Challenges in Endocrine Disruptor Toxicology and Risk Assessment

Cover
Preface
Contents
Chapter 1 Endocrine Disruptor Effects on Estrogen, Androgen and
Thyroid Pathways: Recent Advances on Screening and
Assessment
1.1 Introduction – What is an Endocrine Disruptor?
1.1.1 What Parts of the Endocrine System Do We Look at and Why?
1.1.2 What Endocrine Mechanisms Do We Look At?
1.1.3 What Regulatory Guidance Exists?
1.1.4 What Information Can Be Obtained From OECD-Compliant Studies?
1.1.5 How Does the AOP Concept Help to Facilitate Screening?
1.2 Estrogen Pathway
1.2.1 Why Look at the Estrogen Pathway?
1.2.2 AOP Related to Estrogen Signaling
1.2.3 Test Guidelines Based on Functions in Relation to the Schematic AOP
1.2.4 Alternative Testing Strategies Based on Highthroughput Screening
1.2.5 Example Substance: DES
1.3 Androgen Pathway
1.3.1 Why Look at the Androgen Pathway?
1.3.2 AOP Related to AR Signaling
1.3.3 Test Guidelines Based on Functions in Relation to the Schematic AOP
1.3.4 Example Substance: Linuron
1.4 Thyroid Pathway
1.4.1 Why Look at the Thyroid Pathway?
1.4.2 AOP Related to Thyroid Function
1.4.3 Assays
1.4.4 Screening
1.4.5 Example Substances
1.5 Regulation
1.6 Summary and Outlook
References
Chapter 2 Epigenetic Reprogramming by Endocrine Disrupting
Chemicals
2.1 Introduction
2.2 Overview of Epigenetic Regulation
2.2.1 DNA Methylation
2.2.2 Histone Modifications
2.2.3 Non-coding RNAs
2.3 EDCs as Disruptors of Epigenetic Regulation
2.3.1 Environmental Pollutant – Benzene
2.3.2 Fungicide – Vinclozolin
2.3.3 Pesticide – Methoxychlor
2.3.4 Plastic-derived Products – BPA
2.3.5 Dietary Agents – Genistein
2.3.6 Therapeutic Synthetic Estrogens
2.4 Epigenetic Biomarkers in Risk Assessment
2.4.1 Challenges of Applying Epigenetic Toxicology
2.5 Conclusion
Competing Financial Interests Declaration Statement
Disclaimer
Acknowledgements
References
Chapter 3 Issues for Hazard Characterization of Endocrine Disrupting Chemicals: The Use of Adverse Outcome Pathways
3.1 Hazard Characterization of Endocrine Disrupting Chemicals
3.1.1 Non-monotonic Dose–Response Relationships
3.1.2 Low-dose Effects of EDC
3.2 Adverse Outcome Pathways
3.3 Conclusions
References
Chapter 4 Integrated Translation Framework for Endocrine Disruptors in the area of Computational Toxicology
4.1 Endocrine Disruptors (EDs) and Human Health
4.2 From Classical Dose–Response to Integrative Translational Toxicology
4.3 PBPK (Physiologically Based Pharmacokinetic) Model
4.3.1 Introduction
4.3.2 Approaches to Building PBPK Models
4.3.3 Model Parameterization
4.3.4 Cheminformatics and Toxicokinetic Models for Chemical Assessment
4.4 Pharmacodynamics Model – Dynamic System Analysis
4.4.1 Introduction
4.4.2 Types of Pharmacodynamic Models
4.4.3 Signal Transduction Model
4.4.4 Irreversible Effect Model
4.5 Translation through PK–PD Models
4.6 Quantitative In Vitro to In Vivo Extrapolation (QIVIVE)
4.7 Systems Biology
4.7.1 Introduction
4.7.2 Models for Systems Biology Research
4.7.3 Systems Biology Model and Endocrine Disruptors
4.7.4 The Future of Systems Biology
4.8 Adverse Outcome Pathways (AOPs)
4.8.1 Introduction
4.8.2 AOP Development Principles
4.8.3 AOPs Knowledge and Models
