust pollution on Calotropis procera species. Indian J Environ Prot 23(7):764–767 Prasad MSV, Inamdar JA (1990) Effect of cement kiln dust pollution on groundnut. Indian Bot Cont 7:159–162 Qadar H, Al-Talmati A, Mohammed A (2017) Assessment of gaseous pollutants in the city of Zliten from the Tower Cement Plant. Third Scientific Conference on Occupational Safety, Health and Environmental Protection (12–13 December 2017) Rai B (1987) Effects of air pollutants on incidence and severity of early blight of potato. Acta Bot Indica 15:221–224 Rai B, Pathak KK (1981) Studies on phylloplane microflora of potato in relation to air pollutants. Environ Pollut Series A: Ecol Biol 26:153–166 Ramesh V, Ahmed John S, Koperuncholan M (2014) Impact of cement industries dust on selective green plants: a case study in Ariyalur industrial zone. Int J Pharm Chem Biol Sci 4(1):152–158 Robert L (1956) Transformations of sulfur by microorganisms. Ind Eng Chem 48:1429–1437. https://doi.org/10.1021/ie51400a022 Rosyid A, Boedisantoso R, Iswara A (2020) Environmental impact studied using life cycle assessment on cement industry. IOP Conf Ser: Earth Environ Sci 506:012024. https://doi. org/10.1088/1755-­1315/506/1/012024 Rovira J, Mari M, Schuhmacher M et al (2011) Monitoring environmental pollutants in the vicinity of a cement plant: a temporal study. Arch Environ Contam Toxicol 60:372–384. https://doi. org/10.1007/s00244-­010-­9628-­9 Saha D, Padhy P (2011) Effects of stone crushing industry on Shorea robusta and Madhuca indica foliage in Lalpahari forest. Atmos Poll Res 2:463. https://doi.org/10.5094/APR.2011.053 Salama F, Alsol M, Mostfa S et al (1997) The effect of cement dust pollution on the plants life from the area between Alkomos and Misurata - Libya unpublished work, Nasser University-Libya. Nasser University, Misurata, p 5 Saralabai V, Vivekanandan M (1995) Effects of application of cement kiln-exhaust on selected soil physico-chemical and biological properties. Fertil Res 40(3):193–196. https://doi.org/10.1007/ bf00750465 Saric M, Kalacic I, Holetic A (1976) Follow up of ventilatory lung function in a group of cement workers. Br J Ind Med 33:18–24. https://doi.org/10.1136/oem.33.1.18 Saunders P (2007) Air pollution in relation to lichens and fungi. Lichenologist 4:337–349. https:// doi.org/10.1017/S0024282970000439 Senthil KP, Sobana K, Kavitha K et al (2015) A study on the effect of cement dust pollution on certain physical and biological parameters of Sessamum indicum plant. Asian J Plant Sci Res 5(1):1–3 Shah F, Ilahi I, Rashid A (1989) Effects of cement dust on the chlorophyll contents, stomatal clogging, and biomass of some selected plants. Pak J Sci Ind Res 32:542–545

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Shamssain M, Thompson J, Ogston S (1988) Effect of cement dust on lung function in Libyans. Ergonomics 31:1299–1303. https://doi.org/10.1080/00140138808966769 Shen W, Liu Y, Yan B et al (2017) Cement industry of China: driving force, environment, impact and sustainable development. Renew Sust Energ Rev 75:618–628. https://doi.org/10.1016/j. rser.2016.11.033 Shukla J, Pandey V, Singh SN et  al (1990) Effect of cement dust on the growth and yield of Brassica campestris. Environ Poll 66:81–88. https://doi.org/10.1016/0269-­7491(90)90200-­V Singh AK, Rai B (1990) Effect of cement dust treatment on some phylloplane fungi of wheat. Water Air Soil Poll 49:349–354 Singh SN, Rao DN (1980) Growth of wheat plants exposed to cement dust pollution. Water Air Soil Pollut 14:241–249. https://doi.org/10.1007/BF00291839 Sowski J, Kowalski D, Kowalska B et al (2019) Water quality changes in cement-lined water pipe networks. Appl Sci 9:1348. https://doi.org/10.3390/app9071348 Subramanian D, Sundaramoorthy P, Baskaran L et al (2011) Cement dust pollution on growth and yield attributes of ground nut (Arachis hypogaea L.). Int Multidiscip Res J 1(1):31–36 Takatsuka Y (1978) Environmental contamination by heavy metals around the cement factory. J Environ Lab Ass 3:75–82 Treshow M (1968) Impact of air pollutants on plant populations, United States, pp 1108–1113. https://www.osti.gov/biblio/5414514 Utgikar V, Tabak H, Haines J et  al (2003) Quantification of toxic inhibitory impact of copper and zinc on mixed cultures of sulphate reducing bacteria. Biotechnol Bioeng 82(3):306–312. https://doi.org/10.1002/bit.10575 Vandana T (1993) Impact of cement factory environment on soil and microbes  - a preliminary survey. Adv Plant Sci 6:103–109 Vidal-Cros A, Viviani F, Labesse G et al (1994) Polyhydroxynaphthalene reductase involved in melanin biosynthesis in Magnaporthe grisea: purification, cDNA cloning and sequencing. Eur J Biochem 219:985–992. https://doi.org/10.1111/j.1432-­1033.1994.tb18581.x Wainwright M (1984) Sulphur oxidation in soils. Adv Agron 37:350–392 Wainwright M (1999) An introduction to environmental biotechnology. Kluwer Academic, Boston. https://doi.org/10.1007/978-­981-­10-­1866-­4_1 Weill H, Ziskind MM, Waggenspack C et al (1975) Lung function consequences of dust exposure in asbestos cement manufacturing plants. Arch Environ Health 30:88–97. https://doi.org/1 0.1080/00039896.1975.10666650 Wolf K (1986) In: Förstner U, Wittmann G (eds) Metal pollution in the aquatic environment. Springer-Verlag, Berlin--Heidelberg--Tokyo--Secaucus, 1984, rev. ed., xviii 486. https://link. springer.com/book/10.1007/978-­3-­642-­69385-­4 Zhao Y, Jiayu Z, Guorui L et al (2017) Evaluation of dioxins and dioxin-like compounds from a cement plant using carbide slag from chlor-alkali industry as the major raw material. J Hazard Mater 330:135–141. https://doi.org/10.1016/j.jhazmat.2017.02.018

4

Microplastics: An Overview Hina Javed

4.1 Introduction There is a growing concern worldwide that different kinds of plastic materials in the environment are affecting the life of living organisms from the bottom of the sea to the terrestrial climax community. Globally there is a rise in the yield of plastics since the 1950s and in 2016 its production crossed 335 million tons (Plastics Europe 2017). This increased production pointed towards its high demand for use and which finally deposits in sea and oceans. Hence, plastic forms the major share of marine debris worldwide (UNEP 2016). The menace of large chunks of plastic has already been known since the 1980s (Laist 1987) but there is an increasing awareness among scientists as well as in society toward the small and fine fractions like microsized, nanosized particles, etc. (GESAMP 2016). Among the microsized particles, microplastic (MP) is the major component which is widely spread in the marine water resources from the Arctic to the tropics (Ivar do Sul and Costa 2014; Obbard et al. 2014), and from the surface of the sea to the bed of the ocean (Van Cauwenberghe et al. 2013; Moore et al. 2001; Setälä et al. 2016a; Woodall et al. 2014). In the last few years, several research investigations have been made on MPs worldwide. Although many studies on sources, distribution, and adverse effects of MPs are in progress, however, it is very pitiful that our planet Earth has been packed and overloaded with plastic waste and so named the plasticene era (Mashirin and Chitra 2022). MPs are microsized fragments of plastic size   20 mm. They are primarily formed from the remnants of plastic food packages, plastic bottles, automobile spares, plastic bags, etc. The enormous use of use and throw plastic products and their improper disposal result in the deposition of macroplastics in the environment. If it is accumulating in the soil (landfills and garbage dumps), then it alters the soil quality, makes complexes by interacting with other chemical compounds, and may also affect biogeochemical cycles (Mashirin and Chitra 2022).

4.2.3 Mesoplastics Their fragment size is in the range of 5–20 mm. They can be formed by the breakdown of macroplastics or by accidental spillages from manufacturers. For example, the filaments, needles, plastic films are the waste produced during the molding and welding of plastics, etc. They are finer particles therefore present in the air, water, and on land. These fragments are not visible and mainly responsible for occupational toxicity to the workers of plastic factories and their recycling sections. The wastewater released from these factories consequently has detrimental effects on the organisms of aerial, aquatic, and terrestrial ecosystems.

4.2.4 Microplastics The plastic fragment size 32  °C, antioxidant responses were substantially higher than at 16 °C (Islam et al. 2021b). Fish exposed to 25 °C for 3 weeks had greater GPx, CAT, SOD, GR, and LPO activity than fish subjected to 18  °C (Almeida et  al. 2015). During a 96-day heat exposure research, Carney Almroth et al. (2019) found higher antioxidants and protein carbonyl (PC) activity at 5 °C compared to fish at 18 °C in Atlantic halibut (Hippoglossus hippoglossus). The antioxidant response to temperature stress in fish differs significantly. A deviation from conventional antioxidant responses to temperature stress can cause cellular and protein deficiencies, which will reduce aquaculture production efficiency directly or indirectly.

5.6 Immunity Status Under Temperature Stress Increased antibody response is the most typical feature of immunological responses to temperature stress (Bowden 2008; Makrinos and Bowden 2016). In teleosts, serum lysozyme activity (LSZ) are key innate immune defence molecules that break down bacteria’s cell walls (Saurabh and Sahoo 2008). This opsonic enzyme stimulates complementary systems as well as phagocytosis (Bowden 2008; Saurabh and Sahoo 2008). Furthermore, immunoglobulin M (IgM) is an important antibody in fish (Uribe et al. 2011). Hepcidin is released by the inflamed liver, and it plays a role in antimicrobial defence (Alvarez et al. 2014). Furthermore, the inflammatory mediators are considered necessary in fish (Chen et al. 2019). For example, when turbot (Scophthalmus maximus) was subjected to thermal stress (20, 23, 25, 27, and 28 °C), the level of mucosal immunity, hepcidin, IgM, IL-1, and acid/alkaline phosphatase increased significantly (Huang et al. 2011). During the 96-h exposure trial, alternative complement pathway (ACH50) activities, respiratory burst, and phagocytic index were dramatically reduced in Oreochromis mossambicus and Mozambique tilapia as compared to fish at 27 °C (Ndong et al. 2007). Another study indicated that after 4 weeks of exposure to 33 °C, Nile tilapia (Oreochromis niloticus), had a substantial drop in LSZ activity (Dominguez et  al. 2005). Olive flounder (Paralichthys olivaceus) exposed at 28 and 30  °C for 2 weeks had considerably greater plasma IgM and LSZ (Kim et  al. 2019). At 19  °C, Atlantic cod, Gadus morhua, had higher levels of beta-2 microglobulin (b2-M), Major histocompatibility class (MHC) class 1 gene upregulation, and IgM-L gene overexpression compared to fish at 10  °C (Pérez-Casanova et  al. 2008). After 7 days of exposure to temperature, a research on turbot (Scophthalamus maximus), found higher IgM

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levels at 17, 20, 27, and 28 °C, showing the relevance of temperature as an immunological competent (Huang et al. 2015). The leucocyte population, LSZ, and serum protein level of Atlantic halibut (Hippoglossus hippoglossus) were significantly affected by exposure to 8, 12, 15, and 18 °C for 3 months in fish maintained at 18 °C (Langston et al. 2002). During low-temperature stress, teleosts are thought to rely on generic immunity, whereas at higher temperatures, they depend on a particular immunological level (Cabillon and Lazado 2019). For example, in low-temperature acclimated perch (Perca fluviatilis), glucan-binding proteins predominated. At the same time, opsonin was more effective when exposed to thermal stress (Marnila and Lilius 2015). In Oryzias latipes and Japanese medaka, a sudden change of temperature from 25 to 30 °C resulted in lymphocyte proliferation and reduced respiratory burst (RB). TNF-1, RB, and leucocyte counts were all greater in European seabass (Dicentrarchus labrax), when they were exposed to a higher temperature (33 °C) for 10 days (Islam et al. 2020c).

5.7 Haematological Responses to Temperature Stress The shape of cells and nuclei reflects haematological responses to heat stress (Islam et al. 2020d). As a typical cellular stress response mechanism, this causes lipid miscibility and increases thermostability to heat stress (Shahjahan et al. 2019). When European seabass (Dicentrarchus labrax) was subjected to low temperatures (24 °C) for a period of 10–30 days, white blood cells (WBC) increased significantly, whereas red blood cells (RBC), haemoglobin (Hb) and haematocrit decreased significantly (Islam et  al. 2021a). Hb and RBC contents were significantly reduced in striped catfish (Pangasianodon hypophthalmus), after 7 days at 36 °C, compared to fish at 28  °C, when WBC exhibited opposite tendencies (Shahjahan et  al. 2018). Blood indices were considerably reduced in Tilapia (Oreohromis niloticus), exposed at 13 °C (Panase et al. 2018). Changes in the lipid layer and energy storage can cause temperature stress to affect blood cell numbers and cellular shape. Several recent investigations have found that climate-induced temperature events cause erythrocytic cellular and nuclear abnormalities (Shahjahan et al. 2018; Islam et al. 2020a, b). Thermal stress increased erythrocytic cellular and nuclear abnormalities in striped catfish subjected to 28, 32, and 36 °C for 7 days (Shahjahan et al. 2018). In another research, the same fish were exposed for 28 days to temperatures of 24, 28, 32, and 36 °C and showed considerably increased erythrocytic cellular abnormalities (ECA) and erythrocytic nuclear abnormalities (ENA) at the higher temperatures (Ariful et al. 2019). Both ENA and ECA frequencies were considerably greater in European seabass (Dicentrarchus labrax), raised at 8 and above 32 °C compared to 16 and 24 °C over the 10–30 days of exposure (Islam et al. 2021a). Similarly, changing morphologies of erythrocytes in Epinephelus akaara subjected to thermal stress (31 and 34 °C) for 42 days were studied by Rahman and Baek (2019). Comparing fish at 25 and 28 °C, the erythrocyte and nucleus major axis were dramatically reduced (Panase et al. 2018).

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5.8 Growth and Metabolic Responses to Temperature Stress Energy supply is proportionally distributed in non-stressed settings to sustain growth activities and body upkeep. Maintenance costs, on the other hand, rise under stressful circumstance to cover the higher demand for energy in stress alleviation, which counteract energy allotted for growth and development. Quicker metabolic activities coupled with higher absorption rates, and faster physiological activities ensue from a modest temperature increase (eustress), resulting in a faster growth rate (Sotoyama et al. 2018). Laboratory-controlled temperature tests, on the other hand, showed that temperature might reach a threshold where it was detrimental to growth performance (Angilletta et al. 2010). Reduced feed intake, and food efficiency are frequent under thermal stress. During a 56-day investigation, striped catfish showed poor growth performance than fish subjected to 30 and 35 °C (Phuc et al. 2017) exposed to 25 °C. During the 5 months of research, at 17 and 22 °C compared to 10 °C, Atlantic salmon and Salmo salar showed worse growth (Wade et al. 2019). Another study found that the same fish exposed to 16 and 20 °C for 99 days had considerably worse growth performance than fish exposed to 12 °C (Tromp et al. 2018). The growth performance of European seabass (Dicentrarchus labrax) drastically decreased after 30 days of thermal exposure (32 °C) and extreme cold (8 °C) (Islam et al. 2020a, b). Higher thermal stressors are linked to alterations in metabolic rate in both acute and chronic situations (Almroth et al. 2019; Benitez-­ Dorta et  al. 2017). High respiratory rates and oxygen consumption worsen these alterations in metabolic rate (Kyprianou et  al. 2010). This review, however, is restricted to the thermal stress on fish growth and metabolic responses. Donaldson et al. (2008) discussed cold stress response mechanisms in fish in depth, so they are not duplicated here. Because blood glucose is closely related to metabolism, hyperglycaemia is a common sign of cold shock reactions in the winter (Nie et al. 2019). The glucose concentration of Cyprinus carpio was raised at lower temperatures (7 and 9 °C) after 120 days of exposure at 25 °C (Tanck et al. 2000). Cold shock also impaired enzymatic activity, allowing lactate to be drained and energy to be restored. When compared to fish at optimal temperature, cold temperature stress caused increased lactate concentration and reduced white muscle energy storage in largemouth bass, Micropterus salmoides (Suski et al. 2006). According to Majhi et al. (2013), elevated blood glucose in Neolissochilus hexagonolepis at 6 °C was observed as compared to fish at 27 and 30 °C. The protein, cholesterol, and glucose content of Tilapia (Oreochromis niloticus) subjected to 13 °C was greater than that of fish exposed to 25  °C (Panase et  al. 2018). When European seabass (Dicentrarchus labrax) was exposed to 8 °C for 30 days, plasma triglycerides and lactate concentrations were considerably higher than in fish bred at 16 and 24 °C (Islam et al. 2020a, b). Stress from high temperatures also affects metabolism (Shahjahan et al. 2018). Striped catfish were shown to have higher blood glucose levels after being exposed to 36 °C for 28 days compared to fish subjected to 24, 28, and 32 °C (Ariful et al. 2019). Similarly, in another study, fish exposed to 36 °C for 7 days had higher blood glucose levels than fish exposed to 30 °C (Shahjahan et al. 2018). The triglyceride

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level of European seabass acclimated to 32 °C for 30 days was considerably lower than that of fish acclimated to 16 and 24 °C (Islam et al. 2020a, b).

5.9 Biochemical Response to Temperature Stress Because biochemical response rates are governed by temperature, living in warmer water has fundamental consequences on fish physiology (Somero 2010). As a result, physiological acclimation under thermal stress is expected to increase the basal activity of the chromaffin cells in brain and neurotransmitter activity. Temperature impacts on biological reaction rates and may be difficult to distinguish from those induced by prolonged stress. Nonetheless, evidence concerning the consequences of long-term exposure increases fish stress indicators. First, continuous exposure to high temperatures may disrupt the catecholaminergic (noradrenergic and dopaminergic) systems in the brain, affecting the synthesis, release, and/or metabolization of their primary neurotransmitters. Temperatures of 5 and 8 °C, on the other hand, did not affect brain DA levels in fish bred at 2 °C in the same research. In the brain of Chinook salmon (Oncorhynchus tshawytscha), however, exposure to a greater temperature for 2 weeks resulted in a drop in DA levels (Giroux et al. 2019). These findings demonstrate that the dopaminergic system’s reaction to a temperature change may be influenced by the length of exposure, temperature fluctuations, and the species under investigation. In vertebrates, the serotonergic system of the brain is playing an important role in orchestrating stress reactions (Puglisi-Allegra and Andolina 2015). Brain serotonin levels were increased in Harpagifer antarcticus after 10 days of exposure to 8 and 11 °C, whereas levels of the primary serotonin metabolite were affected by temperature and salt (Vargas-Chacoff et  al. 2020). Cortisol levels in the blood were found to be higher overall when people were exposed to high temperatures over lengthy periods of time (Samaras et al. 2018; Kim et  al. 2019). However, in certain cases, such as in the Emerald rockcod (Trematomus bernacchii), no change in cortisol after acclimatization to warmer water (up to +3.8  °C) was recorded with no change in other outcomes (Hudson 2008). The absence of increased baseline cortisol in such circumstances might be explained by a negative feedback mechanism affecting cortisol production (Mommsen et al. 1999). Senegalese sole (Solea senegalensis) cortisol returned to normal after the stress reaction seen on sudden exposure to thermal stress (24 vs. 18  °C), making them comparable to fish at 18  °C (Benitez-Dorta et  al. 2017). Cortisol increased once more a week later, but this time by a comparable amount. The secondary stress response, which is known for an increase in blood glucose and lactate or a change in plasma osmolality, is typically associated with elevated blood cortisol levels (Samaras et al. 2018). However, there have been several outliers to the overall tendency (Samaras et al. 2018). Fishes’ baseline stress physiology and monoamine activity in the central nervous system are both stimulated by dwelling at higher temperatures. It is still not clear if these effects are brought on by prolonged mild stress or higher metabolic rates at high temperatures. It needs further

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investigation to compare metabolic rate and baseline levels of stress markers at different temperatures.

5.10 Response of Ionic Balance to Temperature Stress Freshwater fish get more ions in salty water, whereas saltwater fish lose electrolytes (Vargas-Chacoff et al. 2018). During thermal stress, which can cause osmotic failure, ion transportation is heavily dependentent on metabolic energy rather than passive ion diffusion between the water and fish (Evans and Kültz 2020). In freshwater fish, temperature changes diminish ion inflow, resulting in net ion loss, whereas in marine fish, temperature changes increase ion input, resulting in net ion gain. Fish enhance Na+-K+ ATPase and Na+-K+-Cl cotransporter (NKCC) activities in the gills, kidneys, and gut to compensate for ion loss (freshwater) and gain (saltwater). Furthermore, in freshwater, fish reduce epithelial permeability to slow down loss, but in saltwater, it rises to speed up ion outflow (Kang et al. 2015; Vargas-Chacoff et al. 2020). As a result of the ionic disturbance, the function of the CNS is jeopardized. The effectiveness of synaptic transmission, for example declines, triggering main stress responses and influencing all physiological activities in fish (Vargas-­ Chacoff et al. 2018). In general, the activity of the Na+-K+ ATPase is lowered at low temperatures and raised at thermal stress (Chadwick and McCormick 2017; Vargas-­ Chacoff et al. 2018). Changes in electrochemical equilibrium between blood and the surrounding water (Fig. 5.3), Na+-K+ ATPase activity impacts cells responsible for Na+ and Cl− absorption (Lorin-Nebel et al. 2006; Honoré et al. 2020). Increased Na+, Cl, and K+ levels were seen in European seabass exposed to 33 °C from 24 °C (Islam et al. 2020a, b). Freshwater (FW) and saltwater (SW) fish were subjected to 8 days of warm stress at 14, 17, 20, and 24 °C. Fish exposed to SW and 24 °C died completely, although no mortality was seen in the other groups. Chanos chanos acclimatized to cold stress (18 °C) for 21 days demonstrated higher Na+-K+ ATPase, and 11-hydroxysteroid dehydrogenase 1 and 2 (11-Hsd1 and 2) activities in gills compared to elevated temperature (28 °C) according to Hu et al. (2019). When turbot, Scophthalamus maximus, sole and Solea senegalensis were acclimatized at 18 and 11 °C for 21 days, their plasma Na+ and Cl− ions concentrations were much lower than when they were bred at 4 and 0 °C (Foss et al. 2019). During 90 days of exposure, Bernard et al. (2019) found that Atlantic salmon, Salmo salar, raised at 5 and 8 °C had higher Na+-K+ ATPase activity and plasma Na+, Cl− than fish reared at 15 and 20  °C.  During acclimation in both low- and high-saline water, European seabass (Dicentrarchus labrax), showed dramatically enhanced Na+-K+ ATPase and Cystic fibrosis transmembrane conductance (CFTR) upregulation (Islam et  al. 2021a). Ionic balances, unlike body temperature, must be maintained according to thermal stress for proper function. Thermal stress aggravates osmotic stress and fish’s capacity to tolerate salt.