4.8.4 AOPs and Endocrine Disruptors
4.9 Integrative Translational Toxicology
4.10 The Future of the Integrative Translational Toxicology Approach
Abbreviations
Acknowledgements
References
Chapter 5 Sex-specific Actions of Endocrine Disruptors
5.1 Introduction
5.2 Sex Differences in EDCs’ Effects on Hormones, Brain and Behavior
5.2.1 Animal Experiments
5.2.2 Sexual Development and Sexual Behavior
5.2.3 Effects of EDCs on Hormone Balance
5.2.4 Effects on the Immune System
5.2.5 Effects of EDCs on the Structure of Other Organs
5.2.6 EDCs, Body Weight, Fat Tissue and Metabolism
5.3 Human Data
5.3.1 Effects of EDCs on Hormone Balance in Developmental Life Stages
5.3.2 Developmental Effects on Cognition and Behavior
5.3.3 Effects on Body Growth and Maturation
5.3.4 Sex Specific Effects of EDSs on the Immune System
5.3.5 Effects on Hormone Balance in Adults
5.3.6 Effects on Body Weight in Adults and Adolescents
5.4 Mechanisms Potentially Leading to Gender Differences in Response to Endocrine Disruption
5.4.1 Brain
5.4.2 Effects of EDCs on Sex Specific Gene Expression
5.4.3 Sex-specific Molecular Mechanisms of EDCs
5.4.4 Endocrine Disruption Resulting from Binding to Proteins Important for Homeostasis
5.4.5 The Action of PCBs Goes Beyond Estrogenic Pathways
5.4.6 EDCs Cause Sex Specific Disturbance of Nonapeptide Hormone Signaling
5.4.7 Sex-specific Action of Tributyltin and Other Obesogenic EDC
5.4.8 EDCs and Sexual Activity
5.5 Conclusion
References
Chapter 6 Health Risks of Transplacental Exposure to Endocrine Disruptors
6.1 Introduction
6.2 Birth Outcomes
6.2.1 Gestational Age
6.2.2 Infant Anthropometrics
6.3 Metabolic Effects
6.3.1 Inorganic Pollutants
6.3.2 Persistent Organic Pollutants
6.3.3 Non-persistent Organic Pollutants
6.4 Neurodevelopmental Disorders
6.4.1 Inorganic Pollutants
6.4.2 Persistent Organic Pollutants
6.4.3 Non-persistent Organic Pollutants
6.5 Reproductive Effects
6.5.1 Cryptorchidism and Hypospadias in Newborn Males
6.5.2 Puberty in Male and Female Offspring
6.6 Conclusions
References
Chapter 7 Endocrine Disruptors and Cancer: From Genotoxicity Mechanisms to Ethnicity-related Susceptibility
7.1 Introduction
7.2 EDCs and the Hallmarks of Cancer
7.3 Genomic Actions of EDCs
7.4 Epigenetic Actions of EDCs
7.5 Non-genomic Actions of EDCs
7.6 Paediatric Neoplasms Associated with Transplacental Exposure to EDCs
7.7 Ethnicity-related Differences in Susceptibility to EDC Actions
7.8 Conclusions
References
Chapter 8 Bone as a Target for Endocrine Disruptors
8.1 Introduction Bone as a Tissue
8.2 Endocrine-disrupting Chemicals (EDC) and Effects on Bone
8.2.1 Dioxins and TCDD
8.2.2 Tributyltin (TBT)
8.2.3 Phthalates
8.2.4 Diethylstilbestrol (DES)
8.2.5 Polyfluoroalkyl and Perfluoroalkyl Substances (PFAS)
8.2.6 Bisphenol A (BPA)
8.3 Discussion
8.3.1 Conclusion
References
Chapter 9 Pathways of ED-induced Neuro-developmental Disturbances: An Overview
9.1 Introduction: Neurodevelopment and Environmental Chemicals
9.2 Endocrine Disruption and Neurodevelopment
9.3 Mechanisms of Disturbance of Brain Development
9.3.1 Alteration of Intracellular Ca21 Levels and Dynamics
9.3.2 Induction of Oxidative Stress