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Fig. 5.3  Sodium (Na), Potassium (K), and Chloride (CI) activities in fish (Ionic balance)

5.11 Reproductive Responses to Temperature Stress Temperature is a crucial physical regulating element in fish survival, with implications ranging from gametogenesis to hatching, and larval to juvenile growth and survival. As a result, thermal stress may have a negative impact on fish reproduction. Under thermal stress, inhibitory events result in a series of conformational changes in some proteins’ reproductive hormones and their receptors, steroids synthesis enzymes, and water-soluble conjugates (Akash and Neha 2017). Catecholamine-­ mediated responses can also cause thermal suppression of reproduction in fish. The temperature has been linked to sex in fish in a number of earlier studies. Higher temperatures suppress aromatase activity, causing sex determination to shift towards the male phenotype (Guiguen et al. 2010). Rising sea temperatures are predicted to increase the fish maturing as males where reproductive function may be preserved. Higher temperatures cause hypoxia, which can disrupt reproduction and lead to a species’ population number being reduced or extinction, resulting in an ecological calamity. However, Das et  al. (2006) suggested that Labeo rohita embryos may withstand climatic changes of up to 33 °C owing to global warming without impairing reproduction and embryonic development. The temperature of the water influences the start and end of the spawning season, as well as the generation of melatonin. Melatonin is the first indicator that a fish is ready to reproduce. Gametogenesis, pituitary gonadotropin secretion, hormone metabolic clearance,

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hepatic oestrogen response in vitellogenesis synthesis, and gonad responsiveness to hormonal stimulation are all affected by temperature (Boswell et  al. 2009). Low temperatures encourage the development of primordial spermatocytes (meiotic phase), whereas higher temperatures encourage spermatogonial proliferation and spermitation. In the case of marsh killifish, low temperatures increase early-phase oocyte development. Low temperatures are required for ovulation in rainbow trout; otherwise, the ova only survive for a brief period. Water temperatures over 17 °C impact ovulation and oocyte hydration in gulf croaker. The rise in temperature has also been linked to spawning. Temperature events caused by climate change are likely to have an impact on teleost reproductive success (Servili et al. 2020). Through endocrine disturbance, thermal stress promote, or delay gametogenesis and maturation (Mateus et al. 2017). Increased temperature during gametogenesis causes impairment in gonadal steroid synthesis, liver vitellogenin production capacity, and changes in the hepatic oestrogen concentration in Atlantic salmon, Salmo salar (Takasuka and Aoki 2006). These modifications have the effect of lowering reproductive increment and gamete liveability (King and Pankhurst 2004). High-temperature exposure delays or inhibits pre-ovulatory shift throughout various stages of gonadal development (Zarski et al. 2017). During exposure to increased temperature, suppression of spermiation was found in Esox lucius (Cejko et al. 2019), Salmo salar (Taranger et al. 2003), and Oncorhynchus mykiss (Dadras et al. 2019). In Oncorhynchus mykiss (Dadras et al. 2019) and Prochilodus lineatus, climate change-induced temperatures reduced sperm motility and quality (Paula et al. 2019). As a result of the preceding discussion, we may anticipate that climate change-driven severe temperature occurrences would impair the reproductive success of aquaculture species in both confined and wild contexts. To better understand reproductive success, more research on aquaculture species and heat stress-induced changes are needed.

5.12 Effects of Temperature on Sex Determination and Differentiation Higher water temperature is one of the most harmful aspects of climate change affecting gonads most severely (Miranda et  al. 2013). The methylation of the gonadal cyp19a1a gene promoter appears to be one of the impacts of higher water temperatures, resulting in the suppression of aromatase production and masculinization of genotypic females (Navarro-Martín et  al. 2011). High-temperature-­ induced masculinizing effects in this species (Piferrer et al. 2005) were found to lower the production of gonadotrophin-inhibitory hormone (GnIH) in developing sea bass in a recent research. GnIH has also been positively associated with gonadal steroidogenesis in sea bass, with Paullada-Salmerón et  al. (2016) finding that it reduces testosterone and 11 ketotestosterone plasma levels. As a result, by working at multiple levels of the developing reproductive axis, higher temperatures may regulate masculinization by acting on gonadal steroid synthesis. Water temperature in nature fluctuates on daily basis, rising up after sunrise and sharply decreasing

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after nightfall (Villamizar et al. 2012). Under daily cycle, thermocycles may constitute major entrainment variables for hatching circadian rhythms (Villamizar et al. 2012). When compared to inverted thermocycles, natural daily thermocycles raised oestrogen and lowered testosterone concentration resulting in altered sex differentiation by a larger proportion of females (Blanco-Vives et  al. 2011). In another experiment, when zebrafish larvae was exposed to natural thermocycles, a greater female-to-male ratio was occurred (Villamizar et al. 2012). Increased water temperature as a result of global warming can disrupt gonadal growth and maturation by affecting daily thermocycles. There is mounting evidence that stress regulates temperature effects on sex determination partly by changes in hypothalamus pituitary interrenal (HPI) axis (Pankhurst 2016). Medaka, Pejerrey, and Japanese flounder larvae were masculinized under raised temperatures. Treatment with cortisol mimics the masculinizing effects of increased temperature. Cotreatment with the cortisol production inhibitor metyrapone prevents it (Yamaguchi et al. 2010). Finally, global warming is a result of human activity. At higher temperatures, masculinization is more frequent than feminization in fish, according to several studies. As a result, globalization may also lead to feminization. As a result, the anticipated impacts of masculinization and feminization must be taken into account.

5.13 Thermal Imprinting in Fish Early exposure to different stressors causes the plasticity of HPI on subsequent stress exposure, according to empirical investigations in fish (Varsamos et al. 2006; Auperin and Geslin 2008). Because continuous exposure to high temperatures can be considered as stressful, exposure during embryonic development, may have long-term consequences on fish physiology and capacity to cope with unexpected environmental difficulties. The term “thermal imprinting” is used to describe this phenomenon (Mateus et al. 2017). Despite a similar thermal history throughout the post-larval stage, adult Gilthead seabream, Sparus aurata, demonstrated a lower cortisol response to confinement stress when raised at high temperatures during developmental stages (embryo and larvae) (Mateus et al. 2017). The stress response to a cold test was also higher in individuals who were raised at high temperatures during the embryonic stage (Mateus et al. 2017). Thermal imprinting caused alterations in the transcription of critical genes involved in the control of the HPI axis, which might explain some of the changes in coping capacities (Mateus et al. 2017). The biochemical mechanisms by which fish physiology is influenced as a result of earlier exposure to high temperatures are yet unknown. Changes in monoaminergic signalling in specific parts of the brain, as well as epigenetic alterations, may all play a role in the reported results (Fokos et  al. 2017; Vindas et  al. 2018; Zhang et al. 2010).

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5.14 Mitigation Measures to Temperature Stress Many solutions are currently in vogue to mitigate the impacts of thermal stress on fish. Where there are huge swings in water temperature, it is critical to develop techniques to increase the physical fitness of fish (Islam et al. 2021a). To combat temperature variations induced by climate change, fish are also given supplementary and functional food flavours (Schrama et al. 2017). Essential oils, nanoparticles, fennel seeds, mushrooms, carotenoids, and vegetable oils can be used to alleviate the negative effects of high and cold stress in fish (Liu et al. 2019; Kumar et al. 2019; Dawood et al. 2020). Takifogo obscures that dietary astaxanthin improves pufferfish development and antioxidant activity, stimulates the immune system, and increases resilience to heat stress (Cheng et  al. 2018). According to the findings, adding astaxanthin to fish diet enhances growth performance whilst decreasing the immune system and antioxidant activity. Fei et al. (2020) found that amino acids improved the production of sex steroid hormones in yellow catfish. Dietary modification also enhanced the physiology of Clarias gariepinus, Trichogaster leeri, and Pagrus major (Hossain et  al. 2019). During suboptimal temperature stress exposure, barramundi, Lates calcarifer, had significantly improved growth performance and metabolic responses when fed a polyunsaturated fatty acid-supplemented diet (Alhazzaa et al. 2013). A winter diet fortified with vitamins phycocyanin, propolis, choline, minerals, and highly unsaturated fatty acids inositol have been shown to improve immunological status of gilthead seabream, Sparus aurata (Schrama et al. 2017). Both winter cold and summer heatwave stress have been documented in Nile tilapia, Oreochromis niloticus, fed diets high in vitamins E and C and polyunsaturated fatty acids (Marston 2010). Nutraceuticals have been demonstrated in studies to stimulate defensive mechanisms in fish, even under stressful environments, and so can lessen detrimental effects mediated by stressful conditions to some extent (Akhtar et  al. 2012). Microbial levan, l-tryptophan, vitamin C, pyridoxine, vitamin E, and methyl donors have been demonstrated for positive effects (Rairakhwada et al. 2007; Tejpal et al. 2009; Sarma et al. 2009; Gupta et al. 2010; Prusty et al. 2011; Akhtar et al. 2012; Muthappa et al. 2014). As a result, future aqua-feed compositions should go beyond those already in use. The use of nutraceuticals as stress relievers is relatively new. In this aspect, more study is necessary. However, the scope for further study and their field effectiveness must be determined. Exploring innovative feed components and nutraceuticals for fish immune regulation and stress reduction is critical for the improvement of aquaculture growth and development.

5.15 Levans Levans are fructose polymers that form a non-structural carbohydrate. In Levans, pyridoxine, a monomer of Vitamin B6 (Pyridoxine), can increase the synthesis of serotonin and gamma-aminobutyric acid (GABA), both of which are important for stress regulation. Pyridoxine in the diet helps with stress reduction,

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immunomodulation, and heat tolerance. In Labeo rohita fingerlings, dietary supplementation of pyridoxine (100 mg/kg) led to immunomodulation and stress reduction owing to endosulfan (Akhtar et  al. 2012). Dietary administration of 100  mg pyridoxine per kg might improve the heat tolerance of L. rohita fingerlings (Akhtar et  al. 2012). Pyridoxine supplementation at 100  mg/kg food may counteract the negative effects of increasing temperature and safeguard the haemato-­immunological health of L. rohita fingerlings raised in hotter water. The treatment groups had considerably greater haemato-immunological parameters than the control group (Akhtar et  al. 2012). Dietary pyridoxine supplementation at 100  mg/kg food has been shown to improve development and reduce stress in L. rohita fingerlings fed at thermal stress. Dietary pyridoxine had a considerable impact on development, as well as the activity of several antioxidative enzymes and stress indicators. Higher Specific Growth Rate (SGR), SOD of the liver and gills, lower levels of blood glucose and cortisol, and acetylcholinesterase in brain were found in the therapy groups. Levans are mostly found in microbial products, plants, and grasses. In aquaculture, they are employed as excellent prebiotic and immunological supplements. Gupta et al. (2013) discovered that dietary microbial levan had stress-relieving, protective, and immunostimulant activities in Cyprinus carpio fry exposed to fipronil’s sub-lethal toxicity. Dahech et al. (2011) found that rats given levan polysaccharide had less oxidative stress. In diabetic rats, dietary levan caused various positive benefits, including a drop in blood glucose levels and an increase in pancreas and liver antioxidant capacity. Histological methods were used to corroborate these findings. L. rohita fed with 1.25% levan coupled with their meals showed improved thermal tolerance and protection against thermal stress (Dahech et al. 2011).

5.16 Proteins and Amino Acids Even in the absence of dietary protein, an organism’s physiology maintains a reasonably significant free amino acid reserve in the blood. The bioavailability of amino acids in tissues for the formation of different types of proteins and neurotransmitters is ensured by this free amino acid pool. Amino acids are gluconeogenic substrates under certain situations like stress, malnutrition, and so on, depleting the amino acid pool. As a result, appropriate protein supplementation is unavoidable under stressful situations (Lieberman and Marks 2009). In Corydoras punctatus, a high protein diet with vitamin C reduced bioaccumulation and stress caused by endosulfan poisoning (Sarma et al. 2009). During the recovery of claw ablated Macrobrachium rosenbergii, high protein and vitamin C-supplemented diets were given to enhance the regeneration of chelate claws (Kumar et al. 2011). These findings indicated that a high dietary protein and vitamin C intake might reduce stress caused by chelate claw ablation and perhaps boost the healing potential of M. rosenbergii males’ ablated claws. The findings showed that additional concentration of high protein in the diet heightened the amino acids reserve in the cells and works as an alternative for gluconeogenesis, which helps to combat stress caused by claw ablation (Manush et al. 2005). By enriching the amino acid pool and

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acting as an energy substrate, the supplemental protein was shown to decrease the negative effects of stress in several fish and crustaceans (Kumar et al. 2011; Abdel-­ Tawwab 2012). Under stressful husbandry conditions, the higher demand for certain protein molecules has been associated with improved production of immune-potentiating molecules such as antibodies (Aragao et al. 2008). Changes in blood or tissue amino acids in fish may act as a signal of their increased demand during stress, according to studies (Aragao et  al. 2008). In recent years, dietary modification using amino acids has gotten a lot of interest for reducing/controlling stress-induced physiological changes/damage in a variety of fish species. Herrera et al. (2019). have evaluated the impact of various amino acids in stress management in aquaculture Certain amino acids in fish, such as aromatic amino acids, sulphur amino acids, basic amino acids, branched-chain amino acids, vitamins, minerals, and nucleotides have certainly stress-relieving potentials.

5.17 Tryptophan Tryptophan, a precursor of serotonin (5-hydroxytryptamine, 5-HT, a neurotransmitter), has been shown to improve stress abilities in teleosts probably by reducing corticosteroid levels (Ciji et al. 2015). According to Hoseini et al. (2019b), tryptophan is one of the most essential stress mitigator in fish. In this vein, previous research has revealed that dietary tryptophan can help to reduce cortisol and glucose levels linked with stress (Kumar et al. 2014). However, Acipenser persicus fed with 0.5% tryptophan for 15 days showed an increase in both baseline and post-stress cortisol (Hoseini et al. 2016). Serotonin is thought to increase lymphocyte proliferation and control immunological processes (Hoseini et al. 2016). In Acipenser persicus, feeding tryptophan inhibited a stress-induced reduction in the alternative complement pathway and serum lysozyme (Hoseini et al. 2016). Furthermore, tryptophan and its numerous metabolites have been shown to have antioxidant properties, which may contribute to its stress-relieving abilities (Ciji et al. 2015). Furthermore, tryptophan’s anti-stress properties can be linked in part to its role in the creation of the melatonin hormone. As reported by various writers, melatonin modulates antioxidant capacity, immunological functions, and therefore stress tolerance via a reduced glucocorticoid response (Cuesta et  al. 2007, 2008; Lopez-­ Patino et al. 2013; Gesto et al. 2016; Maitra and Hasan 2016). Dietary tryptophan supplementation has been shown to improve stress tolerance in a variety of fish (Ciji and Akhtar 2020; Herrera et al. 2020). In a variety of fish, eating tryptophan lowers aggressive behaviour, cannibalism, and conflicts (Neto and Giaquinto 2020). Supplementing tryptophan in Sparus aurata plant-based diets was proven to influence immunological functioning in a recent study (Cerqueira et al. 2020). Tryptophan, an amino acid that is a precursor to serotonin (5-­hydroxytryptamine), has a stress-relieving effect (Lepage et al. 2002). l-tryptophan is essential for development, immunological modulation, and disease resistance in L. rohita fingerlings reared under heat stress, according to research. In this study, l-tryptophan supplementation improved heat stress, increased growth, and modulated immunity in

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L. rohita fingerlings (Kumar et  al. 2014). Similarly, (Akhtar et  al. 2010) found promising findings in research on the impact of l-tryptophan in resisting combined temperature and salinity stress in L. rohita juveniles. Under thermal and salinity stress, tryptophan supplementation in the diet augmented the growth, respiratory burst activity, WBC count, blood protein, and serum lysozyme activity of L. rohita juveniles (Lardi et al. 2016). In Cirrhinus mrigala fingerlings, l-tryptophan mitigated high-density stress (Tejpal et  al. 2009). Treatment groups showed higher weight gain when compared to the control group. With increasing levels of dietary l-tryptophan, biochemical stress markers and liver enzymes exhibited a falling tendency (Abdelhamid et al. 2020). According to the evidence thus far, supplementing with 1.4% tryptophan reduces combined stress caused by temperature and salt, improves development, physiological state of selected hormones, and regulates non-specific immunological activities.

5.18 Phenylalanine and Tyrosine Other aromatic amino acids, such as phenylalanine and tyrosine, have lately garnered attention for their ability to alleviate the negative effects of stress in fish. Tyrosine and phenylalanine are precursors of hormones and neurotransmitters (Herrera et  al. 2017, 2019). Supplementing the diet with phenylalanine reduced stress indicators in Atlantic cod exposed to air or at high temperatures (Herrera et al. 2017). Phenylalanine may reduce oxidative damage (Li et al. 2015). Thyroid hormones and neurotransmitters have also been identified to boost antioxidant enzyme activity and assist maintain structural integrity (Li et al. 2015). Feeding Senegalese sole juveniles a diet containing phenylalanine, arginine, methionine, and lysine reduced stress associated with frequent handling and was linked to increased dopamine production (Costas et al. 2012).

5.19 Methionine Recent research has advised that methionine be included in functional fish meals as a nutritional approach to combat stress caused by management and infections (Nazir et al. 2017). Methionine’s anti-stress capacity may be linked to its ability to boost the antioxidant defence system (Herrera et al. 2019). It also acts as an indirect precursor for the production of glutathione, the master antioxidant. Furthermore, as a major methyl donor, methionine can affect the amount of immune cells required for a broader immunological response by regulating the production of polyamines (needed for stabilizing freshly created DNA) required for cell division and proliferation (Machado et al. 2015). Taurine, which is made from methionine, is involved in a variety of physiological processes in fish, including osmotic control, antioxidation, immunoregulation, and detoxification (Li et al. 2016). Taurine is thought to react with the harmful hypochlorous acid generated by a leukocyte’s respiratory burst, reducing stress (Wang et  al. 2009). Supplementation of N-acetyl cysteine

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(NAC), a cysteine precursor that has been found to improve the antioxidative and immunological capabilities of Nile tilapia and decreased oxidative stress in European eel and common carp (Sevgiler et al. 2011; Xie et al. 2016).

5.20 Arginine Hoseini et al. (2020) reported that employed as a stress reliever in fish, arginine, which is the precursor of nitric oxide (NO). In several teleosts, arginine has been identified as a regulator of antioxidant defence, immunological responses, and health (Zhou et al. 2015). A few studies have been conducted to assess the stress-­ relieving effect of arginine in fish, but the results have been inconsistent. Under stressful husbandry conditions, the reduced blood level of arginine in some fish species such as turbot and Senegalese sole implies an increased demand and a probable function in stress reduction (Costas et al. 2013). Varghese et al. (2020) recently demonstrated that dietary arginine (0.7%) supplementation might restore the hypoxia-induced immunosuppressive effects in Cirrhinus mrigala. Furthermore, dietary arginine decreased the sensitivity of hypoxia-stressed Cirrhinus mrigala to bacterial infection, according to the investigators. Higher doses of dietary arginine levels (beyond the optimal need) had a detrimental influence on yellow catfish and common carp stress-coping abilities when they were grown under crowding and ammonia stress (Hoseini et al. 2019a). The mechanism of action of arginine relieving stress response in fish is unknown at this time. The importance of arginine in stress protection is thought to be owing to its participation in the production of NO and polyamines, which are engaged in a variety of physiological processes (Hoseini et al. 2020). Arginine can improve cell proliferation by fueling polyamine production under stressful conditions when the need for polyamines in fish increase (Andersen et  al. 2016). In addition, arginine enhances non-enzymatic and enzymatic antioxidative capabilities, lowering stress-induced oxidative damage (Wang et al. 2016). Because of its antagonistic action on the important amino acid lysine, arginine at greater levels of inclusion has been shown to affect development and health of fish (Zhou et al. 2015; Hoseini et al. 2020). As a result, arginine’s stress-­ relieving and health-promoting effects are mostly dependent on the dietary amount as well as the stressful situation (Hoseini et al. 2019a).

5.21 Branched-Chain Amino Acids Few studies have reported the effects of branched-chain amino acids like isoleucine, leucine, and valine on reducing the negative effects of stress in fish has not been studied. Inclusion of butyrate in the diet has been shown to improve immunological function against pathogen in a variety of vertebrates, including fish (Siwicki et al. 2005). In Ctenopharyngodon idella, L. rohita, Trachinotus ovatus, and Megalobrama amblycephala (Giri et al. 2015; Jiang et al. 2015; Tan et al. 2016), adequate dietary leucine levels were observed to improve antioxidative defence and

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immunocompetence (Liang et al. 2018). Excess dietary leucine, on the other hand, appears to have a negative effect due to its antagonistic relationship with some amino acids such as isoleucine and valine (Abidi and Khan 2007). Haemoglobin synthesis is highly sensitive to l-leucine availability because of the high amount of leucine in globin proteins (Giri et al. 2015). As a result, it is plausible to believe that enough leucine availability can fulfil increased oxygen demand under stressful situations by raising haemoglobin synthesis rates. This, however, requires further investigation.

5.22 Glutamine Glutamine is required for the synthesis of purine and pyrimidine nucleotides, and so can influence immune cell growth and proliferation via controlling nucleic acid production. Glutamate is essential for fish immunological responses. Further, glutamine can provide glutamate and hence can support antioxidative defence (Andersen et al. 2016). Additionally, glutamine may protect against oxidative damage via its enzymatic forms (Hu et  al. 2014). Glutamine regulates nucleic acid production, which might impact immune cell growth and proliferation (Cheng et  al. 2011). Glutamate is essential for fish immunological responses since it is a primary energy source for WBCs and a key regulator of nitric oxide and cytokine synthesis (Li et al. 2007). Furthermore, glutamine can also provide a substrate to produce glutathione, and so can help with antioxidative defence (Andersen et al. 2016).

5.23 Tyrosine, Glycine, and Phosphatidylserine Tyrosine is a non-essential amino acid that also functions as a precursor to catecholamines. Several studies have found that taking tyrosine supplements reduces the effects of stress and weariness. In animals, norepinephrine and dopamine are depleted when they are stressed (Chiu et  al. 2016). Tyrosine supplementation reduces catecholamine depletion and stress-induced performance deterioration. Supplementing with tyrosine 2 h before a low-temperature exposure returned human performance to the level seen when the ambient temperature was 22°. In adults exposed to a combination of cold and hypoxia, tyrosine supplementation improved mood and memory (Rider et al. 2009). Glycine is the most basic amino acid, and it plays a critical role in fish and shellfish osmoregulatory responses to stress. Oysters quickly absorb free glycine from adjacent water, and in response to abrupt changes in salinity or anoxia, they synthesize gill glycine. Glycine enrichment improves oyster survival when they are transferred from sea to freshwater (Takeuchi 2007). Phosphatidylserine appears to have significant anti-stress activity, possibly due to its ability to buffer the hypothalamus–pituitary–adrenal (HPA) axis and adrenal cortisol production. It modulates endocrine responses by acting as a buffer for high cortisol and adrenocorticotropic hormone (ACTH) levels in response to physical stress. Phosphatidylserine has been shown in tests to reduce the effects of cortisol

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and ACTH in stressed subjects. Stress-induced stimulation of the HPA axis is counteracted by their activity (Benton et al. 2001; Hellhammer et al. 2004).

5.24 Essential Fatty Acids and Phospholipids Dietary lipids supply enough fatty acids as a fuel substrate to meet the increased energy requirement under stressful situations. Inhibition of fatty acid β-oxidation was recently discovered to limit stress-coping abilities in Nile tilapia, demonstrating the role of lipids in stress tolerance (Pan et al. 2017). In fish, however, the specific significance of individual fatty acids in stress response is unknown. The majority of research on the stress-relieving effect of essential fatty acids has been done on fish larvae. Several teleosts, including Paralichthys dentatus, Sparus aurata, Morone saxatilis, and Sander lucioperca (Koven et al. 2001; Harel et al. 2001; Lund and Steenfeldt 2011), have shown that arachidonic acid affects growth performance, stress tolerance, and mortality of larval fish by altering basal cortisol (Lund and Steenfeldt 2011). Eicosanoids are generated during stress and inflammation, and long-chain polyunsaturated fatty acids (LC-PUFAs) such as arachidonic acid (principal/preferred) and eicosapentaenoic acid (EPA) act as precursors (Anagha et al. 2021). Feeding sole larvae (Solea solea) LC-PUFA-enriched Artemia increased their resistance to several husbandry stresses, including hypoxia (McKenzie et al. 2008). Previous research on Japanese flounder (Paralichthys olivaceus) and larval pikeperch (Sander lucioperca) showed that dietary docosahexaenoic acid (DHA) supplementation improved salt stress tolerance (Lund et al. 2012). Phospholipids have also been shown to improve stress-coping abilities in many fish species (Zhao et al. 2013). Little knowledge on the mechanism through which phospholipids protect against stress in fish is known, it indicates that the positive effects are achievable via increasing membrane fluidity and antioxidative capability (Zhao et  al. 2013), as well as enabling lipid digestion and absorption (Cai et al. 2016; Herrera et al. 2019). In numerous teleosts, studies have shown that soy lecithin improves stress tolerance, particularly heat tolerance limits (Ciji et  al. 2021). Phosphatidylinositol has been known to enhance stress tolerance through changing membrane lipid composition (Liu et al. 2013).

5.25 Vitamins Vitamins are employed in aquaculture to address various husbandry and physical stresses since they are engaged in several physiological activities (Cheng et  al. 2018). l-ascorbic acid (vitamin C) and a-tocopherol (vitamin E) are two of the most frequently researched and used stress-relieving vitamins in aquatic species, including fish. Under severe husbandry situations, vitamin C requirements typically increase as seen by several organs’ decreased ascorbic acid levels, especially liver and kidney (Datta and Kaviraj 2003). Several other investigations, on the other

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hand, found that the ascorbic acid concentration of stressed fish did not alter (Henrique et al. 2002).

5.26 Vitamin C Vitamins are employed in aquaculture to address various husbandry and physical stresses since they are engaged in several physiological activities (Cheng et  al. 2018). Vitamin C and E are two of the most frequently researched and used stress-­ relieving vitamins in aquatic species, including fish. Under stressful husbandry situations, the need for vitamin C rises, as demonstrated by lower ascorbic acid levels in several organs, notably the liver, blood plasma, and kidneys. Several other investigations, on the other hand, found that the ascorbic acid concentration of stressed fish did not alter (Henrique et al. 2002). Additionally, the antioxidant properties of vitamin C support the fundamental integrity of a variety of cells and biomolecules by scavenging free radicals in response to various stressors (Falcon et  al. 2007; Yousef 2004). Vitamin C’s antioxidant properties are bolstered by its capacity to replenish additional antioxidants like vitamin E (Yousef 2004). Furthermore, in stressed fish, vitamin C supplementation influences the expression of heat shock proteins (HSPs) and genes associated with antioxidant defence (Vieira et al. 2018). Furthermore, vitamin C serves as a cofactor for a number of enzymes involved in the biosynthesis of collagen and carnitine (a substance required for the transport of fat to the mitochondrion, where it is oxidized for energy conversion), and some neurotransmitters (Yousef 2004). Under low-temperature stress, dietary vitamin C supplementation has been shown to diminish apoptosis in Takifugu obscures (Cheng et al. 2018). Vitamin C is a possible biomolecule to prevent or lessen the negative effects of stress linked with inadequate aquaculture husbandry settings due to its complex physiological actions. Adrenal gland on the kidney in fish serves as a storage site for vitamin C.  Therefore, under stressful conditions, vitamin C content drops rapidly, along with the generation of adrenal hormones. Evidence shows that taking large doses of ascorbic acid can help maintain adrenal function and lower cortisol levels. Vitamin C is a powerful reducer in a variety of reactions. Vitamin C helps control cortisol and thus prevents increased blood pressure in reaction to stress by neutralizing oxidants produced during normal cellular reactions from various stressors (Ashor et al. 2014).

5.27 Vitamin E Another possible vitamin for stress management in aquaculture is vitamin E. Vitamin E supplementation protected fish from the negative effects of stressors in golden shiner (Chen et al. 2004), lead toxicity, and microcystin in Nile tilapia (Tanekhy and Khalil 2014), titanium dioxide nanoparticle toxicity, and nitrite stress in rohu (Ciji and Akhtar 2020; Anagha et al. 2021), ammonia stress in a puff (Liu et al. 2014). Furthermore, dietary fortification of vitamin E was used to counteract

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nitrite-induced suppression of steroidogenesis in L. rohita (Ciji et  al. 2013). The authors also discovered that giving stressed fish vitamin E helped them survive the bacterial attack (Ciji et al. 2013). Vitamin E, like ascorbic acid, protects the body by acting as an antioxidant, modulating HSPs expression, lowering cortisol (Montero et al. 2001) and glucose levels (Liu et al. 2014), and improving immune responses through lysozyme, increased phagocytic index, total serum protein content, and total immunoglobulin (Liu et al. 2014). A lack of vitamin E has been associated to increased erythrocyte fragility and lower stress resistance, as well as protecting red blood cells from haemolysis (Montero et  al. 2001; Halver 2002). Vitamin E has been proven to protect the body from a wide spectrum of free radical impacts as an antioxidant (Droge 2002). A study found that supplementing vitamin E together with food might significantly alleviate nitrite stress in L. rohita juveniles. The detrimental effects of nitrite such as nitrite impacts on growth, haematology, and ionic balance, were shown to be mitigated by dietary supplementation with additional levels of vitamin E in this research. Stress (acute or chronic) increases free radical production throughout the body, although antioxidant enzyme activity, such as catalase (CAT) and superoxide dismutase (SOD), was shown to be decreased in the experimental group receiving the most benefit from vitamin E. The levels of blood glucose were decreased in the vitamin E-supplemented groups, indicating that this vitamin has a function in stress reduction (Patrocínio-Silva et  al. 2016). Dietary vitamin E has also been proven to be useful in preventing oxidative harm caused by hypoxia (Varghese et al. 2017).

5.28 Vitamin A Vitamin A is a fat-soluble vitamin, required for proper erythropoiesis and boosting immunity in vertebrates, including fish (Herrera et al. 2019), its ability to reduce stress in fish has yet to be completely investigated. Guimaraes et al. (2016) found that vitamin A supplementation had no effect against infectious challenge and protection against cold stress in Nile tilapia. Other fat-soluble vitamins (vitamins D and K) have not been studied for their stress-relieving properties in aquaculture. Under environmental hypo/hypercapnia, Graff et al. (2002) found that nutritional supplementation of vitamin D3, vitamin K, and calcium had no effect on bone mineralization in smolting Atlantic salmon. Unlike water-soluble vitamins (such as ascorbic acid), fat-soluble vitamins may produce hypervitaminosis in higher doses and longer feeding duration (Miao et al. 2015). The antioxidants retinoic acid/retinol and carotenoid precursors have been found to have a role in the formation of steroid hormones (Everts et al. 2013). The adrenal cortex of rats on a diet lacking in retinoic acid was significantly stunted, and typical levels of corticosteroids, which are important in stress management, were not produced. Vitamin A is also needed for the formation of cortisol, and even minor vitamin A deficiency causes significant reductions in cortisol production (Jessani et al. 2015). According to studies, retinoic acid or retinol has a positive influence on adrenal health. Before utilizing fish as

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stress mitigators in aquaculture, it is vital to determine the best feeding period and fat-soluble vitamin inclusion levels for various fish species.

5.29 B Group Vitamins: Vitamins B2 and B3 B complex vitamins are frequently utilized as anti-stress supplements. They are required to catalyze most anabolic pathways due to their role in energy generation. In the adrenal gland, B complex is required for steroid production (Wilson et al. 2003). A lack of vitamin B complex has been linked to adrenal dysfunction in several studies (Peterson et  al. 2020). Pyridoxine (vitamin B6), a B-group vitamin, looks to be a viable nutritional prophylactic for stress control in a variety of vertebrates, including fish (Akhtar and Ciji 2020). In L. rohita and Chanos chanos fingerlings, dietary pyridoxine supplementation (45–60 days) increased growth performance and stress tolerance (Kumar et al. 2017). In adult zebrafish and rainbow trout (Schjolden et  al. 2006), studies indicated that modulating serotonergic signalling, GABAergic and stress-related behavioural responses (Mosienko et  al. 2012). Furthermore, pyridoxine is required as a cofactor by various enzymes required in the metabolic pathway of tryptophan, resulting in kynurenine synthesis, which has neuroprotective and immunomodulatory properties (Ueland et al. 2017). Pyridoxine is thought to boost the immunological response by increasing the production of immunomodulatory kynurenines. Pyridoxine’s stress-relieving properties can also be attributed to its essential role in erythropoiesis, which ensures enough oxygen supply to the vital tissues during stress (Akhtar and Ciji 2020). Research reports on the stress-relieving benefits of additional B-vitamins complex are scant in fish, but their role as “anti-stress” cannot be overlooked (Barros et al. 2009). In Jian carp, supplemented thiamine improved antioxidant defence and reduced the lipid peroxidation process (Li et al. 2014). Furthermore, thiamine (vitamin B1) has been found to protect rats and common carp against lead-induced oxidative damage (Mirmazloomi et al. 2015). Riboflavin and niacin are also known to have powerful antioxidant capabilities and alter immunological activities in fish (Marashly and Bohlega 2017; Xun et  al. 2019). Niacin supplementation reduced methyl mercury-induced oxidative stress and genotoxicity in rats recently (Pereira et al. 2020). As a result, dietary niacin appears to be an effective strategy for reducing the negative consequences of stress in fish. However, little data is available in this area in fish. Kumar et al. (2019) discovered that dietary selenium nanoparticles and riboflavin have a synergistic effect on improving thermal tolerance in Pangasianodon hypophthalmus.

5.30 Vitamins B9 and B12 Folic acid/vitamin B9 (active form: tetrahydrofolate) is required for one-carbon metabolism of amino acids and nucleotides. Folic acid also boosts fish’s immune, antioxidant defence, and resistance to bacterial infections (Sesay et al. 2016). Earlier

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animal experiments clearly demonstrated folic acid’s protective action against chemical/metal toxicity and oxidative stress (Reus et  al. 2018). According to the study of Sesay et al. (2017), dietary supplementation of folic acid in feed improved the internal capacity against high temperature of Megalobrama amblycephala by affecting HSP expression levels, blood cortisol and glucose concentrations, immunological reactions, and antioxidative capacities. Similarly, dietary folic acid ameliorated the deleterious effects in L. rohita by titanium dioxide nanoparticles in a recent research (Anagha et al. 2021). Cobalamin (vitamin B12) interacts with superoxide anion and helps to maintain cellular redox state in higher animals, including humans, according to research (Suarez-Moreira et  al. 2009, 2011). Cobalamin’s capacity to scavenge superoxide anion is most likely associated with its core ring structure (Chan et al. 2018). In the olive flounder Paralichthys olivaceus (Seo et al. 2020), intramuscular injection of butaphosphan and cyanocobalamin combination medication attenuated stress effects, as found in other species (Tabeleao et al. 2017).

5.31 Vitamins B5 and B7 No attempt has been made to assess the effect of pantothenic acid (vitamin B5) and biotin (vitamin B7) administration on stress relief in aquatic animals. All fish research has centred on determining the minimum requirements for optimal development (Yossa et al. 2015). Despite the fact that Feng et al. (2014) found that supplementation of biotin improved antioxidant capacity and lowered oxidative stress in Jian carp, the underlying mechanism remains unknown and requires additional exploration. Pantothenic acid and its derivatives have a protective role on cell membranes against oxidative damage (Slyshenkov et  al. 2004), whilst dietary pantothenic acid deficit in juvenile blunt snout bream caused oxidative stress (Qian et al. 2015). The administration of pantothenic acid improved the functioning of the adrenal cortex in several experimental animal models. In humans, pantethine treatment under stressful situations reduced cortisol hypersecretion (Herman et  al. 2016). Pyridoxine supplementation in feeds can increase the synthesis of serotonin and gamma-aminobutyric acid (GABA), which are important for stress management. Dietary pyridoxine has been shown to help with stress reduction, immunomodulation, and temperature tolerance. In L. rohita fingerlings, dietary treatment with pyridoxine (100  mg/kg) led to immunomodulation and relief from endosulfan stress (Akhtar et al. 2012). Dietary feeding of 100 mg pyridoxine per kg improved the heat tolerance of L. rohita fingerlings (Akhtar et al. 2012).

5.32 Minerals Finding the minimum/basic need for optimal development and health is the main goal of the majority of mineral nutrition research in fish (Herrera et  al. 2019). Reports on the advantages of different minerals and trace elements in aquaculture on stress management have yet to receive attention, with the exception of a few

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minerals and trace elements including selenium, manganese, zinc, and copper. The most well-researched trace mineral in terms of stress management is selenium, which has been shown to have favourable effects on a variety of vertebrates, including teleosts. Due to the increased selenium consumption caused by physical stress (transport, handling, and confinement) in Chinook salmon and rainbow trout, which resulted in carcass selenium loss, selenium supplementation may be required in stressful husbandry settings (Rider et al. 2009). In several fish, the optimal level of different forms (organic/inorganic/nano-selenium) of selenium was shown to reduce the stress including hypoxia stress, nitrite stress, low salinity stress, high-­temperature stress in (Kucukbay et al. 2009; Yu et al. 2020). In various fish species, selenium has been shown to protect against heavy metal and pesticide-induced oxidative damage (Xie et  al. 2016). In contrast, Wang et  al. (2006) reported that dietary selenium (1 mg/kg) was found to enhance nitrite toxicity in Penaeus vannamei. The antioxidative properties of selenium are thought to have a protective role in overcoming the negative effects of stress (Yu et al. 2020). Selenium is a part of a variety of selenoproteins and antioxidant enzymes, which are involved in metal detoxification (Pacitti et al. 2016; Xie et al. 2016). Several immune system components require selenium/selenoprotein to operate properly (Pacitti et al. 2016). Furthermore, recent research has shown that selenium inhibits cortisol release in adrenocortical cells of many fish (Mechlaoui et al. 2019). Although selenium is beneficial only at lower concentrations in the diet, it can be hazardous at greater ones (Xie et al. 2016). The amount of selenium that should be consumed daily must be carefully considered in all species and life stages to prevent adverse consequences. Animals need minerals to maintain their metabolic functions and provide building blocks for the bulk of their physical components. Additionally, it has been shown that several minerals have anti-stress qualities. Kucukbay et al. (2006) investigated the effects of dietary zinc picolinate (ZnPic) in the diet on the feed conversion ratio (FCR), feed intake, growth, and Zn, Cu, Mn, and MDA activity in rainbow trout. ZnPic supplementation reduced oxidative stress significantly, according to the findings. Stress causes increased selenium (Se) use, hence Se supplementation in commercial diets may be necessary. In grouper, Epinephelus malabaricus, dietary Se supplementation lowered oxidative stress and boosted the fish’s immunological response. Se-yeast was more efficacious than selenite in preserving Se status during stress (Rider et  al. 2009). Deficiencies in magnesium, in particular, cause negative effects across the HPA axis (Held et al. 2002). In times of extreme stress, a calcium-to-magnesium ratio of 1:1 is recommended. Magnesium is an important cofactor for a variety of functions, and it is especially important for triggering and transporting pyridoxine (Eby et al. 2010). Manganese, selenium, zinc, copper, molybdenum, chromium, and iodine are critical micro-minerals that play a protective role against oxidative stress and are also an important part of the adrenal cortex’s function.

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5.33 Nucleotides The fundamental elements of nucleic acids, nucleotides/nucleosides, can regulate immune cell proliferation, resulting in increased immunity (Hossain et al. 2016b). Earlier research found that including nucleotides/nucleosides in the diet improved fish innate immunity by increasing serum albumin and globulin (Hossain et  al. 2016b), augmenting peroxidase activity (Kenari et al. 2013) and increasing WBC counts (Kenari et al. 2013). Furthermore, nucleotides such as guanosine and adenosine act as toll-like receptors (TLR) that have been shown to increase the content of blood immunoglobulin in fish (Lin et al. 2009). Certain nucleotides, especially hypoxanthine and inosine are accepted to augment iron blood bioavailability (Tahmasebi-Kohyani et al. 2012). Another investigation indicated a higher haemogram profile in different teleosts supplemented with nucleotides (Hossain et  al. 2016a). By supplying the increased oxygen demand, nucleotides’ capacity to control haematopoiesis may improve stress tolerance. Furthermore, the fact that fish fed on nucleotides and nucleosides had lower blood glucose and cortisol suggested that they may have the ability to reduce stress (Palermo et al. 2013). Dietary supplementation of commercial nucleotides has also been reported to improve acute stress tolerance by decreasing plasma cortisol and glucose in several fish (Kenari et al. 2013). Nucleotides, especially inosine and hypoxanthine, are considered to improve iron absorption (Tahmasebi-Kohyani et  al. 2012), and previous research found greater haematological profile in teleosts supplemented with nucleotides (Hossain et al. 2016a). The capacity of nucleotides to control haematopoiesis may improve stress tolerance by allowing the body to satisfy the increased oxygen demand. Furthermore, the fact that nucleotide/nucleoside-fed fish had lower blood glucose and cortisol levels suggested that they may have stress-relieving properties (Palermo et  al. 2013). In some fish, dietary supplementation with commercial nucleotides increased acute stress tolerance and reduced plasma cortisol and glucose levels (Kenari et  al. 2013). Although the exact mechanism of nucleotides/nucleosides through which antioxidative benefits are achieved has yet to be fully explained, according to Hossain et al. (2020), nucleotides may make it easier for the antioxidative enzymes needed to combat oxidative stress to be made by boosting RNA synthesis. Furthermore, dietary nucleotide was found to improve osmoregulation in Salmo salar, Pagrus major, and Seriola dumerili (Hossain et  al. 2016a, 2018; Burrells et al. 2001). Burrells et al. (2001) found that Atlantic salmon given nucleotides in response to saltwater consumption had significantly lower blood chloride levels than the normally predicted levels. Higher Na+, K+ ATPase activity and chloride cell proliferation in the gill are thought to be the cause for this gain in osmoregulatory competence (Burrells et al. 2001). Other reports have indicated that given nucleotides in the diet caused lower serum cortisol in rainbow trout after infectious pancreatic necrosis virus inoculation (Burrells et al. 2001; Leonardi et al. 2003). In the case of challenged fish, increased disease resistance was seen, as well as a reduction in stress connected to dietary nucleotides (Low et al. 2003). The nucleotides can help to reduce the deleterious consequences of stress-related cortisol release. As a result, exogenous supplementation increases the positive benefits.

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5.34 Methyl Donors Kumar et al. (2014) evaluated betaine, choline, and lecithin in alleviating the detrimental effects of endosulfan under thermal stress in L. rohita. He discovered that adding methyl donors to the diet, particularly betaine and lecithin, reduces stress and improves the growth and health of L. rohita fingerlings throughout the culture phase. Another study (Muthappa et  al. 2014) found that betaine and lecithin can help reduce oxidative stress caused by low-dose endosulfan exposure. Even after prolonged low-dose endosulfan treatment, the livers of L. rohita fingerlings showed better erythropoiesis, antioxidant status, lipid profile, serum protein, neurotransmission, immunological competence, and protective action.

5.35 Conclusion and Future Perspective Recent multi-generational studies in the context of temperature stress have demonstrated that after several generations of acclimatization to higher temperatures, the progeny were in a better position to endure thermal stress, particularly by lowering their metabolic rate. More research is needed to figure out how this links to stress physiology and other stress-coping abilities. Fish sensitivity to global warming is difficult to generalize since their reaction is dependent on a number of factors, including innate metabolic capacity, their natural distribution, and life history or genetic background. Furthermore, the reactions of different fish species or people to certain stressors, such as increasing temperature, varied significantly. It is unknown if this variation in susceptibility to stress will be advantageous or disadvantageous for animals to the looming climate change. To accurately estimate the effects on ecosystems of aquaculture, we contend that this calls for a significant research effort. Because interactions between two or more stressors are difficult to predict, multi-stressor studies are required to better understand how high temperatures may affect fish populations. Fish’s thermal experiences, particularly early in life, can shape their HPI response to future stressors. To understand how early life exposure to high temperatures affects the capacity to cope with the many dangers posed by temperature stress, more study is needed. Acknowledgement  MS students (2020–22) of GSCWU Zoology Department are thankful to Dr. Saima Naz Assistant Professor at Government Sadiq College Woman University, Bahawalpur, Pakistan for their help in this work.

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Part II Biomarkers of Human Health

6

Thrombophilia and Its Markers: A Comprehensive Insight Humira Jeelani, Qudsia Fatima, Shuja Abass, Khalid Bashir Dar, Muzamil Farooq, Nahida Tabasum, and Fouzia Rashid

6.1 Thrombosis Thrombophilia defined as a tendency of forming clots inappropriately is an increasingly recognizable source of morbidity and mortality (Hoppe and Matsunaga 2002). There occurs an enhanced tendency of forming arterial or intravascular venous clots, mainly either due to acquired changes in the clotting factors of coagulation cascade or due to mutations in genetic factors or may be due to an interaction between acquired and genetic factors. There is usually a proper balance between the pro- and anti-coagulants in the coagulation system and a shift to the pro-coagulant state usually manifests clinically as thrombosis. The shifting of the coagulation system to a prothrombotic state where there is an excess of thrombin generation is not only due to excess of coagulation factors and mutation in genetic factors but also depends on the dynamic interactions with the vessel wall, platelets, endothelial cells, and other circulating cells in the body. Rudolf Virchow in 1856 was the first one who proposed the hypothesis to describe the underlying pathology behind

Humira Jeelani and Qudsia Fatima contributed equally and hold first authorship.  H. Jeelani · Q. Fatima · K. B. Dar · F. Rashid (*) Department of Clinical Biochemistry, University of Kashmir, Hazratbal, Srinagar, Jammu and Kashmir, India S. Abass Department of Clinical Biochemistry, SKIMS, Soura, Srinagar, Jammu and Kashmir, India M. Farooq Department of Advanced Centre for Human Genetics, SKIMS, Soura, Srinagar, Jammu and Kashmir, India N. Tabasum Department of Pharmaceutical Sciences, Pharmacology Division, University of Kashmir, Hazratbal, Srinagar, Jammu and Kashmir, India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 M. I. Ahmad et al. (eds.), Toxicology and Human Health, https://doi.org/10.1007/978-981-99-2193-5_6

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pulmonary embolus which leads to the proper understanding of three major bases of arterial and venous thrombosis. The first one is stasis, the second is a vessel wall injury and the third one is the abnormality in the circulating clotting factors. Afterward, numerous investigations were performed to understand the notion of hemostatic stability between the production and disbanding of fibrin molecules (Rosendaal 1999; Lane et al. 1996).