9.3.3 Alteration of Neurotransmitter Levels
9.3.4 Epigenetic Effects
9.4 The Role of Thyroid Hormone in Brain Development
9.4.1 Functional Elements of the TH System
9.4.2 Central Regulation of TH Homeostasis
9.4.3 TH Synthesis and Release
9.4.4 Systemic Distribution and Transport of TH
9.4.5 Metabolism and Excretion of THs
9.4.6 Cellular Uptake of THs
9.4.7 Local Cellular Responses of THs
9.5 Effects of Low THs on the Developing Human Brain
9.6 Models to Test for Alterations of Neurodevelopment
9.7 Conclusions
References
Chapter 10 Vitamin A and the Retinoid System – From Nutrition to Endocrine Disruption
10.1 Vitamin A and the Retinoid System
10.2 Chemical Perturbation of the Retinoid System
10.3 Regulatory Toxicology and Retinoid Disruption
10.4 Concluding Remarks
Abbreviations
Acknowledgements
References
Chapter 11 Linking Ecohealth and One Health approaches. A Case Study on the EU Water Framework Directive Strategy About Alkylphenols in Aquatic Ecosystems
11.1 Introduction
11.2 The Ecosystem Approach of the Water Framework Directive (WFD)
11.2.1 Strategies Against Chemical Pollution of Aquatic Ecosystems
11.3 Tiber River Case Study on Environmental Fate of Nonylphenols
11.4 Conclusions
References
Chapter 12 Pollution of Water and Food by Hormonally Active Pesticides and Drugs (Human and Veterinary): Focus on Emerging Countries: Emerging Contaminants with Endocrine Disruption Potential in Brazil
12.1 Introduction
12.2 Water Pollution in Brazil
12.2.1 Water Criteria and Regulation
12.3 Pesticides Residues
12.3.1 Pesticides Approved in Brazil but Prohibited in Other Countries
12.3.2 Pesticides Regulation and Trade Agreements
12.4 Pharmaceutical and Veterinary Drugs Residues and Water Contamination
12.4.1 Pharmaceuticals and Other Chemicals – Regulatory Aspects
12.5 Health Implications, Detection and Endocrine Disruptors Regulation
12.5.1 Regulation and Human Health Rights
12.5.2 Endocrine Disruptors Risk Assessment in Brazil
12.5.3 National Programs to Comply with International Agreements
12.6 Conclusions
Disclaimer
Acknowledgements
References
Chapter 13 Pollution of Food and Water by Hormonally Active Pesticides and Veterinary Drugs Residues: Focus on Sub Saharan African Countries
13.1 Uses of Agricultural Pesticides and Veterinary Pharmaceuticals in Africa
13.1.1 Use of Agricultural Pesticides
13.1.2 Importance of Pesticides Identified as EDCs in African Agriculture
13.1.3 Endocrine Disrupting Pesticides Residues in the Most Consumed African Foods and Dishes
13.1.4 Estimation of Consumers Exposure to Selected ED Pesticides from Staple Foods in the Four Countries Included in the Region
13.2 Veterinary Drugs Uses and their Residues in Foods
13.2.1 Livestock Diseases and Veterinary Drugs in Africa
13.2.2 Veterinary Drugs Residues in Foods
13.2.3 Water Pollution by Pesticides and Veterinary Drugs
References
Chapter 14 Natural Substances in Supplements and Nutraceuticals as Endocrine Disruptors
14.1 Introduction
14.2 Case Studies
14.2.1 Seaweed as a Source of Iodine
14.2.2 Isoflavones of Soy
14.2.3 Other Possible Case Studies
14.3 Considerations for the Safe Use of Nutraceuticals
14.4 Concluding Remarks
References
Chapter 15 Endocrine Disruptors in Building Materials