6.2 Coagulation Cascade The process of formation and breakdown of fibrin is mediated by two separate but enzyme-linked cascades, coagulation, and fibrinolysis, respectively. The coagulation pathway is a proteolytic cascade similar to the complement system. The enzymes of the coagulation pathway are present in an inactive zymogenic state in plasma and they later become active by undergoing proteolytic cleavage. The coagulation system consists of a chain of positive loops and negative loops that regulate the initiation course. The components of the coagulation cascade terminate in the thrombin production which has a role to convert soluble fibrin into insoluble fibrin molecules to generate clots. Thrombin generation is prompted by three pathways, the intrinsic and extrinsic pathways that provides alternate means for factor X generation, and finally the common pathway that produces the thrombin. The coagulation system is activated when factor VIIa forms a complex with tissue factor (TF) on the endothelial cell surface, monocytes, and the vessel wall. The activated complex TF-FVIIa then activates factor IX and factor X to generate, respectively, factor IXa and factor Xa. The activated factors Va and Xa, stimulate thrombin production from prothrombin. The generated thrombin has several pathological functions, it first converts fibrinogen (soluble) to fibrin (insoluble) that ultimately forms a hemostatic cap and activates several factors in the sequence V, VIII, XI, and XIII. Thrombin poses anti-coagulatory effects by complexing with thrombomodulin to stimulate protein C (PC). TF-pathway inhibitor rapidly inactivates the TF-VIIa complex. The activity of coagulatory factors which belong to the serine protease class is modulated by several plasma inhibitors occurring naturally. Among them most important ones are antithrombin, PC, and protein S. Inherited deficiency in one of these proteins is reported in almost 15% of individuals having venous thrombosis before 45 years of age. Antithrombin (AT), interacts with heparin, directly inactivating thrombin and by forming a covalent complex it promotes the inactivation of factor IX, factor X, and factor XI but the process of inhibition is not so fast. It can be enhanced to 1000 folds by the addition of heparin and compounds like heparin. Thrombin also activates PC, which is prompted by thrombin–thrombomodulin interactions. The active PC inactivates other factors including Va and VIIIa factors on the endothelial and platelet surface thereby blocking thrombin generation. PC needs a vitamindependent cofactor protein S for its proper functioning. The reduction in the levels of coagulatory inhibitors and raised coagulation factor levels leads to a thrombotic state. There are specific enzymes that catalyze the elimination of clots and maintain the turnover number of extracellular matrix proteins. An important enzyme involved

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in these processes is plasmin. Plasmin degrades fibrin that forms the base of clot formation. Plasmin is present in an inactive state in circulation known as plasminogen and its activation to plasmin is proceeded by tissue-type plasminogen activator (t-PA) and urokinase (u-PA) proteases. Both the enzyme activities in turn are modulated by proteases namely plasminogen activator inhibitor (PAI)-1 and PAI-2 (Esmon 1987; Heijboer et al. 1990).

6.3 Epidemiology The overall annual prevalence of venous thrombosis is  3 mg/L than normal subjects with hs-CRP less than 1 mg/L (Ridker 2007). Endothelial Inflammation  Chronic persistent inflammation leads to endothelial dysfunction and endothelial inflammation. Endothelial dysfunctioning has an important role in hypertension and cardiovascular diseases and the production of atheromatous plaques (Schulz et al. 2011). PCOS is a state related to endothelial dysfunction and a rise in endothelial inflammatory markers. In one study, age and weight-matched PCOS women and healthy control subjects were taken and were evaluated for endothelial functioning as measured by leg blood flow with a subsequent infusion of insulin and methacholine chloride, an endothelium-dependent vasodilator. PCOS was found to be related to insulin resistance as well as endothelial dysfunction. These were observed to be consistent with other studies reporting endothelial dysfunction in PCOS women. Additionally, PCOS is shown to be linked with raised inflammatory biomarkers namely sICAM-1 (soluble intercellular adhesion molecule-1), endothelin-1, plasminogen activator inhibitor-1, sVCAM-1 (soluble vascular cell adhesion molecule-1) and asymmetric dimethylarginine. Insulin resistance directly correlates with endothelial dysfunction in females with PCOS (Paradisi et al. 2001; Orio Jr. et al. 2004; Tarkun et al. 2004; Diamanti-Kandarakis et  al. 2005; Carmina et  al. 2006; Nasiek et  al. 2004; Diamanti-Kandarakis et  al. 2006; Moran et al. 2009). WBC  White blood count is an additional important inflammatory biomarker. Even slight elevations in WBC levels are linked with several CVD risk factors like lipid abnormalities, periodontal diseases, and increased BMI (Orio Jr. et al. 2005). WBC count was considered an important predictor of mortalities due to coronary heart diseases in a large cohort study and this was independent of traditional risk factors like smoking (Brown et al. 2001). It was first in 2005 that Orio and associates found raised WBC count in PCOS subjects (Orio Jr. et al. 2005). Age and BMI-matched 150 PCOS and normal women were included in this particular study. The median for WBC was found to be 7260 and 5220 cells/mm3 in PCOS cases and healthy controls respectively. Significantly raised levels of monocytes and lymphocytes were found in women with PCOS. WBC count was found to be directly associated with decreased insulin sensitivity as determined by HOMA-IR. Elevated WBC levels were reported in several other studies as well (Kebapcilar et al. 2009; Ruan and Dai 2009; Herlihy et al. 2011).

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Infections  PCOS is associated with chronic inflammation, chronic infection, or infections. Various pathogens including Helicobacter pylori and Chlamydia pneumonia are reported to have an association with chronic inflammation and CVDs (Mayr et  al. 2000). The presence of Chlamydia pneumonia is directly correlated with the presence of acute myocardial infarction and atherosclerosis (Saikku et al. 1988). Helicobacter pylori are reported to be positively associated with the incidence of unstable angina and arterial stiffness (Ohnishi et al. 2008; Pellicano et al. 2003). Some more chronic infectious diseases associated with cardiovascular diseases and inflammation includes pathogens involved in periodontal disease. Recently a study documented the association between cardiovascular mortality and periodontal disease (Xu and Lu 2011). Very few studies show an association of pathogen in PCOS, but these reports so far suggest there is an association of PCOS with Helicobacter pylori, Chlamydia, and periodontal disease (Morin-Papunen et al. 2009; Yavasoglu et al. 2009; Dursun et al. 2011). In girls with oligomenorrhea and hirsutism, Chlamydia trachomatis and Chlamydia pneumonia were found to be in greater quantity than in control subjects (Morin-Papunen et al. 2009). This association is strengthened together with the association of raised hs-CRP levels. Among these, Helicobacter pylori infections were more commonly found in age-matched PCOS cases than in healthy control subjects. PCOS women present with multiple raised clinical periodontal parameters together with gingivitis (Dursun et al. 2011).

9.8.2 Oxidative Stress Markers Inflammation and oxidative stress are strongly connected forming a vicious cycle wherein inflammation promotes the production of ROS (reactive oxygen species) and oxidative stress exaggerates and promotes the inflammatory cascade (Hulsmans and Holvoet 2010). This vicious cycle of oxidative stress and inflammation is appreciable in adipose tissues and endothelium. Oxidative stress is also reported to be related to metabolic syndrome, obesity, atherosclerosis, and diabetes mellitus. The study that first reported the presence of oxidative stress in PCOS females was depicted years before (Sabuncu et al. 2001). In this study, aged 27 years and BMI-­ matched PCOS women were compared with 17 healthy control subjects. Oxidative stress was confirmed by the occurrence of lipid peroxidation via erythrocyte malondialdehyde assay. Increased lipid peroxidation was reported in PCOS females which further were found to be strongly associated with insulin levels, hyperandrogenism, blood pressure, and BMI.  These reports were later affirmed by other investigations wherein both the protein carbonyl content and lipid peroxidation levels were measured (Kuscu and Var 2009; Fenkci et al. 2003). In addition to raised oxidative stress, the total antioxidant status, glutathione levels, haptoglobin, and proteins with antioxidant properties were shown to be reduced in PCOS females in comparison to healthy control subjects. PCOS women are more susceptible to DNA injury which is aggravated by oxidant molecules, and this susceptibility is directly associated with raised testosterone and insulin levels. Gonzalez reported an increased generation of reactive oxygen species in response to hyperglycemia by

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mononuclear cells in PCOS cases than normal healthy controls (Fenkci et al. 2003; Dinger et al. 2005; Insenser et al. 2010; Gonzalez et al. 2006). Advanced Glycation End-Products  Advanced glycation end-products (AGEs) are formed by the combination of proteins (amino group) and reducing sugars, forming adducts and eventually cross-linked reactive compounds. AGEs bind to signal-transducing receptors (RAGE) and lead to the generation of oxidative stress. AGEs can act either directly or via binding to RAGE resulting in the progression of cardiovascular diseases. AGEs are usually detected in diabetes but are recently shown to be raised in PCOS females. There is a study wherein AGEs were reported to be greater in PCOS women diagnosed via NIH than those diagnosed with Rotterdam and AE-PCOS.  Intermediate AGEs levels were reported in ovulatory normo-androgenic women and hyperandrogenic ovulatory females having typical ovaries. However, normal AGEs levels were found in hyperandrogenic women having polycystic ovarian morphology and isolated anovulation. More recently, AGEs were observed in PCOS and anovulation along with the levels of the anti-Mullerian hormone (Barlovic et  al. 2010; Diamanti-Kandarakis et  al. 2008; Diamanti-­ Kandarakis et al. 2009).

9.8.3 Adipose Markers The increased severity of metabolic disturbances and cardiovascular risk factors is mainly attributed to the production and release of inflammatory mediators known as adipokines by the adipose tissue. Emerging evidence strongly supports the fact that adipose tissue is actually an endocrine rather than a storing organ. The disrupted function of adipose tissue mainly leads to cardiometabolic instabilities in PCOS. It is mainly known that obesity together with the dysregulated generation of adipokines is the main contributor to PCOS (Teede et al. 2010; Faulds et al. 2003). Leptin  Leptin is a protein formed by adipocytes that is responsible for suppressing the appetite of an individual and enhancing energy expenditure (Vázquez et  al. 2015). It is reported that there is leptin resistance in obese individuals which is determined by the raised levels of leptin in the serum of obese individuals. The increased levels of leptin called leptin resistance is a positive stimulator of cardiovascular diseases (Wallace et al. 2001; Reilly et al. 2004). Although there are studies that have found raised leptin levels in PCOS girls compared to healthy ones, but a majority of other studies have shown no difference among the PCOS girls and healthy BMI-matched control subjects (Brzechffa et al. 1996; Yildizhan et al. 2011; Gennarelli et al. 1998; Chen et al. 2013). The majority of studies have found that adiposity determined by BMI is the chief predictor of leptin concentrations in PCOS women (Gennarelli et al. 1998; Telli et al. 2002). The mRNA expression levels of leptin didn’t vary between PCOS and healthy BMI-matched control subjects, suggesting obesity instead of PCOS changes the circulating levels and production of leptin (Svendsen et al. 2012). After keeping the adjustments in BMI, authors have

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reported that leptin levels slightly relate to free androgen index but were not found to differ between hirsut and non-hirsut women with PCOS (Hahn et  al. 2006; Gennarelli et  al. 1998; Pirwany et  al. 2001; Laughlin et  al. 1997). It was also observed that leptin levels do not show any association with insulin levels after adjusting for BMI.  However, there are few studies that reported a correlation between leptin levels with insulin levels (Yildizhan et  al. 2011; Gennarelli et  al. 1998; Hahn et al. 2006; Mantzoros et al. 1997; Sepilian et al. 2006; Svendsen et al. 2012; Laughlin et al. 1997). However, in studies where an association was observed between leptin and insulin levels, it was observed that on treating such patients with insulin-sensitizing agents like rosiglitazone or thiazolidinediones, troglitazone was reported to reduce the levels of insulin but not that of serum leptin (Sepilian et al. 2006; Mantzoros et al. 1997). Adiponectin  Adiponectin, released by the adipose tissue, has insulin-sensitizing effects directly as well as indirectly by stimulating the tyrosine phosphorylation of insulin receptors in the skeletal muscles (Kadowaki et al. 2006; Stefan et al. 2002). Among all ethnic groups, adiponectin levels were shown to be low in insulin-­ resistant and diabetic states (Weyer et  al. 2001). The low levels of adiponectin enhance the risk of diabetes mellitus and cardiovascular diseases at a greater faster rate and are also reported to have a relation with impaired ovulation and reduced LH/FSH ratio because there is an effect of adiponectin in lowering LH levels through activation of mitogen-activated protein kinase (MAPK) phosphorylation without affecting the release of FSH (Zyriax et  al. 2008; Lu et  al. 2008). Meta-­ analysis reports have shown low levels of adiponectin in BMI-matched PCOS women and healthy control subjects (Toulis et al. 2009). Recently a meta-analysis study has reported an association of T45G polymorphism in adiponectin with PCOS (Gao et  al. 2012). But there are reports which depict that adiponectin levels are important determinants of insulin resistance and it is also proposed that adiponectin levels and the ratio of high molecular weight adiponectin to whole adiponectin are reduced in BMI and age-matched PCOS women than control subjects (Pajvani et al. 2004; Wickham III et al. 2011). Visfatin  Visfatin is a cytokine produced by adipocytes to stimulate glucose uptake producing the same insulin-analogous effects (Fukuhara et al. 2005). Several meta-­ analysis studies have reported significantly high visfatin levels in individuals with metabolic syndrome, obesity, diabetes mellitus, and CVDs (Chang et  al. 2011). Serum levels of visfatin are raised in diabetic subjects due to the slow degradation of β cells (López-Bermejo et al. 2006). It is reported from a study that insulin manifests a negative effect on the release of visfatin from the adipose tissue of healthy subjects signifying an association of visfatin levels with insulin resistance (Haider et  al. 2006). Few authors propose that visfatin concentrations are elevated in an attempt to combat insulin resistance and to prevent further generation of insulin resistance (Tan et al. 2009). Nevertheless, the raised visfatin levels lead to harmful

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consequences and it has been found to be associated with the dysfunctioning of the endothelium, impaired renal clearance, and decreased vasodilation (Takebayashi et al. 2007). Visfatin has a role to activate NF-𝜅B, a well-known nuclear transcription factor in the endothelium. Lipid-laden macrophages found in the atherosclerotic lesion result in the activation of matrix metalloproteinases (MMPs) usually MMP-9 and MMP-2 ultimately leading to inflammation of vasculature and destabilization of plaque, respectively (Adya et al. 2001; Fan et al. 2011; Dahl et al. 2007). For those patients who undergo the procedures such as carotid endarterectomy or percutaneous coronary interventions, levels of visfatin were reported to be enhanced in the atherosclerotic lesions of symptomatic cases compared to atherosclerotic lesions of asymptomatic patients suggesting the importance of this particular adipokine in the deterioration of plaque and the development of acute cardiovascular events (Dahl et al. 2007). Raised levels of visfatin are the indicators of cardiovascular events in PCOS women mostly in those that are insulin resistant. Since this adipokine has widely been shown to be related to vascular inflammation and insulin resistance which are common features observed in PCOS therefore a series of studies were taken to evaluate the impact of visfatin in PCOS. Raised visfatin levels and expression were noted in adipocytes of PCOS females compared to healthy control subjects (Tan et al. 2009; Kowalska et al. 2007; Ozkaya et al. 2010; Panidis et al. 2008). High levels of visfatin were observed to be related to insulin resistance, BMI, LH, and free androgen index. It is found that metformin treatment at least for 3 months has a role in decreasing visfatin levels. However, some parameters like BMI, insulin resistance, LH, and free androgen index which were shown to be significantly linked with visfatin levels in PCOS women were not reported to be associated in some other studies (Tan et al. 2009; Kowalska et al. 2007). These variations may be due to small sample sizes, and variations in the racial phenotypic expression of PCOS. Recently some reports indicated that there exists no variation between visfatin concentrations in women with PCOS and healthy control subjects. Therefore, further studies with extra participants in the future are needed to elucidate the exact role of visfatin in women with PCOS. Chimerin  One of the chemoattractant proteins secreted by adipocytes is chimerin that is essential for the proper differentiation of adipocytes (Bozaoglu et al. 2007; Sell et al. 2009; Roh et al. 2007). It has the ability to drag macrophages expressing their receptor known as chimerin receptor CMKLR1 (chemokine-like receptor 1). This adipokine serves as a connecting link between chronic inflammation and obesity. By activating NF-𝜅B and extracellular signal regulated kinase (ERK-1/2) Chimerin has a tendency to induce insulin resistance in peripheral tissues and halt the uptake of glucose peripherally. Insulin is the stimulator of the release of chimerin generating a vicious cycle and in turn, enhancing insulin resistance (Sell et al. 2009; Zabel et al. 2005; Tan et al. 2009). Chimerin serves as a connection between diabetes and obesity. Serum chimerin levels were reported to be correlated with triglycerides, BMI, raised blood pressure, waist-to-hip ratio, and adipocyte volume (Bozaoglu et al. 2007; Sell et al. 2009). Adipocyte volume is reported to be enhanced

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in females with PCOS as well as in lean ones compared with the BMI-matched healthy control subjects. Chimerin is of important interest to study because it may serve as an underlying pathological determinant of insulin resistance in PCOS. Chimerin levels are found to be associated with inflammation which may have a role in leading to vascular damage and CVD risks. Obese PCOS women have shown enhanced levels of chimerin as compared to the lean PCOS cases and BMI-­ matched healthy control subjects. Treatment with metformin was shown to reduce chimerin levels thus enhancing insulin sensitivity (Tan et al. 2009; Guzel et al. 2014).

9.8.4 miRNA as Biomarkers in PCOS MicroRNAs (miRNAs) are a recent class of small, single-stranded, endogenous, noncoding RNA molecules formed of 20–25 nucleotides, produced from large precursor transcripts. MiRNAs regulate posttranscriptional gene expression by getting attached to the 3′untranslated regions of the target messenger RNA resulting in mRNA destabilization and repressed expression and translation (Ambros 2001; Flynt and Lai 2008). MiRNAs have been shown to regulate numerous biological activities such as metabolism, development and growth, apoptosis, hematopoietic differentiation, and stress response (Flynt and Lai 2008; Xue et  al. 2018). Furthermore, miRNAs control the expression and function of numerous genes through the feedback mechanism thus allowing for the amplification or suppression of a specific signal. Thus any appreciable modification in the expression of miRNA expression may contribute to various disorders including ovarian cancer, poor ovarian response, endometriosis, and CVDS (Cortez et al. 2011; Romakina et al. 2018). A mounting amount of data describes the effect of miRNAs in the pathophysiology of diabetes and potentially could act as a novel marker for diabetes mellitus (Guay and Regazzi 2013). However, recent research suggests that miRNAs are strongly linked to the incidence of PCOS and there is differential miRNAs expression in females with PCOS and non-PCOS cases (Long et al. 2014). Presently elevated LH (luteinizing hormone) and androgen levels, decreased or normal FSH (follicle stimulating hormone) levels, and abnormal estrogen production are suggested as diagnostic methods for PCOS women (Franks 1995). In addition, miRNAs are easy to detect as they are more stable in serum and resistant to nuclease activity. Therefore, miRNAs could potentially act as a candidate, non-invasive diagnostic biomarkers, and a remedial target for PCOS. However, our knowledge of the precise association between PCOS and miRNAs is still limited, and their role in the diagnosis and treatment of PCOS has yet to be determined. Using miRNA arrays, miRNA expression in PCOS women in comparison to age-matched controls was assessed (Long et al. 2014). Following primary profiling of miRNA, 9 miRNAs including miR-24, miR-186, miR-16, miR-19a, miR-30c, miR-320, miR-106b, miR-146a, and miR-222 were selected for more investigations. There was an increased expression of eight miRNAs, whereas the miR-320 expression was dysregulated in women with PCOS (Long et al. 2014). In this study population (68 PCOS and 68 normal women), among nine miRNAs, only miR-30c, miR-222, and miR-146a were

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notably upregulated in women with PCOS following Q-PCR analysis. Furthermore, miR-222 in association with miR-30c and miR-146a could be employed to differentiate PCOS women from women without PCOS.  Interestingly, the increased miR-222 expression has also been reported to be linked with diabetes and gestational diabetes mellitus (Shi et al. 2014). Additionally, miR-146a was shown to be negatively related to testosterone levels in PCOS females. Also, reduced miR-146 expression was related to insulin resistance and inflammation in diabetic patients (Long et al. 2014). Furthermore, the abnormal miRNA expression corresponds to the metabolic and inflammatory processes as found by target gene analysis and bioinformatics analysis. Several miRNAs like miR-21, miR-155, miR-103, and miR-27b are increased in PCOS females and may possibly be involved in reproductive processes and hormone metabolism following target gene and bioinformatics analysis (Murri et  al. 2013). More importantly, according to KEGG (Kyoto Encyclopedia of Genes and Genomes) and GO (Gene Ontology) analysis, these abnormally expressed miRNAs in PCOS patients participate in angiogenesis, apoptosis, ATP binding, immune system, p53 signaling, MAPK signaling pathways, and the response to harmful reactive oxygen species. Hence, all these findings conclude that altered miRNA expression might contribute to PCOS pathogenesis. miRNAs and Follicular Fluid  Follicular fluid offers a proper and suitable atmosphere for oocyte formation and maturation. Besides, it allows for the proper exchange of molecules between blood, theca and granulosa cells. In addition, the follicular fluid comprises several components such as estrogen, androgens, LH, FSH, anti-Mullerian hormone, growth hormone, transforming growth factor (TGF-­ β), activin, inhibin, anti-apoptotic factors, like Fas-ligands, metabolic and secretory products of the oocyte, and lastly amino acids, peptides, proteins, and nucleotides (Chen et al. 2019). Research has confirmed that follicular fluid provides an optimal, abundant, and less invasive source of miRNAs. Therefore, follicular fluid is valuable in describing the association between abnormal expression of miRNA and PCOS development (Roth et al. 2014). In a more recent study, 176 miRNAs were detected in the follicular fluid, among them, 29 were shown to be differentially expressed in the PCOS women and normal healthy control subjects (Butler et al. 2019). miR-382-5p was positively associated with free androgen index (FAI) and age, miR-127-3p was related to insulin resistance, and miR-199b-5p was linked with anti-Mullerian hormone. Further analysis suggested the connection of 12 miRNAs with the reproductive processes (Butler et al. 2019). Sathyapalan and associates demonstrated the possible clinical importance of miR-93 as an important marker for the diagnosis of PCOS as it was reported to be significantly elevated in PCOS women in comparison to women having no PCOS (Sathyapalan et al. 2015). Another study revealed that there are almost a hundred miRNAs that are differentially expressed in the follicular fluid to modulate the process of steroidogenesis in PCOS women. Two miRNAs including miR-320 and miR-132 were considerably reduced in the follicular fluid of PCOS subjects (Sang et al. 2013). Another investigation has found that miRNAs-235 and miRNAs-29 were expressed differentially in PCOS women and healthy control subjects, but miR-9, miR-18b, miR-32, miR-34c,

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and miR-135a have displayed a considerably greater expression in PCOS females (Roth et al. 2014). Also, the mRNA expression profile of synaptotagmin I (SYT1), insulin receptor substrate 2 (IRS2), and interleukin 8 (IL8) based on in silico target site predictions in follicular fluid was done. All five miRNAs were inversely linked with the expression of IRS2, SYT1, and IL8 in women with PCOS, thus indicating a suppressive mode of action (Roth et al. 2014). To sum up, these reports suggest that miRNAs are differentially expressed in the follicular fluid of PCOS women. Thus, it may be proposed that evaluating various miRNAs in the follicular fluid of these women may facilitate the elucidation of novel biomarkers for PCOS diagnosis and management. Furthermore, this may help us in classifying the various phenotypes of PCOS as well. miRNAs and Ovarian Dysfunction  In the current scenario, efforts are being made to recognize the exact pattern of anovulation and unusual folliculogenesis in subjects with PCOS. MiRNAs induce the expression of different proliferation markers, one among them is proliferating cell nuclear antigen protein (PCNA) (Sirotkin et al. 2010). They additionally modify follicular granulosa cells by altering expression on the particular organ and these may be differentially expressed among specific follicular sizes in the course of follicular atresia (Chen et al. 2019). Among the maximum miRNAs altered in the course of follicular atresia is miR-1275 that is likewise regarded to modify follicular granulosa apoptosis (Liu et  al. 2018). The miR-27a and miR-23a target SMAD5 thus stimulating apoptosis of follicular granulosa cells, at the same time as miR-93 targets cyclin-dependent kinase inhibitor 1A (CDKN1A) protein and promotes proliferation (Nie et  al. 2015). The miR-23A, miR-22-3p, miR-Let-7c, and miR-27a have been additionally expressed in women with untimely ovarian failure in comparison to healthy control subjects (Guo et al. 2017). Most current research has proven extraordinary expressions of miRNAs, frequently visible with follicular maturation in PCOS (Xue et  al. 2018; Yang et  al. 2013). In an experiment with PCOS rat model treated with dihydrotestosterone (DHT), 72 miRNA were found to be highly expressed and the 17 miRNA had been downregulated in DHT-treated ovaries in comparison to normal ovaries, with miR-32, miR-21, miR-96, miR-182, miR-183, and miR-184 chiefly downregulated (Hossain et al. 2013). miRNA-376 is related to primordial follicular improvement and it impacts granulosa cell proliferation via miRNA-376a, which binds to 3′untranslated region of PCNA mRNA (Zhang et al. 2013). Some investigation confirmed that miRNA-143 expression prevents primordial folliculogenesis by repressing granulosa cell proliferation (Zhang et  al. 2014). miRNA-224 additionally is expressed in granulosa cells of the ovaries, where it stimulates proliferation through transforming growth factor-β (TGF-β) and its receptor (Yao et al. 2010). miRNA-224 is also known to target Pentraxin 3 (PTX3), a protein associated with expansion of cumulus (Yao et al. 2014). MiRNA-PTX3 expression in PCOS is related to the fertilization method, and can doubtlessly serve as a marker to evaluate the oocyte quality (Huang et  al. 2013). miRNA-15a and miR-182 play an important function in granulose cells by causing their proliferation and apoptosis, and modulating

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s­ teroidogenesis. However, their concentrations had been notably low in the ovarian cells of PCOS rats (Sirotkin et al. 2014; Hossain et al. 2013). Therefore, the expression of those miRNAs may affect the maturation period of the oocyte by influencing the pathway of gonadotropin-releasing hormone (GnRH) (Moreno et  al. 2015). Hence, these reports summarize the significance of miRNAs for regulating the processes of propagation and apoptosis of the ovarian granulosa cells and ultimately folliculogenesis, which may serve as a possible goal to evaluate for ovulation in women with PCOS. miRNAs and Androgen Synthesis  The role of miRNAs in steroidogenesis in ovarian cells has been investigated in many animal species. miR-24 transfection led to a reduced level of estradiol production. Conversely, the increased expression of miR-320, miR-520c-3p, and miR-132 resulted in higher estradiol formation, and the transfection of miR-24, miR-483-5p, and miR-193b was linked to low progesterone secretion (Sang et al. 2013). miR-513a-3p was shown to be inversely associated with the luteinizing hormone and gonadotropin receptor (Troppmann et  al. 2014). Moreover, miR-107 was found to be related to testosterone production; whereas, miR-146a has been reported to significantly decrease testosterone production (Long et al. 2014). MiR320, miR-29a, and miR-518 were reported to be directly associated with greater serum testosterone levels while as miR-151 was inversely related to serum testosterone levels (Sorensen et al. 2014). A recent study reported that miR-29a and miR-155 are inversely related to serum amyloid  A4  in PCOS women (Arancio et al. 2018). Increased miR-181a and miR-378 expression decrease estrogen formation in granulosa cells by downregulating aromatase enzyme (Zhang et al. 2013). Inversely, various miRNAs have been reported to be positively related to estradiol synthesis, such as miR-133b overexpression raising estradiol formation along with the rise in CYP19A1 in granulosa cells of FSH-stimulated rat by impacting forkhead box L2 (fox12) (Dai et al. 2013). On the other hand, miR-224 overexpression targets SMAD4 of mouse granulose cells leading to an increase in estrogen discharge (Yao et al. 2010). miR-199a-3p and miR-193a-5p are inversely associated with levels of testosterone and directly correlated with estradiol and SHBG in PCOS women (Murri et al. 2018). This profound understanding of the role of miRNAs in steroidogenesis may explain the underlying metabolic abnormalities in PCOS and may aid in the early diagnosis of this condition. miRNAs and Insulin Resistance  About 70% of PCOS cases have insulin resistance (Diamanti-Kandarakis 2006). Ling et al. (2009) in an animal study, demonstrated that 3 T3-L1adipocytes became insulin-resistant cells by administration of high insulin and glucose levels after a remarkable rise in miR-320 expression. Treating insulin resistance with anti-miR-320 oligos restored insulin sensitivity by increasing the expression of glucose transporter 4 (GLUT4) and enhancing insulin-­ stimulated glucose uptake (Mao et al. 2013). It was found from a study by Jiang et al. that expression of miRNAs including miR-122, miR-193b, and miR-194 were

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raised in females with PCOS specifically those with altered glucose by influencing various signalling pathways, such as those of insulin, follicular development, and glycometabolism pathways (Jiang et al. 2016). miR-33b-5p has been found to be inversely associated with sterol regulatory element binding protein1(SREBF1), high mobility group A2 (HMGA2), and GLUT4 expression in a PCOS rat model with insulin resistance demonstrating that miR-33b-5p play a critical role in developing insulin resistance in PCOS women by suppressing the expression of GLUT4 (Yang et al. 2018). Various miRNAs such as miR-19a, miR-29, miR-126, and miR-1 were reported to promote insulin-facilitated glucose uptake by regulating the PI3K pathway (Chakraborty et al. 2014). miRNAs and Lipid Disorders in PCOS  Approximately 70% of women with PCOS have unusual lipid profiles such as elevated triglycerides, raised LDL, and diminished HDL levels (Berneis et al. 2007). Now, it is recognized that miRNAs play critical impacts on cholesterol and lipid metabolism. The miR-33 is found to target ATP binding cascade transporter A1 (ABCA1), an imperative controller, which increments the HDL levels and promotes the disposal of cholesterol by the liver (Najafi-Shoushtari et al. 2010). Additionally, miR-33 also modulates various genes implicated in the reverse transport of cholesterol like ABCG1, ABCB11, and cholesterol 7-α hydroxylase (CYP7A1) (Li et al. 2013). The miR-30c and miR-122 adjust LDL by altering the VLDL production and cholesterol biosynthesis. They also reduce Apo B lipoproteins by influencing the microsomal triglyceride transferase protein (Soh et al. 2013). MiRNA-33 regulates ABCG1 and ABCA1 by activating SREBP-2, and its inhibition increases ABCA1 hepatic expression subsequently increasing HDL levels (Najafi-Shoushtari et al. 2010). Besides, few miRNAs have regulation over the metabolism of LDL.  For example, restricted expression of miR-128-1, miR-185, and miR-148a lead to diminished levels of LDL (Wagschal et al. 2015). Moreover, miR-148a expression has been found to modify LDL blood levels by targeting LDLR and other important genes in lipid metabolism including AMP-activated protein kinase (AMPK), ABCA1, salt inducible kinase 1 (SIK1), and peroxisome proliferator-activated receptor-gamma coactivator α (PGC1α). In addition, miR-148a raises levels of HDL through the expression of ABCA1 in the liver (Wagschal et  al. 2015; Fernandez-Hernando et  al. 2011). MiR-143 and miR-130 are primarily related to adipogenesis, miR-143 is overexpressed in the overweight animal model (Jordan et al. 2011), whereas, miR-130 overexpression prevents adipocyte differentiation by repressing PPAR-γ activity (Lee et al. 2011). It is reported that the expression of miR-27b and miR-103 is considerably raised in PCOS females as compared to the non-PCOS controls (Murri et al. 2013). These findings demonstrated the solid relationship between miRNAs, dyslipidemia, and obesity and set out its possibility as an important therapeutic target in treating the metabolic aspects of PCOS.

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9.9 Treatment Strategies Lifestyle Changes  Physical activity enhancement and diet modifications are considered the cornerstone that leads to weight reduction and cardiovascular risk loss in PCOS women. Recent guidelines have recommended the use of exercise and a calorie-­restricted diet as a critical part of managing obesity and overweight in PCOS women. Indeed, lifestyle changes are regarded as a first-line, cost-effective treatment and as an important adjunct to drugs. Increased weight is related to worse reproductive and metabolic health consequences in PCOS women. A significant reduction in fertility rate with a BMI of more than 30–32 kg/m2 is recorded. A multitude of studies has revealed that a slight decrease in body weight by as little as 5% benefits fertility, decreases testosterone and insulin levels, reduces acne, and hirsutism, and improves psychological well-being. In addition, restrained lifestyle activities have proven equivalent to controlled exercise regarding weight reduction in obese women. Reduction in sedentary habits may exceptionally be essential in weight-reducing exertions. One study showed that spending 2 hours per day watching television was related to a 23% enhancement in body weight and an increase of 14% pre-disposition to type 2 diabetes over a period of 6 years. Physicians should stress increasing lifestyle activity, reducing sitting behaviors, increasing physical activities, and starting to do modest exercise. So far, no optimal exercise or specific diet has been established for treating PCOS. Also, it is hard to determine the usefulness of the above-mentioned strategies built on the inadequate facts which could deal with particular subcategories of PCOS females. More studies in the future are required to obtain a proper comparison of the efficiency of various lifestyle treatment and management programs to treat PCOS (Naver et al. 2014; Lovvik et al. 2019; Misso et al. 2014; Teede et al. 2011; Norman et al. 2007; Hu et al. 2003). Oral Contraceptive Pills  Oral Contraceptive Pills (OCPs) are the most frequently used medication in PCOS and have been suggested by the PCOS Consensus Group, the Task Force and the Endocrine Society, and the Australian Alliance. These are considered the first treatment options for menstrual disturbances and hyperandrogenism in women with PCOS. OCPs decrease LH secretions by repressing the hypothalamic–ovarian axis, reducing ovarian androgen production, decreasing adrenal androgen secretion, increasing SHBG, and preventing the transformation of testosterone to more potent dihydrotestosterone and its binding to the androgen receptors which ultimately reduces levels of testosterone in circulation. This improves acne, androgen-associated hirsutism problems, and regularization of the menstrual cycle, and also leads to effective contraception. A minimum of a total of 6 months of effective OCP supplementation is needed to attain reasonable results against hyperandrogenism. Although guidelines have not specified the usage of one OCP over the other, oral contraceptives containing a low dose of neutral progestins or anti-androgenic are considered a good choice. Progestin acts as an antagonistic to androgen at its receptors. Progestin is also shown to protect the endometrium from hyperplasia and decreases the risk of endometrial cancer. Besides the useful

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effects, there are still various adverse effects of OCPs on metabolic parameters. Clinical studies have found that the consumption of OCPs in women with PCOS enhances the risk of developing hyperinsulinemia, insulin resistance, type 2 diabetes mellitus, and CVDs. Combined Oral Contraceptives (COCs) have been found to cause an increase in triglycerides and cholesterol (Costello et al. 2007; Yildiz 2008; Balen 2011; Lidegaard et al. 2012; Mastorakos et al. 2002). Clomiphene citrate: is suggested as the first treatment for anovulatory infertility in PCOS women. Clomiphene is an estrogen receptor antagonist and promotes the secretion of FSH and the maturation of follicles in the ovaries. Clomiphene citrate is a safe, cheap, and efficacious agent, easy to administer and manage. Clomiphene citrate is primarily given at the beginning of progestogen-induced or spontaneous menses that enhance FSH levels, sufficient to stimulate further follicular growth and maturation in the ovary. Estradiol levels rise steadily after the appearance of a dominant follicle and a preovulatory LH surge is seen in most of the women treated with this drug. Clomiphene is observed to promote ovulation successfully in almost 80% of patients and hence was useful in increasing pregnancy rate in comparison to placebo. According to standard protocol, clomiphene citrate is given from either the 2nd or 3rd day of the menstrual cycle for about 5 days, beginning with a fairly low dose of 50 mg per day, and in subsequent cycles increasing to 250 mg per day if unsuccessful. Some other substitute protocols for the consumption of clomiphene in women with known resistance were proposed. Obese PCOS women often show no response to low doses of clomiphene, and it was observed that at a dosage of 50 mg only a 20% ovulation rate was reported in women weighing greater than 91 kg. There is a direct relationship between the dosage of clomiphene with the degree of obesity. The increased dosage requirement may cause so many harmful effects but may raise the chances of multiple gestations (Thessaloniki ESHRE/ASRM-PCOS consensus 2008; Hull 1992; Nasseri and Ledger 2001). Metformin  Metformin (Glucophage), a biguanide, is the most commonly used drug for treating diabetes mellitus. It has been comprehensively studied in infertility associated with PCOS. The earliest report using metformin on PCOS females was described by Velazquez et al. (1994). Since then, a multitude of investigations has assessed the role of metformin in the management of PCOS. Insulin resistance is the main causative factor that leads to PCOS and is the central focus to treat these patients. So, metformin insulin-sensitizing drug is given in medical practice for the treatment of PCOS. Metformin acts by suppressing hepatic glucose formation and by enhancing the sensitivity of insulin peripherally. Metformin is shown to increase the degree of ovulation in PCOS women; however, it is unclear whether this outcome is independent of weight loss. Metformin after 3 months of treatment seems to benefit the ovulatory function and hence could be suggested in PCOS females who are clomiphene resistant and also in those wishing to avoid multiple gestations. Moreover, the earlier data recommended that metformin acts by reducing the occurrence of gestational diabetes mellitus and early pregnancy loss without raising the risk for birth defects in these PCOS women. A retrospective study showed females

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who receive metformin, became easily pregnant and its continued use during pregnancy prevents early pregnancy loss rate which was reported to be 8.8% in comparison to 41.9% of women who did not use the drug. Glueck et al. (2001) found that among women consuming metformin during the whole pregnancy period, normal live births were noted in 58%, 32% had pregnancies ongoing beyond the first trimester, and miscarriages in the first trimester were reported in 10.5% and no birth defects were observed. In a meta-analysis of randomized controlled trials, compared to placebo or no treatment, metformin was shown to improve the frequency of ovulation and clinical pregnancy did not affect the live birth rate. In a recent randomized, multicenter, placebo-controlled double-blind study, metformin enhanced live birth rates as compared to the placebo with the most positive effect observed in obese women. These conclusions are in line with other research that assessed pre-­ treatment with metformin for 3 months before in vitro fertilization or intracytoplasmic sperm injection. In addition, metformin in clomiphene-resistant patients is given in combination with clomiphene to promote fertility outcomes. Additionally, ovulation was found in 76% of women administered with both metformin and clomiphene citrate as compared to 42% of females treated with clomiphene alone. However, the ESHRE/ASRM in its 2008 consensus concluded that there is no benefit of adding metformin to clomiphene as metformin is less efficacious than clomiphene in ovulation induction. Although, there is limited research regarding the role of metformin in inducing ovulation in PCOS, however, the present data indicate that metformin may have a critical role in improving live birth frequencies. However, guidelines have rejected metformin as a first-line therapy for inducing ovulation in PCOS women. It is considered a pregnancy category B drug (Velazquez et al. 1994; Glueck et  al. 2001; Tang et  al. 2006; Palomba et  al. 2009; Cassina et  al. 2014; Jakubowicz et  al. 2002; Tang et  al. 2012; Morin-Papunen et  al. 2012; Kjotrod et al. 2011). Thiazolidinediones  Thiazolidinediones also known as glitazones, belong to insulin sensitizer drugs and are usually used in the treatment of diabetes mellitus. These drugs bind to peroxisome proliferator-activated receptor-gamma (PPARγ), a transcription factor in adipose tissue, and include drugs like troglitazone, rosiglitazone, and pioglitazone (ActosR). The effect of pioglitazone was studied in PCOS patients and its administration reduces fasting serum insulin levels, hyperinsulinemia, and insulin resistance. But, its use is reported to lead to the risk of bladder cancer. Troglitazone enhances the ovulation rate in PCOS females but its usage has been stopped due to hepatotoxicity. Troglitazone alone resulted in an increase of more than 40% ovulatory rates and the success of clomiphene citrate pre-treatment together with troglitazone enhanced the rate from 35% to 75%. Also, its administration in clomiphene-resistant women leads to higher rates of pregnancy and ovulation respectively at 39% and 83%. Rosiglitazone also benefits the rate of ovulation in PCOS patients but is associated with weight gain. Thiazolidinediones are neither recommended for ovulation induction nor during pregnancy. These are considered as pregnancy category C drugs. Furthermore, because of increased cardiovascular

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effects have limited its prescription and consent that it is not reasonable to suggest thiazolidinediones in PCOS women who are young and trying to conceive (Stabile et al. 2014; Azziz et al. 2001; Mitwally et al. 1999). Spironolactone  Spironolactone, an anti-androgen, is a mineralocorticoid aldosterone antagonist that typically binds to the androgen receptor and prevents adrenal, and ovarian steroidogenesis by directly inhibiting the activity of 5-α-reductase and by competing for binding to androgen receptors in hair follicles. Spironolactone is usually given to PCOS patients together with OCPs because if it is given alone it can lead to menstrual disturbances and may increase the risk of feminizing a male fetus. Spironolactone consumption may lead to hyperkalemia, and hence, it must be given with proper caution in renal impairment patients. One study showed that spironolactone decreases insulin resistance and was found to be useful in improving PCOS symptoms such as hirsutism and acne. But, other investigations failed to validate these results. Guidelines, in general, do not recommend specific protocols for spironolactone to treat PCOS, and thus, extra studies are required to elucidate its benefits for the management of this syndrome (Badawy and Elnashar 2011; ACOG Committee 2009; Ganie et al. 2004; Ganie et al. 2013). Finasteride  An anti-androgen that blocks hepatic and tissues 5-α-reductase competitively, further inhibiting the formation of potent dihydrotestosterone from testosterone and promoting repression of dihydrotestosterone concentrations. This drug is considered a pregnancy category X drug due to the higher risk of feminizing a male fetus in pregnancy. Those who consume this drug should also take adequate contraception that will be a better option which may potentially enhance synergistic effects (Badawy and Elnashar 2011; ACOG Committee 2009). Aromatase Inhibitors  Aromatase inhibitors are those compounds that reduce the conversion of androstenedione and testosterone to estrone and estradiol, respectively, resulting in increased secretion of FSH. Aromatase inhibitors were permitted by the Food and Drug Administration as first-line adjuvant treatment for estrogen receptor-positive breast cancer. The most commonly used aromatase inhibitor, known as letrozole, is regarded as the first treatment for the induction of ovulation in PCOS women. A dosage of 2.5 mg per day of letrozole for 5 days is given from 3rd to 7th day of the menstrual cycle. Some of the beneficial findings of using letrozole include an enhanced rate of mono-follicular ovulation generation. Letrozole has a lesser half-life compared to clomiphene and it has antiestrogenic effects on the endometrium. Studies comparing letrozole and clomiphene in PCOS women reported that letrozole consumption is associated with a higher degree of ovulation but letrozole intake did not lead to ovulation per cycle or live birth rate per person. Another study that compared letrozole with clomiphene citrate in 103 infertile PCOS women, described that letrozole dose was related to a similar ovulation rate

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but a significantly higher pregnancy rate. Presently, letrozole is considered an off-­ label medicine. Additional research is required to verify the beneficial effects of aromatase inhibitor over clomiphene and its role in inducing ovulation in PCOS women. Hence, the intake of aromatase inhibitors in medical practice and non-­ experimental situations should be evaded possibly (Casper and Mitwally 2011; Palomba 2015; Misso et al. 2012; Kar 2012). Gonadotropins  The keystones in the treatment of ovulatory infertility are gonadotropins. Gonadotropin like recombinant FSH or human menopausal gonadotropin is usually used to induce ovulation in PCOS females, who normally do not respond to other therapies. However, the use of gonadotropin is considered expensive and has greater chances of getting multiple pregnancies and ovarian hyperstimulation syndrome (OHSS), especially in PCOS women. OHSS may result in ovarian enlargement and serous effusions, and may be life-threatening in severe cases. Hence, gonadotropins are chosen as the last option in treating the PCOS population. Available guidelines suggest an initial gonadotropin dose of 37.5–50 IU per day, with a little increment of 50% of the preceding FSH dose to decrease the risk of OHSS and multiple pregnancies. A recent study demonstrated that in comparison to clomiphene, the low-dose FSH treatment resulted in a high rate of pregnancy in the first cycle, and also increases both the cumulative pregnancy rate as well as high cumulative live birth rate (Humaidan et al. 2010; Homburg et al. 2012). Laparoscopic Ovarian Drilling  It is presently regarded as the safest, most efficient, less costly, and substitute for gonadotropin ovulation induction in sterile and PCOS women who are resistant to clomiphene treatment. In ovarian drilling, approximately 4–10 holes are drilled by means of electrocautery or laser treatment in the ovarian stroma and surface. A single treatment may result in the improvement of menstrual cycles and pregnancy to about 92% and 58%, respectively. Despite its advantages, concerns arise about the effect of drilling on ovarian functions and thus should be regarded as an optional treatment procedure for PCOS due to the accessibility of inexpensive, effective, and less invasive alternatives (Gjonnaess 1984). In Vitro Fertilization  The third-line procedure for the treatment of infertility in PCOS is in vitro fertilization (IVF). Individuals with PCOS have comparable miscarriages and less live birth rates with conventional in vitro fertilization in comparison with women without PCOS. In a study comparing the GnRH agonist and GnRH antagonist protocols in PCOS women undergoing IVF treatment, there was no major difference noted in the ongoing or medical pregnancy rate. However, with the antagonist protocol, the OHSS rate was reported to be 10% lesser. In a double-blind, randomized, placebo-controlled trial, metformin considerably decreased the risk of OHSS in PCOS females undergoing IVF (Heijnen et al. 2006; Al-Inany et al. 2011; Palomba et al. 2011).