15.1 Introduction
15.2 Phthalates
15.3 Flame Retardants
15.4 Styrene
15.5 Bisphenols
15.6 Timber Processing
15.7 Heavy Metals
15.8 Trends in the Construction Sector
15.9 Conclusion
References
Chapter 16 Endocrine Disrupting Chemicals in Clothing and Cosmetics
16.1 Introduction
16.2 EDCs in Clothing
16.3 EDCs in Cosmetics
16.4 Risk Assessment
16.5 EDCs in Clothing and Cosmetics: Aggregate and Combined Exposure
16.6 Conclusions
References
Chapter 17 Challenges in Endocrine Disruptor Toxicology and Risk Assessment
17.1 Introduction
17.2 Mechanism of Action of EDCs
17.2.1 Low-dose Mechanisms of EDCs
17.3 Challenges and Uncertainties of Endocrinedisruptors Risk Assessment
17.3.1 Administration of the Test Substance
17.3.2 Adverse Effects of Endocrine Disruptors
17.3.3 Features of Hormone Action
17.4 Approaches by Different Regulatory Agencies in Tackling These Challenges
17.5 Discrepancies and Arguments for and against Inter-agency Approaches and Harmonization of Opinions
17.6 Conclusion
References
Chapter 18 Biomarkers of Effect for EDCs and Indicators to be Used in Epidemiological Studies on Reproductive Health
18.1 Introduction
18.2 Biomarkers of Effect
18.3 EDCs Environmental Exposure Effects: Epidemiological Studies Biomarkers
18.4 Critical Windows of Exposure to EDCs and Effects
18.4.1 Embryonic Development
18.4.2 Early Post-natal Life
18.4.3 Puberty
18.5 EDCs Occupational Exposure and Effects
18.6 Conclusion
Acknowledgements
References
Chapter 19 Occupational Exposure to Endocrine Disruptors and Reproductive Health
19.1 General Introduction
19.2 Bisphenol A
19.2.1 Introduction
19.2.2 Uses and Sources
19.2.3 Human Data
19.2.4 Experimental Reproductive Toxicity Data
19.2.5 Discussion and Conclusions
19.3 Lead
19.3.1 Introduction
19.3.2 Uses and Sources
19.3.3 Human Data
19.3.4 Experimental Reproductive Toxicity Data
19.3.5 Discussion and Conclusions
19.4 Hexachlorobenzene
19.4.1 Introduction
19.4.2 Uses and Sources
19.4.3 Human Data
19.4.4 Experimental Reproductive Toxicity Data
19.4.5 Discussion and Conclusions
19.5 Pesticides
19.5.1 Introduction
19.5.2 Human Data
19.5.3 Conclusions
19.6 Final Considerations
Abbreviations
References
Chapter 20 Interdisciplinary Collaboration between Environmental Health and Clinical Experts on Cancers and Infertility Associated with Exposure to Endocrine Disruptors
20.1 Introduction
20.2 Multidisciplinary Management of Cancer Risk
20.3 Multidisciplinary Management of Infertility
20.4 An Example of a Multidisciplinary Effort
20.5 Suggestions on Ways Forward
References
Chapter 21 Regulation and Risk Management of Endocrine Disruptors: Current Status and Future Perspectives
21.1 Background
21.2 EU Policy on EDCs
21.3 Current Legal Status
21.3.1 REACH
21.3.2 Plant Protection Products Regulation (PPPR)
21.3.3 Biocidal Products Regulation (BPR)
21.3.4 Other Regulations in the EU
21.3.5 Outside the EU – Management of EDCs in Selected OECD Member States
21.4 Specific Trade Concerns (STC) Case at the World Trade Organisation (WTO)
21.5 EU Definition of Scientific Criteria for the Identification of EDCs (BPR/PPPR)
21.6 Risk Management
21.7 Future Perspectives
References
Subject Index