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9.10 Conclusion PCOS is a complex common syndrome linked with a spectrum of manifestations including reproductive, metabolic, psychological, and cardiac features. It represents a major economic and health burden, as it is a chronic disorder with clinical features across the lifespan. Much has been elucidated about the etiology of PCOS since its first clinical picture in 1935. Yet, the primary pathophysiology of PCOS is still unexplainable. Also, it is difficult to identify such patients as a specific diagnostic criterion is still lacking. If properly diagnosed, the risk of reproductive and metabolic derangements and the resulting risk of cardiovascular diseases may be deferred or stopped. There is a need for proper biomarkers that may act as predictors of metabolic, cardiometabolic, reproductive, and gynecological disorders. This chapter has summarized all the various biomarkers which may help in early diagnosis and in developing early prevention strategies. Besides we have elaborated on lifestyle modifications which seem to be the first measure in PCOS treatment, as it addresses all the complications associated with excess body weight. Pharmacotherapy is used to manage the most common symptoms like menstrual disturbances, hirsutism, metabolic and fertility problems, and the risk of cancer in aged persons. Overall, supplementary investigations are required in this state and broad evidence-based strategies are required to direct physicians in the optimal treatment of PCOS. Acknowledgment  We are highly thankful to the Faculty of the Department of Clinical Biochemistry, University of Kashmir, Srinagar for providing us with the research-based environment to compile this work.

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Impact of Environmental Stress on Gene Modification, Cancer, and Chemoresistance

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Shamila Fatima, Moinuddin, Asif Ali, and Safia Habib

10.1 Introduction Human activity has contributed to a significant deteriorative change in the composition of the environment. However, nature has reverted and affected the health status of human beings. Any toxicant, unwanted entity added to the environment and released to become an indispensable part of the ecosystem is an environmental pollutant, which induces ecological stress. That, in turn, affects the lifestyle and human environment relationship. Most environmental pollutants resist biodegradation and are ubiquitously present. Toxic compounds are mainly present in commodities required by us in our daily activities, like cosmetic products, automobile exhausts, food containers, and chemicals used for industrial-level cleaning. Pollutants are released into the environment gradually in small concentrations but are potent enough to cause health issues and malignant changes. Some substances are directly carcinogenic, while others accumulate in the biological system and are metabolized into carcinogens. Further, most of them synergize with other toxicants to exert a harmful effect. There is a long list of toxic environmental pollutants. Here for clarity, we would focus only on carcinogenic chemicals that induce resistance to cancer therapy.

S. Fatima Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, India Moinuddin · A. Ali · S. Habib (*) Department of Biochemistry, Faculty of Medicine, JN Medical College, Aligarh Muslim University, Aligarh, India e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 M. I. Ahmad et al. (eds.), Toxicology and Human Health, https://doi.org/10.1007/978-981-99-2193-5_10

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10.2 Environmental Pollutant Exposure and Genome Instability The human body is an example of complex biochemical mechanisms. Any physical, chemical, endogenous, or exogenous agent that could interfere with this equilibrium or increase the system’s entropy could induce carcinogenic changes (Langie et al. 2015). Everyday human system is exposed to different types of chemical agents. Some can interact with the human system for lifestyle or behavioral reasons. A larger population faces the problem of chemical exposure due to occupational reasons. Studies have suggested that it is not only the type of chemical that matters, but how, when, and where the exposure occurs. This question needs to be addressed. In terms of exposure, what scientifically appears essential is the dosage and the nature of exposure. Is it acute or chronic? Reports support that if a mutagen of a similar dosage is exposed chronically, it is more likely to induce carcinogenesis (Peto et al. 1991a; Peto et al. 1991b; Lewtas et al. 1997). A study by Van Schooten et al. (1997) reported that for individuals who were occupationally exposed to polycyclic aromatic hydrocarbons, the amount of DNA adduct accumulation depends upon the dose of exposure. Workers exposed to relatively high concentrations of these polycyclic aromatic hydrocarbons had a low pile of DNA adducts and vice versa (Van Schooten et  al. 1997). The process of carcinogenesis involves the collection of mutations and mutagenic adducts. The ability of a tissue to repair DNA lesions or clear any mutagenic adduct varies, and so is its susceptibility to environmental mutagenesis. Most DNA damage and mutagenesis are expected to develop in the stem cells, germ cells, and during the embryonic stages of development (Cervantes et al. 2002; Leyns and Gonzalez 2012; Barouki et al. 2012). Stem cells are pluripotent cells with the potential for self-renewal and differentiation. Stem cells are also crucial in that, compared to somatic cells, their ability to repair lesions and maintain genome integrity is much more stringent because of accurate cell cycle regulations (Langie et  al. 2015). Reports show that the parent’s lifestyle is associated with increased childhood cancers (MacArthur et  al. 2008). One of the studies by MacArthur et  al. (2008) reported that the habit of maternal alcoholism could increase the risk associated with childhood leukemia. Environmental exposure to male germ lines is said to be more dangerous; it is reported that offspring were found to show an accumulation of mutagens related to minisatellite DNA. This was more explicitly pronounced when the father was exposed to environmental chemical mutagens (Linschooten et al. 2013). During the embryonic stages of development, the genome is more vulnerable to accumulating mutagenic components than the matured tissues (Jansen et al. 2001; Perera et al. 2002; Laubenthal et al. 2012; Perera 2011). Studies related to environmental toxicants and mutagens have shown that if there is a low dose exposure (Concentration of a compound to which the general population is exposed (Hernández et al. 2013), then the likely development of any disorder may continue up to the stage of puberty, and may or may not be reflected during in utero stages of development (Barouki et  al. 2012). The same study also quoted that the individual’s nutrient status can modify the risk of

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developing cancer or disease, provided proper care is taken during the early stages of life (Heindel and Vandenberg 2015). Environmental pollutants induce carcinogenesis through genome instability. The chemicals that are present as ubiquitous toxicants have their specific action mechanism; apart from just creating DNA adducts or DNA lesions, some of the toxicants are such that they may not only induce cancers but may also interfere with the action mechanism of chemotherapeutic drugs. The last part of this chapter will focus specifically on two aspects. First, a brief action mechanism of chemotherapeutic medicines, and second how chemoresistance may develop in the presence of some specific chemical pollutants in blood. A long list of chemicals could induce genome instability leading to cancers. Humans are exposed to these harmful chemicals daily. Most are either slow to degrade or even resist degradation (Lagunas-Rangel et al. 2022). These chemicals can enter the human body through the skin, food consumed, and inhalation. Once inside, they can accumulate, cause mutations and biological oxidations, and interfere with mitochondrial membrane potential (Khan et  al. 2021a, b; Warsi et  al. 2021). Apart from cancer induction, some of the environmental pollutants are such that they directly interfere with drugs used to treat cancers and are responsible for chemoresistance (Fig.  10.1). There are some contaminants/pollutants that can reduce the efficacy of chemotherapeutic compounds; this may impact the outcome and prognosis of the protocol planned for cancer treatment (Yeldag et  al. 2018). Before understanding how environmental pollutants interfere with the chemotherapeutic action of drugs, it becomes essential to view the mechanism of commonly used drugs to treat cancers.

Fig. 10.1  Carcinogenic induction and reduced efficacy of cancer therapy due to environmental pollutants. Biological agents here refer to bacteria and viruses

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10.3 A Brief Overview of the Mode of Action of Some Common Chemotherapeutic Drugs There are many different types of drugs that are used to treat cancers. The chemotherapeutic agents could be categorized into either of the groups. They could be alkylating agents, corticosteroids, nitrosoureas, antimetabolites, and inhibitory topoisomerase and mitotic cell cycle inhibitors. Some commonly used drugs are tamoxifen (TAM), paclitaxel, vincristine, cisplatin, 5-fluorouracil, and vinblastine (VIN). The behavior of these drugs depends on their chemical makeup and the stages of cancer, i.e., when these were prescribed (Lagunas-Rangel et  al. 2017). Most of the medications mentioned here show a significant loss of efficacy when some environmental pollutants are allowed to interfere. Here we will first briefly describe the action mechanism of these drugs to identify the sites where the contaminants may interfere with the activity of chemotherapeutic agents. TAM is used to treat estrogen receptor-positive (ER+) breast cancer. TAM competes with 17β-estradiol to inhibit estrogen receptor-mediated signaling (Shagufta and Ahmad 2018). A patient’s response to relapse events depends on the gene variant cytochrome P2D6 (CYP2D6) and the pro-drug conversion rate to an active metabolite (Beverage et al. 2007). Paclitaxel, a Taxol, is commonly used to treat solid tumors, specifically breast, ovarian, and lung cancers. Paclitaxel results in mitotic arrest and, to some extent, is a microtubule-stabilizing drug (Weaver 2014). VIN and Vincristine (VCR) are mainly used to treat hematological cancers like Hodgkin’s and Non-Hodgkin’s lymphoma. VIN and VCR both interfere with the formation of microtubules by attacking the tubulin. This, in turn, affects the process of spindle formation and ultimately leads to the cell’s death (Keglevich et al. 2012). Cisplatin is used as an anticancer drug against solid tumors. Its anticancer activity is due to its ability to form DNA intrastrand crosslink adducts. Accumulating cellular mutagenic adducts initiate ataxia telangiectasia (ATR), mitogen-activated protein kinases (MAPK), p53, and p73 signal transduction pathways that induce apoptosis. A significant limitation of cisplatin therapy is that it develops resistance (Siddik 2003).

10.4 Target Sites for Developing Chemoresistance and its Molecular Mechanism The major challenge in treating cancer is the resistance to the chemotherapeutic agent. To improve the outcome of a particular drug, the acquired, and the intrinsic drug resistance needs to be overcome. Chemoresistance is one of the obstacles to efficient therapy and a hindrance to a fruitful outcome (Fig. 10.2). Chemoresistance results in relapses. Molecular mechanism commonly associated with chemoresistance includes the following (Brasseur et al. 2017): 1. Pathological remodeling of Extra Cellular Matrix (ECM). 2. Increase in the number of cancer stem cell population.

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Fig. 10.2  Causes for the reduced efficacy of chemotherapy due to environmental toxicants

3. Overexpression of genes coding for CYP450 isozymes. 4. The ability of cancer cells to repair DNA damage. 5. Induction of oncogenic signaling. 6. Enhanced efflux of chemotherapy drugs.

10.5 Pathological Remodeling of Extracellular Matrix The extracellular matrix of a tumor environment is quite different from that of normal tissue. The composition of ECM defines the tissue oxygenation, metabolism, transport, and signaling of a tissue. Therefore, it is reported that ECM governs the growth of a tumor and describes its malignant potential and the response to chemotherapy (Henke et al. 2020). ECM and its component may not be malignant, but change in its structure and composition may be pathological. Such changes may create an environment favorable for the sustenance of tumors and help in infiltration (Brown et al. 2019). Pathological changes to the ECM may also induce oxidative stress, interfere with DNA repair mechanisms, and induce drug resistance.

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10.6 Increase in the Number of Cancer Stem Cell Populations Cancer stem cells possess the ability to differentiate and self-renew. These cells promote the growth of tumors. Different cancers have increased stem cells, showing resistance to most anticancer drugs (Nunes et al. 2018). Also, an increase in cancer stem cells is often correlated with poor prognosis and enhanced chemoresistance (Barbato et al. 2019). Cancer stem cells escape the effect of drugs and induce the state of resistance mainly by increasing drug efflux and inactivation of the drug compound. They create a more aggressive environment (Barbato et al. 2019), favoring metastasis and relapse. The outcome is usually heightened stemness and poor chemosensitivity.

10.7 Overexpression of Genes Coding for CYP450 Isozymes Chemotherapeutic drugs, like all other xenobiotics, are handled by cytochrome P450s (CYP450s). Cytochrome P450s are a large group of enzymes in the endoplasmic reticulum and mitochondria. Different cytochrome isozymes carry out the metabolism of most of the endogenous and exogenous components. Among the many, CYP1B1 is reported to be overexpressed in various cancers and interferes and modulates the biotransformation of drugs like Docetaxel and Mitoxantrone (Pathania et al. 2018). Upregulation of CYP2A6 is mainly involved in detoxifying 5-Fluorouracil, Aflatoxin, and Cyclophosphamide (Lagunas-Rangel et  al. 2022). Increased chemoresistance is also shown with upregulation of CYP2A7, CYP1B1, and CP4Z1 expression (Li et al. 2017).

10.8 The Ability of Cancer Cells to Repair DNA Damage Cancer cells have a much-pronounced ability to repair DNA damage through the overexpression of signaling pathways. Chemotherapeutic drugs that act through DNA damage are reported to become resistant due to activation of various oncogenes, transcription factors, and hypoxic environments. A study by Sakthivel and Hariharan (2017) states that cancer cells that have undergone the repair mechanism acquire more resistance to therapy. At times multiple DNA repair pathways are activated in a cancer cell. The response toward alkylating agents like Temozolomide is handled by overexpression of the nucleotide excision repair proteins (NER) and the enzyme O6-methyl-DNA methyl transferase (Sakthivel and Hariharan 2017; Yu et al. 2020). Cancer cells also show activation of translesion synthesis (TLS) repair pathways. TLS specifically corrects DNA interstrand crosslinks and is associated with chemoresistance (Bukowski et al. 2020).

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10.9 Induction of Oncogenic Signaling Cancer cells show activation of many oncogenic signaling pathways like the mitogen-­ activated protein kinases/extracellular signal-regulated kinase MAPK/ ERK pathway, nuclear factor kappa beta (NF-κB), nuclear factor erythroid 2 related-­ factor (NRF2-ARE), phosphoinositide-3-kinase protein kinase/AK strain transforming (PI3K/AKT), and rat sarcoma virus (RAS). MAP/ERK pathway promotes cancer cell survival by promoting cell proliferation, differentiation, and migration. It also favors the expression of proteins acting as transporters for drug efflux. MAP/ ERK is mainly activated due to the environmental stress faced by the tumor cell (Salaroglio et al. 2019). Overexpression of the NF-κB pathway induces radiation as well as chemoresistance. This pathway imparts aggressiveness to cancer cells (Li and Sethi 2010). The NRF2-ARE is overexpressed in cancer cells to tackle oxidative stress caused by drugs like Doxorubicin, Cisplatin, and Etoposide. NRF2-ARE activates antioxidant enzyme and nonenzyme systems. Also, NRF2-ARE is reported to sustain tissue invasion, angiogenesis, immune evasion, and proteins involved in proliferation (de la Vega et  al. 2018). Cancers of breast, lung, and ovarian tissue escape the effect of chemotherapeutic drugs by activating PI3K/AKT pathway. This pathway stimulates cell growth, inhibits apoptosis, and modulates cellular metabolism (Liu et al. 2020). Despite several traditional and modern methods used to treat cancers, chemotherapy remains the treatment of choice. However, 90% of cancer-­ related deaths are due to multidrug resistance developed by these cells, along with multiple escape mechanisms that a cancer cell uses to lessen the efficacy of chemotherapeutic compounds (Assaraf et al. 2019).

10.10 Common Organic Pollutants Interfering with Chemotherapeutic Drugs Environmental pollutants specifically categorized under organic pollutants pose significant public health concerns. Most sources of such contaminants are usually contributed through unchecked industrial activities, burning waste, automobile exhaust, laboratory waste, and pesticides. Additionally, ubiquitous exposure is always due to cosmetics, plastic products, beverage containers, and atmospheric particulate matter. These compounds resist biodegradation, can cross the blood–brain barrier, interfere with the cellular antioxidant defense system, induce inflammatory responses and modulate signaling pathways, specifically MAPK/ERK, NF-κB, PI3K/Akt, RAS, and glycogen synthase kinase 3-β (GSK3β) (Iqubal et al. 2020). Air pollution is reported to be one of the significant risk factors for the burden of chronic noncommunicable diseases (Al-Kindi et al. 2020). It is also said that air pollution has a more pronounced impact on human health than water or soil pollution. Around 55% of the world’s population face health issues related to air pollution (Landrigan et al. 2018). PM and gases mainly contribute to air pollution. PM ranging from 2.5 μm or more diminutive pose a severe threat to public health (Al-Kindi et al. 2020). The most vulnerable population resides in middle-income countries. Seventy-seven

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percent of the Indian population is exposed to PM 2.5 and more than 40  μg/m3 (Al-Kindi et al. 2020; Landrigan et al. 2018). Environmental pollutants harm human health and are known to induce carcinogenesis. Apart from this, some of the pollutants are specifically reported to cause a state of chemoresistance. Therefore, it appears that with increasing levels of environmental pollution, the chances of reduction in the efficacy of chemotherapy drugs increase. This allows the cancer cells to survive in the presence of toxic trails of drugs (Lelieveld et al. 2019). Here, this chapter will specifically discuss a few of the toxicants that are reported to induce chemoresistance, like (a) Particulate matter, (b) Aluminum chloride (AlCl3), (c) Benzo [a] pyrene, (d) Persistent organic pollutants (POPs), and (e) Bisphenol A (BPA).

10.11 Particulate Matter PM, specifically airborne particulate matter, is a dynamic entity. The composition of PM and its size is quite variable (Fig.  10.3). PM associated with adverse health effects ranges from fine (≤2.5 μm in diameter) to coarse (2.5–10 μm in diameter). PM is mainly formed from metals, biological components, organic sulfates, and nitrites (Kim et al. 2015). PM suspended in the air is purported to cause various ill effects on health. PM mainly affects people living in areas with high air pollution index. They cause reproductive, respiratory, cardiovascular, and central nervous system disorders and cancers (Manisalidis et al. 2020). PM can travel long distances and remain suspended for a long time, leading to chronic exposure through airways. Fine PM can penetrate the cellular machinery and induce changes by activating Notch signaling pathways. Cells exposed to PM with a diameter of 2.5 μm or less transform and cause chemoresistance. In a study by HeBelbach et al. (2017), the

Fig. 10.3  Chemical composition of PM2.5 as described by Bell et al. (2007). PM2.5 are highly heterogeneous and variable in size and composition. PM2.5 can easily penetrate the respiratory tract, affects different organ functions, and induce a state of chemoresistance in cancer cells

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authors reported that bronchial epithelial cells, when exposed to PM2.5, showed enhanced genes associated with ECM remodeling and reduced the genes responsible for cell adhesion (HeBelbach et al. 2017). PM2.5 reduces Doxorubicin’s cytotoxic effects by upregulating multidrug resistance protein-2 (MRP2) (drug efflux transporter) (Merk et al. 2020).

10.12 Aluminum Chloride Aluminum is a crucial constituent of the earth’s crust but not an essential mineral for the human system. Humans are exposed to aluminum mainly through antacids, food additives, aluminum salts, food contaminants, cosmetics, and beverages (Bondy 2016). Aluminum chloride (AlCl3) (≤200 μm) exposure in human hepatoma cells (HepG2) treated with 5-Fluoro uracil (100 μM) was reported to show a reduction in apoptosis in a concentration-dependent manner (Li et al. 2019). AlCl3 causes resistance to treatment with 5-Fluoro uracil (Barouki et al. 2012; Li et al. 2019). Chronic exposure to aluminum salts is also reported to induce tumorigenesis, carcinogenesis, and metastasis and behave as antioxidants. AlCl3 is also said to reduce the effect of chemotherapeutic agents acting through reactive oxygen species production (Mandriota et al. 2016; Sarac et al. 2019). AlCl3 induces chemoresistance by modulating anti and pro-apoptotic proteins, B-cell lymphoma-extra-large (BCL-XL) and Bcl-2-associated X protein (BAX), respectively (Fig. 10.4).

10.13 Benzo [a] Pyrene Benzo [a] pyrene (BP) is a polycyclic aromatic hydrocarbon; it is present as an air contaminant and as a constituent of cigarette smoke. BP is detoxified by liver enzymes like cytochrome P450 and is converted to benzo [a] pyrene-7,8-diol-­9,10epoxide (BPDE). BPDE reacts with N2 of guanine and N6 of adenine to produce BPDE-dG and BPDE-dA adducts. These adducts are toxic to the cellular system (Alexandrov et al. 2010). BP and the DNA adducts are known to activate aryl hydrocarbon receptors and induce cancer progression (Kasala et al. 2015). On the other hand, BP has been shown to cause resistance against drugs given in combination. When cisplatin was administered along with 5-Fluorouracil or paclitaxel in the presence of BP, it reduced the efficacy of the cocktail of drugs and induced a state of resistance. BP increases the activity of PI3K/AKT and MEK/ ERK pathways. BP also reduces the intracellular retention of drugs by inducing the ATP-dependent-P-glycoprotein efflux pump overexpression. This reduces the drug’s efficacy by expelling it out of the cell before it can perform its function (Sugihara et al. 2006). When given along with a combination of drugs, BP increases cell invasion and migration. Also, it affects the pharmacodynamics and pharmacokinetics of the chemotherapy drug and induces chemoresistance (Dzobo et al. 2018). A study by Huang et  al. (2020) reported the effect of BP on the progression of tongue squamous cell carcinoma. Authors have reported that tongue epithelial cells

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Fig. 10.4 AlCl3 modulates different pro and anti-apoptotic proteins to induce chemo/radiation resistance

(CAL 27) and squamous cell line 9 (SCC9) showed chemoresistance to cisplatin (≤ 100 μM) and 5-fluorouracil (≤100 μg/ml). Also, 50 nM of BP (in the same study) was administered simultaneously for 3 months with Doxorubicin. Cotreatment of BP with Doxorubicin is reported to overexpress proteins like sex-determining region Y box 2 (SOX2), master regulator of cell cycle entry (cMYC), kruppel-like factor 4 (KLF4), and ATP binding cassette subfamily member 2 (ABCG2) (Huang et al. 2020; Liu et al. 2016). These proteins represent stem cell markers.

10.14 Persistent Organic Pollutants Persistent Organic Pollutants (POPs) are common toxic contaminants in food items. POPs are nonbiodegradable organic chemicals (carbon-based). POPs are primarily introduced in foodstuff during food processing or storage (Guo et al. 2019). Human exposure to POPs is mainly through raw or processed food of animal origin. The primary source of POP exposure is reported to be fish (Fair et al. 2018). POPs have a long life; some can survive long transports through air and water and accumulate in the biological systems (Vorkamp and Rigét 2014). Therefore, they need monitoring. POPs present in the environment are classified into three categories (Bull et al. 2008):

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1. Industrial by-products: POPs that are released as a by-product of industrial activities mainly include polychlorinated dibenzofurans (PCDFs) and polychlorinated dibenzo-p-dioxins (PCDDs), and polyaromatic hydrocarbons (PAHs). 2. Organochloride pesticides: Metabolites of organochloride-based pesticides like dichlorodiphenyltrichloroethane (DDT) are included in this category. 3. Technical chemicals: This category includes polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), and perfluorooctanesulfonate (PFOS). Exposure to all three POPs is associated with reproductive, cardiovascular, endocrine and metabolic disorders, and cancers (Alharbi et al. 2018). POPs, like other mentioned environmental chemical contaminants, induce a state of resistance to chemotherapy. They are reported to reduce the efficacy of cisplatin and doxorubicin (Lagunas-Rangel et al. 2022; An et al. 2014). POPs cause chemoresistance by activating NF-κB, PI3K/AKT, MAP/ERK, and mouse double minute 4 human homolog of p53 binding protein (MDM4) levels. Also, it is reported that PCB-1254 (polychlorinated biphenyl) increases the levels of DNA repair by producing more proteins involved in the repair mechanism like ataxia telangiectasia mutated (ATM), methylene tetrahydrofolate (MTH), and breast cancer gene 1 (BRCA1) (Loury and Byard 1983). A study conducted on human mammary epithelium 1 (HME1) cells with low doses of hexabromocyclododecane (HBCD  =  0.0015  nM) showed that when cells were exposed for 2  months, an improvement in the DNA response was observed. The cells also showed reduced cytotoxic effects of cisplatin (Nair et al. 2020). On the other hand, some cells were treated with 4-tert-octylphenol (0.0048 nM), simultaneously inducing doxorubicin resistance (Lagunas-Rangel et al. 2022; Lagunas-Rangel et al. 2017). Bisphenol A  Bisphenol A (BPA), i.e., 2,2, bis [4 hydroxyphenyl] propane, is found in regular consumer and health care products. BPA is added to provide strength and flexibility to polycarbonate plastic products and is now ubiquitous. It is reported that BPA is expected to show a 4.8% growth rate during the year 2016–2022 (Noszczyńska et al. 2021). Plastic products suitable for microwave use always have BPA, as they can bear impactful collisions and endure high temperatures (Cariati et  al. 2019). Polycarbonate material in the form of canned food is in demand and is extensively used, in almost every household utensil, containers like tin cans, feeding bottles, toys, and plastic kitchen wares (4–23 μg BPA/can), and electronic equipment contains BPA (Hoekstra and Simoneau 2013; Vandenberg et  al. 2007). BPA is also found in medical equipment like dental sealants, artificial teeth, hemodialyzers, and heart-lung machines. Manufacturing the mentioned commodities releases BPA into the soil, water, and air. BPA is associated with many health hazards. Inside the human body, BPA is detoxified by the liver and converted to BPA-Glucuronide. However, the unconjugated components also exist and remain in the blood that is mainly responsible for the toxic potential of BPA (Vom Saal et al. 2007; Mínguez-­ Alarcón et al. 2016). BPA is an endocrine disruptor involved in the progression of

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Table 10.1  Action of bisphenol A on different types of cancers in females Cancer type Cervical cancer

Cellular changes induced • Stimulates cell invasion, and migration and induces metastasis.

Endometrial cancer

• Activates and induces cell proliferation, invasion, and migration.

Breast cancer

• Upregulates progesterone receptors and epithelial– mesenchymal transition. • Induces cell proliferation. • Induce estrogen receptor-mediated pathway.

Ovarian cancer

• Increases intracellular organic acids. • Increases cellular energy levels. • Favors proliferation and metastasis.

Action mechanism • Activates NF-κB, Inhibitor of kappa light polypeptide gene enhancer in B-cells (IKKb), p-65, and Matrix Metallopeptidase 2 (MMP-2). • Enhanced expression of cell surface adhesion receptor 44 (CD44), (0,105 and Cyclooxygenase (COX) through MAP kinase pathways. • Downregulation of Cadherin-1 (CDH1), Prolactin (PRL), and Insulin-like growth factor binding protein (IGFBP-1). • Downregulates DNA repair genes specifically; p-53. • Activates Signal transducer and activator of transcription (STAT3), cyclins (A, D3), Cyclin-dependent kinases (CDKs), Sarcoma gene in humans (SRC), and Extra cellular signal-regulated kinases (ERK1/2). • Upregulates G Protein-coupled estrogen receptor (GPER), Epidermal growth factor receptor (EGFR), Ak Strain transforming (AKT), Connective tissue growth factor (CTGF), B-Cell leukemia/ lymphoma-2 (Bcl-2), MMP2/9. Activates Janus kinase (JAK/STAT), MAP/ERK, and PI3/AKT pathways. Increases mRNA levels of C-X-C motif chemokine ligand (CXCL 12), Vimentin (VIM), Apelin (APLN), and Estrogen receptor (ER α) Inhibits Caspase 3,7,9 (CASP 3,7, 9) and Tumor necrotic factor β (TNF-β)

References Vandenberg et al. (2007); Mínguez-­ Alarcón et al. (2016) Brasseur et al. (2017); An et al. (2014); Vom Saal et al. (2007)

LaPensee et al. (2009); Fernandez et al. (2012); Khan et al. (2021a, b)

Brasseur et al. (2017); de la Vega et al. (2018); Kim et al. (2015); HeBelbach et al. (2017)

gynecological cancers; hence it can be associated with adverse health effects (Seachrist et al. 2016) (Table 10.1). BPA is a ubiquitous environmental pollutant that is known to induce chemoresistance through the following mechanisms: 1. BPA can attenuate the cytotoxic effects of doxorubicin, cisplatin, and vinblastine (LaPensee et al. 2009).

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2. BPA promotes the expression of DNA repair proteins like breast cancer gene 3 (BRCC3), structural maintenance of chromosomes (SMC1A), protein kinase DNA activated catalytic subunit (PRKDC), X-ray repair cross-complementing (XRCC6), BRCA1, ATM, DNA repair protein (RAD50/51), and gene with multiple roles in DNA repair (CtIP) (Ganesan and Keating 2016). 3. It can cause chromosome compaction and reduction in DNA strand breaks (Fernandez et al. 2012). 4. It reduces intracellular oxidative stress and DNA damage (Ramos et al. 2019). 5. BPA elevates intracellular levels of anti-apoptotic proteins like B-cell lymphoma-­ extra large (BCL-XL) and B-cell leukemia/ lymphoma 2 (BCL 2) (Ramos et al. 2019; LaPensee et al. 2010). A study presented at the 55th Congress of the European Societies of Toxicology in 2019 showed that when breast cancer cells (MCF7) were incubated with Bisphenol A (0.1–100 nM) for 4 h, followed by treatment with tamoxifen (9 nM) and Vincristine (5.45 nM). The chemotherapeutic potential of these drugs was found to be reduced (Costa-Veiga and Viegas 2019; Khan et al. 2021a, b).

10.15 Conclusion What defines carcinogenesis appears to be the type of DNA adducts and mutagenic lesions and when and where they accumulate. It shows us that we must keep our environmental health appropriate for safe living. Endogenous mutagens are always less damaging than exogenous environmental mutagenic contaminants. Environmental contaminants induce a state of genome instability and are also found to corroborate chemoresistance. Cells acquire the form of chemoresistance through multiple mechanisms. What appears is that the protocol designed to treat cancers needs to be more aggressive for any drug to act more effectively. Most of the literature that supports the effect of environmental pollutants in inducing chemoresistance is based on experiments conducted on cell lines. Therefore, what we infer are extrapolated results. Also, the bioaccumulation of these environmental toxicants shows tissue variability. Hence chemoresistance induced must also vary. At this time, what could be said is that we need to understand and consider the increasing levels of environmental pollutants and the geographical predominance of the contaminants. To establish the correlation between the efficacy of the type of drug or combination of drugs to treat cancers and the interference caused by some specific pollutant. Still, more experimental drug trials need to be conducted to establish the exact interaction of chemotherapeutic drugs, environmental pollutant(s), and to what extent the chemoresistance is induced in the system.

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Part III Human Health Risk Assessment

Human Health Risk Assessment (HHRA) for Environmental Exposure: A Brief Account

11

Partha Sarathi Singha and Debosree Ghosh

11.1 Introduction A Human Health Risk Assessment (HHRA) is actually a process by which any risk to human health due to any contaminants present at a particular place is measured (Ashbolt et al. 2013). In other words, it is the way of assessing the impact of any hazardous substance on a human or a group of people, or a community (Health.vic 2018). Various information is gathered and analyzed to assess the potential effects on human health. Basically, factual data is considered and those are technically analyzed to deduce the health impacts. The study involves the assessment of human health risks in the present or near future. The process has some 4–6 steps and it begins with planning (U.S.  Environmental Protection Agency 2022a). Certain guidelines are also made by the concerned authorities for proper and efficient risk assessment of human health. In certain countries, these guidelines include a detailed description of protocols, handbooks and framework documents, and standard operating procedures (SOPs) (U.S.  Environmental Protection Agency 2022a). In the United States, Environmental Protection Agency (EPA) has detailed risk assessment guidelines (U.S.  Environmental Protection Agency 2022b). Even state or region-­ specific guidelines and details are available on the website of EPA.  Each human health risk assessment is unique with respect to the type of hazard and the population considered for the study. Populations considered for the study are either a group of individuals in a community or a community itself. A group refers to a particular

P. S. Singha Department of Chemistry, Government General Degree College, Kharagpur II, Madpur, Paschim Medinipur, West Bengal, India D. Ghosh (*) Department of Physiology, Government General Degree College, Kharagpur II, Madpur, Paschim Medinipur, West Bengal, India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 M. I. Ahmad et al. (eds.), Toxicology and Human Health, https://doi.org/10.1007/978-981-99-2193-5_11

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type of individuals within the population, i.e., children, workers, old people, or people with a particular health condition or disease. Rising environmental pollution around the world is a matter of serious concern for researchers, health workers, environmentalists, administrators, and common people today. Human exposure to the polluted environment around him is unavoidable and is most unfortunate. Several deleterious health impacts have been found, recorded, and studied in detail so far which have been recognized to be associated with human exposure to a toxic environment (Ghosh and Parida 2015). The pathophysiology of certain diseases like COVID-19 has also been found to be adversely affected by exposure to pollutants (Manisalidis et  al. 2020; Ghosh et  al. 2022). HHRA is now a conventional technique which is utilized to evaluate the probable health risk of human beings who are getting exposed to the toxic environment around them. The approach may be limited to a certain specific industrial environment where an individual who works there gets regularly and extensively exposed to certain toxic chemicals and other industrial contaminants. Otherwise, the approach of HHRA may be extended to the broader aspect where the risk to the human health of a community or a part of the community may be assessed who are getting exposed by default to their surrounding polluted environment. The major contributor to the environmental health risk for humans in a particular region may vary depending on the composition of the air, water, or soil of that specific region. Depending on this, the type, kind, and intensity of the health risk of humans may vary. For example, an industrial region in Kolkata, India, which is particularly a metropolitan city in India will have a higher level of industrial contaminants in its air, soil, and water bodies, specifically the Ganges (Ghirardelli et al. 2021). This in turn will impose some specific types of health hazards for the citizens of Kolkata. In this case, HHRA for environmental exposure is the need of the hour. Proper risk assessment can open up avenues for remedial measures for possible health ailments and can also induce the urge in the public and government to take stringent measures to minimize or stop the environmental release of highly toxic and hazardous contaminants. Thus HHRA is a very important aspect of industrial safety and public health maintenance and management (Orzáez et al. 2019). Like other countries, in India now a day’s paid service for industrial HHRA is available (sgsgroup.in/en-gb/ mining/quality-health-safety-and-environment/risk-assessment-and-management/ human-health-risk-assessment). These services can be easily availed by the industries to assess the human health risk issues at their sites and issues may be directly addressed and resolved to minimize health risk of its workers. Similarly, the HHRA services for environmental exposure are available from authorized government agencies in different countries. In India, various government policies and acts have been made against environmental pollution taking into consideration the various human health risk issues associated with exposure to a polluted environment. There are environmental pollution monitoring bodies in various regions of India that gather information about the status and level of various pollutants in those regions from time to time. This information correlated with human health status and utilizing the basic steps of HHRA, the risk to human health because of these environmental pollutants is assessed. New government policies are made and enacted depending

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on the results of such assessments. Nongovernmental organizations (NGOs) are known to participate and play important role in health research (Delisle et al. 2005). HHRA is also made by certain NGOs, private organizations, and research institutes whose findings are also considered by the government for deducing the final status of human health risks for environmental exposures. The prime drawback in India is the lack of strict implications of the existing policies for reducing environmental pollution and less number of pollution monitoring bodies (Chandra 2015). More funds, concern, and manpower need to be allotted and engaged in the evaluation of human health risks in India in order to significantly reduce and control environmental pollution and to effectively fight back the health risks imposed due to exposure to a toxic environment.

11.2 Basic Steps in HHRA The initial step of HHRA is planning and scoping (Fig. 11.1). In other words, proper and compact planning is very essential for the successful execution of any protocol or technique. Similarly, for the successful implementation of HHRA, full-proof planning is inevitable. At first, the planning is done and the issue needs to be identified. The exact situation or the reason for which the HHRA is taken into consideration is identified. Then the possible hazards are addressed. The problem is identified and hazards are addressed. Possible health risks due to the hazards identified are considered (U.S. Environmental Protection Agency 2022c). The association of the identified hazards with adverse health effects is enlisted. Next, the dose–response relationship needs to be interpreted (Fig. 11.1) (Northern Health 2015). The relationship of dose–response needs to be understood, i.e., the relation of the toxicant identified to the toxic response of human health is understood. At the end of the last century, a better-evolved modeling approach was introduced instead of a dose– response assessment. It was called Bench Mark Dose (BMD) approach (Crump Fig. 11.1  Steps of HHRA

Steps of HHRA

Planning and Scoping process

Step 1 - Hazard Identification

Step 2 - Dose-Reaponse Assessment

Step 3 - Exposure Assessment

Step 4 - Risk Characterization

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1984). This technique is much advanced. It considers all available dose–response data in a comprehensive analysis. This in turn allows interpolation between tested doses to predict the BMD. The BMD is the dose which is identified to be associated with a specific health risk or a specific adverse biological response which is termed a Benchmark Response (BR) (Crump 1984). This is followed by exposure assessment (Fig. 11.1). The process involves developing a site or model situation which involves developing pathways that connect the sources of each hazard to human health. This involves collecting and assessing data regarding each hazard or risk factor. The amount of the hazardous material or the toxicant is sampled or measured or assessed in air, water, or soil and the population which might be at risk of being affected by the toxicant under study is identified. The pattern and duration of their exposure to each hazard and the extent to which the population may get affected are identified and assessed. And finally, exposure assessment is done next to toxicity assessment. The risk is characterized. This step involves analysis of the information obtained in exposure assessment (Fig. 11.1). The information is analyzed to understand and estimate the past, present, or future health risks of humans, i.e., people, communities, or populations exposed to the environmental hazard (Crump 1984). Thus briefly, the five major steps of HHRA process are planning and issue identification, hazard assessment, understanding the dose–response relationship, exposure assessment, and risk characterization (https:// www.epa.gov/risk/conducting-­human-­health-­risk-­assessment).

11.3 Utilization of HHRA Consultation of the community and stakeholders is a part of the HHRA process. Human health risk assessment is essential as it lays the foundation for the risk management stage. This process includes recommendations, advice, or actions as required. This is essential to assure the protection and safety of human health. In the risk management stage, possibilities of risk and ways to manage those are communicated. The World Health Organization has taken up initiatives and has published several books as toolkits for handling environmental risk assessment for HHRA. One such toolkit has been developed for public health and environment professionals, experts, regulators, and decision makers with some training in the field and industrial managers who are responsible for conducting HHRA and for formulating decisions on whether to take steps for management of the risk factor (WHO 2021). More such toolkits are necessary at national, state, and regional levels in countries around the world for proper HHRA and management of the risk factors to minimize human health risks for environmental exposures. Studies suggest HHRA for environmental exposure should include environmental aspects of antibiotic-resistance development and this should address antibiotic-resistant bacteria (Ben et  al. 2019). The main utilization and purpose of HHRA for environmental exposure are to address the exact risks associated with the identified risk factors. This helps in risk management. Various policies, plans, programs, and management techniques are

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recommended, made, and undertaken depending on the results of HHRA.  Thus HHRA is actually focused on human health risk minimization and overall human benefits.

11.4 HHRA for Exposure to Polluted Air Air pollution is now an alarming issue concerning its adverse impact on various aspects of human health. Unfortunately, the level of air pollution is increasing daily around the world and India is no exception. Though the pattern of air pollution and the components contributing to the pollution of air are different depending on the geographical regions considered for HHRA, the ultimate ill effect on human health is equally detrimental. Exposure to air pollution is associated with mild to severe health ailments and chronic exposure may even lead to fatal consequences (World Health Organization. Regional Office for Europe 2016). The air pollutants that cause serious to fatal health issues in humans and affect many people are of main concern. Various health problems induced by air pollution include respiratory disorders, allergies, asthma, cancer, and immune disorder (U.S. Environmental Protection Agency 1991). HHRA for exposure to polluted air is technically termed as “air pollution health risk assessment (AP-HRA).” This involves the estimation of the impact on health that is possible due to measures taken that affect the quality of air in various socioeconomic, environmental, and policy circumstances (Maji et  al. 2017). In many countries, AP-HRA has been made formally required. In many countries, the decision-­making process for new projects, programs, regulations, or policies which are associated with air quality needs an AP-HRA formally. In some other countries, due to scientific interventions advanced quantitative analysis of the health risk associated with exposure to polluted air is now possible. Hence, using various methods daily increasing number of AP-HRA are being carried out for different policy making in different countries using different methods (Chepelev et al. 2015). Studies reveal that various environmental toxins impose various types of health hazards on humans. Among various environmental toxins, Benzo[a] pyrene (BaP) is a well-studied one. This compound needs metabolic activation and imposes carcinogenic risks on humans. BaP has a potent neurotoxic effect in humans. Exposure to environmental BaP leads to poor neurodevelopment in children and memory loss in adults. Both carcinogenicity and neurotoxicity of such toxins as BaP are essential to be considered for HHRA (Cheng et al. 2013). A study conducted for HHRA for air pollution exposure in the city of Mumbai reveals that the total number of cases of cardiovascular mortality, mortality, respiratory mortality, hospital admission due to chronic obstructive pulmonary (COPD), cardiovascular disease, and respiratory disease were 4914,8420, 889, 149, 4081, and 10,568, respectively, in 1992. Interestingly and unfortunately, those figures recorded in 1992 increased to 9962,15,872, 1628, 580, 7905, and 20,527, respectively. For the study, a software called AirQ was used and this helped to analyze the various health ailments due to air pollution as mentioned above, and the pattern of their change for 22  years (1992–2013) in Mumbai. WHO guidelines for the concentration of air pollutants

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such as PM 10, SO2, and NO2 were adopted for the purpose of the study. For this, the concept of a relationship between the concentration of hazards and response to relative risk was used. The overall deduction of the study was that the prime contributors to the adverse health situation, morbidity, and mortality were the particulate matters. An increase in the concentration of these particulate matters leads to a sort of dose-dependent increase in the incidences of various health ailments in the people of Mumbai from 1992 to 2006 (Cheng et al. 2013). Though the concept of AP-HRA is not new, it has not been widely and uniformly accepted by all countries equally. Though adoption of AP-HRA by the healthcare system will assist in the easy assessment and management of human health risks due to exposure to polluted air. AP-HRA if adopted, will play an inevitable role in disease prevention and promotion of public health at the community and global levels (Hassan et al. 2021).

11.5 HHRA for Exposure to Polluted Water Several studies have been conducted on HHRA for human exposure to polluted toxic water (Chen et al. 2022). Studies reveal that contamination of surface water and groundwater with heavy metals in regions around mines is recognized as a potential human health risk factor that can impose tremendous health impacts on the nearby residents of the mine (Mohammadi et al. 2019). A study conducted in Iran showed that various metals like arsenic, cadmium, and chromium in drinking water in a village located near the mine were significantly high compared to the WHO standards, and those imposed significant health risks for the children and adults of the local village (Mohammadi et al. 2019). Other toxic metals like aluminum and its compounds are abundantly present on the earth’s crust. These kinds of heavy metals present in the form of various compounds in the earth get distributed and directed to drinking water sources due to certain natural processes (Krewski et  al. 2007). A study conducted in China reveals that tap water can be an additional source of human exposure to pharmaceuticals. Those pharmaceuticals in drinking water may impose a potential threat to human health (Table 11.1). Definitely considering such pharmaceuticals in drinking water for HHRA can be utilized for the protection of water sources and management of risk imposed by such contamination of water (Leung et al. 2013). Whereas, considering the HHRA due to exposure to drinking water (groundwater) near areas of metal mines can be a significant measure for the management of water resources in such areas. Another study conducted in Argentina revealed that people residing in the area got chronically exposed to arsenic in their drinking water and this imposed potential health risks to those human beings. The study was done utilizing special analysis for HHRA. This kind of study is not only helpful in finding the human health risk factors currently but also is useful for predicting future scenarios to be addressed and analyzed (Navoni et al. 2014). HHRA for exposure to contaminated and polluted water is essential and important as in most cases drinking water gets unknowingly contaminated with certain environmental toxins. This, in turn, imposes severe health

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Table 11.1  Contaminated water and improper sanitation lead to several health issues in human beings Sl. no. 1. 2. 3. 4.

6.

Water contaminants/ pollutants Microbial contaminants (salmonella typhi) Microbial contaminants (vibrio cholerae) Microbial contaminants (Entamoeba histolytica) Microbial contaminants (hepatitis A virus (HAV)) Microbial contaminants (polio virus)

Health effects Typhoid Cholera Amoebic dysentery Hepatitis A

Polio

7.

Microbial contaminants (herpes simplex viruses, etc.)

Encephalitis

8.

Pathogens and toxic chemical contaminants Pathogens and chemicals from industry and sewage effluents Aluminum, lead, copper, chromium, cobalt, nickel, etc.

Stomach infection

Toxic hydrocarbons

Cancer

9.

10

11.

Skin infection

Heavy metal toxicity and oxidative damages

Symptoms Fever, muscle ache, cough, weakness, fatigue, etc. Diarrhea, weight loss, weakness, dehydration Nausea, diarrhea weight loss, stomach tenderness, fever Yellowing of skin, nausea, anorexia, upset stomach, fever, etc. Sore throat, headache, tiredness, fever, etc. Disabling and life-threatening disease Fever, seizures, headache, movement disorders, sensitivity to light Sensitivity to sound, neck stiffness, loss of consciousness Indigestion, diarrhea, dysentery, stomachache, stomach flu, etc. Rash, eruption, itching, irritation, etc.

Neural disorders, hepatic and cardiac disorders, diarrhea, nausea, vomiting, chills, abdominal cramps, skin problems, etc. Weakness, lumps, lesions, weight loss, etc.

hazards, and chronic exposure to such toxic and polluted water may turn out to be life threatening. Proper plans, programs, and policies may be undertaken to prevent such contamination of water as part of risk management and assures human health safety. Contamination of drinking water due to improper sewage disposal and sanitation may cause several types of microbial contamination (Ashbolt 2015). This causes diseases like polio, typhoid, dysentery, diarrhea, skin infections, and stomach infection in the people who use that contaminated water in their daily life activities and for drinking purposes (Table 11.1). HHRA for exposure to such contaminated water is extremely necessary, especially in rural areas so that proper arrangements for sanitation and sewage disposal are made. Also, health impacts on humans due to contamination of water bodies with industrial and sewage effluents can be minimized and mitigated by proper treatments of effluent before they are let to run into water bodies like a river. A study conducted on two artificial lakes in the Netherlands showed that with a reduction in the release of contaminants into the lakes, the surface water got better but the pollutants in the sediments were persistent. The sediments of the lakes were

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found to be highly polluted and toxic. The main contaminants were heavy metals and certain carcinogenic hydrocarbons. An exposure assessment model was used for assessing the human health risks associated with the polluted sediments of the freshwater lakes therein (Albering et  al. 1999). Such kind of risk assessment is important for addressing the urgency of the cleaning and treatment of such contaminated water bodies. Certain chemical compounds used as pesticides and fertilizers are known to be washed down to nearby water bodies and thus the harmful chemicals enter the food chain and reach human bodies through the fishes that are cultivated in those water bodies for human consumption purposes (Ghosh and Ghosh 2019). Thus, organic household wastes and chemicals from the agricultural field are known to contaminate water (Ghosh 2015). Human health risk assessment for exposure to toxic and polluted water is essential to identify and take measures for improving the quality of water, especially the water which is used for drinking and for cultivating edible fish.

11.6 HHRA for Exposure to Polluted Soil The basic causes of soil pollution are deforestation leading to soil erosion, nuclear waste disposal, agricultural waste and by-products, industrialization and urbanization, mining activities, overcrowded landfills, improper disposal of waste, construction activities, etc. From any of these recognized sources, the soil may get contaminated with toxic elements. Humans may get exposed to contaminants from contaminated soil and this may cause negligible to severe health impacts on humans. The human health impacts from contaminated soil exposure may range from skin disease to cancer. HHRAs due to contaminated soil exposure are done by using exposure models and measuring the concentration of various toxic contaminants in various body fluids and tissues. This is called biomonitoring. Biomonitoring involves analysis of the history of exposure and measurements of toxicants in the in-contact media to actual exposure measurements (Swartjes 2015). Studies conducted for HHRA from exposure to soil containing certain inorganic and organic contaminants revealed a high risk of occurrence of cancer. In the soil, certain toxic heavy metals like arsenic, cadmium, chromium, and lead were found to be present along with some organic pollutants like polychlorinated biphenyls (PCBs) (Lai et al. 2010). Aluminum and its compounds are known to comprise almost 8% of the Earth’s surface. The compound of such metals are mobilized by natural processes and are released. Metals like aluminum generally are found to be present in high concentrations in the soil near mines of aluminum. Risk assessment is extremely necessary for mine areas for assurance of proper management of the hazards (Agyeman et al. 2021). Soil pollution in general is known to have a long-term impact on human health. A long period of exposure to soil contaminants imposes adverse health effects on humans.

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Basically, the routes of exposure to soil contaminants are recognized to be four. The first one is by accidental intake of soil, dust, contaminated food, etc. Second probable route is the intentional intake of soil. This mostly happens in toddlers who often put anything in their mouth during their dentition process. Inhalation of soil particles during breathing is considered the third possible route of exposure to contaminated soil. Breathing in dust or soil particles may happen indoors or outdoors. The fourth route of possible human exposure to contaminated soil is recognized to occur through dermal contact (Fig. 11.2). A study conducted in Saudi Arabia considered two cities. One was a mining area and the other was an urban area which was primarily an industrial zone. Ecological and human risk assessment revealed that the soil and dust of the city of mining area were more polluted than the city which was an industrial area. The study recommends monitoring dust and soil particles in such residential areas with high human health risks for a sustainable ecosystem and the health of human beings (Al-Swadi et al. 2022). Assessment of human health risks associated with potent soil pollutants is essential for formulating proper remedial steps and measures to be taken for reducing and eliminating such soil pollution.

11.7 Conclusion Improper disposal of solid, liquid, or gaseous waste adds up to the increasing pollution in our environment making it more and more toxic and hazardous for human health (Environmental Pollution 2022). The environment gradually becomes toxic and unsuitable for the healthy dwelling of life forms including Human beings. Regular and proper HHRA is extremely necessary to monitor the pattern and details

Fig. 11.2  Four different routes of exposure to soil contaminants

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of the hazards and their impact on human health. Through the last decade, significant developments have been achieved regarding HHRA and human health management (ScienceDirect 2014). Qualitative and quantitative assessment of various health risks is achieved by HHRA. Different types of advanced regulations, advisory, technological interventions, and technical adaptations have made the identification, analysis, and management of various environmental risk factors for human health easier. The method to be undertaken for regulation and management of risk factors needs to be cost-effective and suitable to the case concerned depending on the geographical location. As per the popular saying, “prevention is better than cure” holds for HHRA for environmental risk assessment. But definitely, proper risk assessment and management have lots of merits. The merits are not only limited to the management and handling of current human health risks but also the findings are beneficial to take necessary measures to minimize the identified risks and hazards in the near future. Acknowledgments  Dr. PSS acknowledges the Department of Chemistry, Government General Degree College, Kharagpur II, West Bengal, India. Dr. DG acknowledges the Department of Physiology, Government General Degree College, Kharagpur II, West Bengal, India.

References Agyeman PC, John K, Kebonye NM et al (2021) Human health risk exposure and ecological risk assessment of potentially toxic element pollution in agricultural soils in the district of Frydek Mistek, Czech Republic: a sample location approach. Environ Sci Eur 33:137 Albering HJ, Rila JP, Moonen EJ et al (1999) Human health risk assessment in relation to environmental pollution of two artificial freshwater lakes in The Netherlands. Environ Health Perspect 107(1):27–35 Al-Swadi HA, Usman ARA, Al-Farraj AS et al (2022) Sources, toxicity potential, and human health risk assessment of heavy metals-laden soil and dust of urban and suburban areas as affected by industrial and mining activities. Sci Rep 12:8972. https://doi.org/10.1038/s41598-­022-­12345-­8 Ashbolt NJ (2015) Microbial contamination of drinking water and human health from community water systems. Curr Environ Health Rep 2(1):95–106 Ashbolt NJ, Amézquita A, Backhaus T et al (2013) Human health risk assessment (HHRA) for environmental development and transfer of antibiotic resistance. Environ Health Perspect 121(9):993–1001 Ben Y, Fu C, Hu M et al (2019) Human health risk assessment of antibiotic resistance associated with antibiotic residues in the environment: a review. Environ Res 169:483–493 Chandra M (2015) Environmental concerns in India: problems and solutions. J Int Bus Law 15(1):Article 1 Chen L, Wang J, Beiyuan J et al (2022) Environmental and health risk assessment of potentially toxic trace elements in soils near uranium (U) mines: a global meta-analysis. Sci Total Environ 816:151556 Cheng SQ, Xia YY, He JL et  al (2013) Neurotoxic effect of subacute benzo(a) pyrene exposure on gene and protein expression in Sprague-Dawley rats. Environ Toxicol Pharmacol 36(2):648–658 Chepelev NL, Moffat ID, Bowers WJ et  al (2015) Neurotoxicity may be an overlooked consequence of benzo[a] pyrene exposure that is relevant to human health risk assessment. Mutat Res Rev Mutat Res 764:64–89

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Crump KS (1984) A new method for determining allowable daily intakes. Fundam Appl Toxicol 4(5):854–871 Delisle H, Roberts JH, Munro M et al (2005) The role of NGOs in global health research for development. Health Res Policy Syst 3:3 Environmental Pollution (2022). https://www.environmentalpollution.in/waste-­management/ waste-­management-­management-­of-­solid-­liquid-­and-­gaseous-­wastes/377. (Accessed on 19.08.2022) Ghirardelli A, Tarolli P, Kameswari Rajasekaran M et al (2021) Organic contaminants in ganga basin: from the green revolution to the emerging concerns of modern India. iSci 24(3):102122 Ghosh D (2015) Quality of Water Paripex. Ind J Res 4(8):374–375 Ghosh D, Ghosh S, Singha PS (2022) Impact of air pollution on the pathophysiology of COVID 19 in Indian population: a brief account. In the book, environment in 21st century (volume III) Kripadrishti Publishers;114–121 Ghosh D, Parida P (2015) Air pollution and India: current scenario. Int J Curr Res 7(11):22194–22196 Ghosh S, Ghosh D (2019) Impact of fluoride toxicity on fresh water fishes: a mini review. Int J Adv Innov Res 6:2. (II) Hassan BT, Jiawen G, Farzaneh H (2021) Air pollution health risk assessment (AP-HRA), principles and applications. Int J Environ Res Public Health 18(4):1935 Health.vic (2018). https://www.health.vic.gov.au/environmental-­health/human-­health-­risk-­ assessments, (Accessed on 06.07.2022) Krewski D, Yokel RA, Nieboer E et al (2007) Human health risk assessment for aluminium, aluminium oxide, and aluminium hydroxide. J Toxicol Environ Health B Crit Rev 10(1):1–269 Lai HY, Hseu ZY, Chen TC et al (2010) Health risk-based assessment and management of heavy metals-contaminated soil sites in Taiwan. Int J Environ Res Public Health 10:3595–3614 Leung HW, Jin L, Wei S et al (2013) Pharmaceuticals in tap water: human health risk assessment and proposed monitoring framework in China. Environ Health Perspect 121(7):839–846 Maji K, Dikshit A, Chaudhary R (2017) Human health risk assessment due to air pollution in the megacity Mumbai in India. AJAE 11:61–70 Manisalidis I, Stavropoulou E, Stavropoulos A et al (2020) Environmental and health impacts of air pollution: a review. Front Public Health 8:14 Mohammadi AA, Zarei A, Majidi S et al (2019) Carcinogenic and non-carcinogenic health risk assessment of heavy metals in drinking water of Khorramabad. Iran MethodsX 6:1642–1651 Navoni JA, De Pietri D, Olmos V et al (2014) Human health risk assessment with spatial analysis: study of a population chronically exposed to arsenic through drinking water from Argentina. Sci Total Environ 499:166–174 Northern Health (2015). https://www.northernhealth.ca/sites/northern_health/files/services/ office-­health-­resource-­development/documents/guidance-­human-­health-­risk-­assessment.pdf. (Accessed on 06.07.2022) Orzáez FL, Domingo R, Marin M (2019) Considerations for the development of a human reliability analysis (HRA) model oriented to the maintenance work safety. Procedia Manuf 41:185–192 ScienceDirect (2014). https://www.sciencedirect.com/topics/earth-­and-­planetary-­sciences/ environmental-­health-­risk-­assessment (Accessed on 06.07.2022) Swartjes FA (2015) Human health risk assessment related to contaminated land: state of the art. Environ Geochem Health 37(4):651–673 U.S. Environmental Protection Agency (March 1991). https://www3.epa.gov/airtoxics/3_90_024. html. (Accessed on 06.07.2022) U.S.  Environmental Protection Agency (2022a). https://www.epa.gov/risk/human-­health-­risk-­ assessment, last updated on July 26, 2022 (Accessed on 06.07.2022) U.S.  Environmental Protection Agency (2022b). https://www.epa.gov/risk/risk-­assessment-­ guidance, last updated on May 31, 2022 (Accessed on 06.07.2022) U.S.  Environmental Protection Agency (2022c). https://www.epa.gov/risk/conducting-­human-­ health-­risk-­assessment, last updated on July 22, 2022. (Accessed on 06.07.2022)

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Human Health Risk Assessment Due to the Consumption of Heavy Metals

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Mehjbeen Javed and Nazura Usmani

12.1 Introduction Industrialization leads to the contamination of water bodies as the waste generated is discharged into them. Fishes are relished by a large mass of population throughout the world. Water-receiving effluents contains appreciable number of heavy metals, therefore, the inhabiting fishes accumulate a significant amount. Heavy metals have a strong tendency to bind with thiol (SH) group of proteins/amino acids/ enzymes, etc., which on consumption of exposed fishes enter the human body. It is an established fact that fishes are an excellent source of polyunsaturated fatty acids (PUFA) and protein. Moreover, the American Heart Association recommended consumption of fishes two times a week for adults who have no history of heart attack (Kris-Etherton et al. 2002). Furthermore, there are evidences of benefits of the consumption of fish such as a lower chance of prostate cancer (Augustsson et al. 2003), cancer of the kidney (Wolk et al. 2006), and cardiovascular diseases (Mozaffarian and Rimm 2006). The PUFA, particularly omega-3 fatty acids have also been confirmed as a strong antioxidant and an anticancer agent in human malignancies (Calviello and Serini 2010; Shaikh et al. 2010), omega-3 fatty acids can also work as an anti-inflammatory compound (Calder 2009; Wall et al. 2010). Unfortunately, in reality fishes or any seafood are labelled as the source of dietary intake of heavy metals due to industrial effluents, and adversity depends on the number of fish

Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/978-­981-­99-­2193-­5_12. M. Javed Department of Medical Elementology and Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, India N. Usmani (*) Aquatic Toxicology Research Laboratory, Department of Zoology, Aligarh Muslim University, Aligarh, U.P., India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 M. I. Ahmad et al. (eds.), Toxicology and Human Health, https://doi.org/10.1007/978-981-99-2193-5_12

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consumed and frequency of exposure. Some of these heavy metals are essential metals and their essentiality depends upon their roles. They are cofactors for many enzymes (Food and Drug Agency [FDA], 2001). Even for these essential metals (selected for the study), there is a limit of an ingested dose beyond which their supply is adequate to the body (Mn 1.8–2.3 mg/day, Fe 8–18 mg/day, Ni 0.5 mg/day, Cu 0.9  mg/day, Zn 8–11  mg/ day) (FDA 2001). However, deviation from these ranges, results in deleterious and toxic effects (FDA 2001; Harmanescu et al. 2011). The concerned study deals with the collection of popular food fishes among locals such as Channa punctatus, Labeo rohita, and Clarias gariepinus, from Rasalganj fish market (27.30°N and 79.40°E), district Aligarh, Uttar Pradesh, India for health risk assessment.

12.2 Materials and Methods C. punctatus, L. rohita, and C. gariepinus were collected from the Rasalganj fish market of Aligarh, Uttar Pradesh, India (Fig. 12.1). This work is an extension of our previous study on fishes from Rasalganj fish market, therefore, the heavy metal values for muscle can be referred to Javed and Usmani (2011). This data was used for the calculation of estimated daily intake (EDI), target hazard quotients (THQ), hazard index (HI), and target cancer risk (TR) values for all metals, separately for adult males and females.

12.2.1 Health Risk Assessment for Fish Consumption 12.2.1.1 Calculation of EDI and THQ EDI ( mg / kg body weight / day ) = Mc × IR / Bw × 10−3 THQ was calculated according to USEPA (2011):



THQ =

Mc × IR × 10−3 × EF × ED RfD × Bw × ATn



where Mc = concentration of metal (mg/kg dry weight). IR = ingestion rate (19.5 × 10−3 kg/day). Bw  =  bodyweight of adult male (57  kg) and adult female (50  kg) individuals (Shukla et al. 2002). EF = exposure frequency (365 days/year). ED  =  exposure duration, 67  years (life expectancy of Indian males is about 65 years and that of females around 68 years). Mean of life expectancy was utilized for further calculation (https://countryeconomy.com/demography/life-­ expectancy/India). RfD = reference dose of metals (mg/kg/day) (USEPA 2012). ATn  =  average time for non-carcinogenic exposure [365  days/year × ED] (USEPA 2011).

Fig. 12.1  Location of Rasalganj fish market, Aligarh (the figure is taken from Google map)

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12.2.1.2 HI It is the summation of all calculated THQs (USEPA 2011).

HI = THQCr + THQMn + THQFe + THQNi + THQCu + THQZn + THQCo

12.2.1.3 TR Its calculation was done by the following formula (USEPA 2011):



TR =

Mc × IR × 10−3 × CPSo × EF × ED Bw × ATc

where CPSo  =  carcinogenic potency slope for oral dose (mg/kg bw-day−1). Heavy metals for example Fe, Mn, Zn, and Cu are not on the carcinogenic list (USEPA 2012). ATc = average exposure time to carcinogens’ exposure (365 days/year × 67 years) as mean life expectancy for Indians. Reference Dose Oral (RfD)  The average daily safe consumption and its value for each metal is given in mg/kg/day by USEPA (2012), and is as follows: Cr (3 × 10−3), Mn (1.4  ×  10−1), Fe (7  ×  10−1), Co (3  ×  10−4), Ni (2  ×  10−2), Cu (4  ×  10−2), Zn (3 × 10−1). Among these studied metals only Cr and Ni are considered carcinogenic. Their carcinogenic Potency Slope factor oral (CPSo), by USEPA (2012) is given in mg/kg bw-day−1 which is: Cr (5.0 × 10−1), Ni (1.7).

12.3 Results and Discussion The amounts of various heavy metals (Cr, Mn, Fe, Ni, Zn, Co, Cu) in the edible or muscle of collected fishes are shown in supplementary Table 12.S1.

12.3.1 EDI, THQ, and HI The results of EDI values of heavy metals in the fishes collected from the Rasalganj fish market are given in Table 12.1. In C. punctatus it ranged from 1.55 to 29.24 mg/ kg body weight/day, whereas, in L. rohita the range is from 0.444 50 to 28.43 24 mg/ kg body weight/day, while in C. gariepinus the range was from 0.342 to 47.19 mg/ kg body weight/day. Here many fold higher values of EDI for each heavy metal were found than the respective reference dose. Among the three fishes highest EDI values were recorded for C. punctatus followed by C. gariepinus and L. rohita. The THQ values are given in Table 12.2. C. punctatus posed the highest hazard and potentiality of the metals were in the order Co > Ni > Cu > Fe > Zn > Mn for both the male and female adult humans. In L. rohita the trend of hazard was Co > Ni > Zn > Cu > Fe > Mn in both the cases, and in C. gariepinus the THQ of heavy metals followed the order: Co > Ni > Zn > Cu > Cr > Fe > Mn. The results of

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Table 12.1  Estimated daily intake (mg/kg body weight/day) values of metals Heavy metals Cr Mn Fe Co Ni Cu Zn

Channa punctatus M F ND ND 1.55 1.77 101.05 115.2 2.32 2.65 11.66 13.29 7.76 8.85 25.65 29.24

Labeo rohita M F ND ND 0.444 0.507 23.57 26.87 1.36 1.56 3.69 4.21 3.21 3.66 24.93 28.43

Clarias gariepinus M F 0.342 0.39 5.13 5.85 56.1 63.96 2.39 2.73 7.18 8.19 5.13 5.85 41.39 47.19

ND not detected, M Adult human male, F Adult human female Table 12.2  THQ calculated values Heavy metals Cr Mn Fe Co Ni Cu Zn

Channa punctatus M F ND ND 0.011 0.012 0.144 0.164 7.76 8.85 0.583 0.664 0.194 0.221 0.085 0.097

Labeo rohita M ND 0.003 0.033 4.56 0.184 0.08 0.083

F ND 0.003 0.038 5.2 0.21 0.091 0.094

Clarias gariepinus M F 0.114 0.130 0.036 0.041 0.080 0.091 7.98 9.10 1.43 1.63 0.128 0.146 0.137 0.157

ND not detected, M Adult human male, F Adult human female

the investigation indicate that on providing the same dose for same time to both adult males and females, the females will be more vulnerable to non-cancer risk. THQ represents non-carcinogenic risk and is a unitless quantity. It should not exceed 1, if it does then it shows the potential non-carcinogenic risk to the exposed population (Harmanescu et al. 2011; Abdou and Hassan 2014; Akoto et al. 2014; Jovic and Stankovic 2014). THQ is not the measurement of risk but it is the reflection of the level of concern (Khan et al. 2009; Harmanescu et al. 2011). In the current study, Co is the only metal showing  THQ values >1  in all the fishes. Like EDI, the THQ measurements for all the studied heavy metals were comparably higher in females than their male counterparts. This could be attributed to variation in average weight; therefore, all the parameters were calculated for them separately. As per the New  York State Department of Health (NYSDOH 2007), if the ratio of EDI of heavy metal to its RfD was = or 1–5 times the RfD then the risk is low, if >5–10 times, moderate risk, if >10 times then high risk. The current study lies in the first group for all heavy metals, except Co because its ratio was more than thousand times higher than the RfD pointing to possible health hazards to the public. The HI values are given in Table 12.3. The highest HI value among all the fishes was found for C. gariepinus followed by C. punctatus and L. rohita. Like THQ its value should not exceed 1 (Zodape 2014; Islam et al. 2014), else it raises a concern for the public health.

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Table 12.3  Hazard Index values for each studied fish

Fishes C. punctatus L. rohita C. gariepinus

HI M 8.77 4.94 9.91

F 10.0 5.64 11.29

M Adult human male, F Adult human female Table 12.4  TR values of metals of fishes obtained from Rasalganj fish market, Aligarh Heavy Metals Cr Ni

Channa punctatus M F ND ND 1.98 × 10−2 2.26 × 10−2

Labeo rohita M F ND ND 6.28 × 10−3 7.16 × 10−3

Clarias gariepinus M F 1.71 × 10−4 1.95 × 10−4 −2 1.22 × 10 1.39 × 10−2

ND not detected, M Adult human male, F Adult human female

12.3.2 Target Cancer Risk (TR) Target cancer risk for adult male and female humans due to the consumption of fishes is given in Table 12.4. Cr was not detected in the muscle tissue of C. punctatus and L. rohita. C. gariepinus pose more risk to females (1.95 × 10−4) than males (1.71 × 10−4). The TR by Ni would be higher on C. punctatus consumption followed by C. gariepinus and L. rohita. Values for TR as well show that females will be more susceptible. Among the heavy metals undertaken for the study, Cr and Ni have been listed as potent carcinogens (USEPA 2012). Therefore, TR was calculated for these two metals only. It is also a dimensionless quantity. According to NYSDOH, the TR categories are reported as, if TR ≤10−6 = Low; 10−4 to 10−3 = moderate; 10−3 to 10−1 = high; ≥10−1  =  very high. In the study undertaken high cancer risk is noted for Ni in C. punctatus, L. rohita, and C. gariepinus. The threat posed by Cr is moderate and also comparatively lower than Ni. Like THQ, the TR is also not a particular indication of awaited cancers, rather, it is just an upper limit of the possibility that the person may have cancer sometime in her/his lifetime if he/she is exposed to that toxicant (NYSDOH 2007).

12.4 Conclusion In the present study, it is found that Co is the only metal where THQ is many folds higher than 1 therefore, posing a non-carcinogenic risk to the exposed population. Unfortunately, no permissible limits are found for Co. Furthermore, high cancer risk was observed for Ni.

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