Endocrine Disruptors in the Environment

SUSHIL K. KHETAN, PhD, a research chemist at the Institute for Green Science in Carnegie Mellon University, has been working at the confluence of environmental and green chemistry. Earlier he worked in the agrochemicals industry and published two books on environmentally-friendly pest control technologies. He has consulted globally for several international organizations.

Foreword xiv

Preface xviii

Acronyms xxi

Glossary xxvi

1 Environmental Endocrine Disruptors 1

1.1 Introduction 1

1.1.1 The Endocrine System 1

1.1.2 Endocrine Disrupting Chemicals (EDCs) 3

1.1.3 Sources of EDCs in the Environment 4

1.1.4 Deleterious Effects of EDCs on Wildlife and on Humans 6

1.1.5 Endocrine Disruption Endpoints 6

1.2 Salient Aspects about Endocrine Disruption 7

1.2.1 Low-Dose Effects and Nonmonotonic Dose Responses 7

1.2.2 Exposures during Periods of Heightened Susceptibility in Critical Life Stages 9

1.2.3 Delayed Dysfunction 11

1.2.4 Importance of Mixtures 11

1.2.5 Transgenerational Epigenetic Effects 12

1.3 Historical Perspective of Endocrine Disruption 12

1.4 Scope and Layout of this Book 19

1.5 Conclusion 20

References 21

Part I Mechanisms Of Hormonal Action And Putative Endocrine Disruptors 27

2 Mechanisms of Endocrine System Function 29

2.1 Introduction 29

2.2 Hormonal Axes 29

2.2.1 Hypothalamus–Pituitary–Gonad (HPG) Axis 31

2.2.2 The Hypothalamic–Pituitary–Thyroid (HPT) Axis 33

2.2.3 The Hypothalamic–Pituitary–Adrenal (HPA) Axis 34

2.3 Hormonal Cell Signaling 35

2.3.1 Receptors and Hormone Action 35

2.3.2 Genomic Signaling Pathway 36

2.3.3 Rapid-Response Pathway (Nongenomic Signaling) 38

2.3.4 Receptor Agonists Partial Agonists and Antagonists 40

2.4 Sex Steroids 41

2.4.1 Physiologic Estrogens 41

2.4.2 Androgens 43

2.5 Thyroid Hormones 45

2.6 Conclusions and Future Prospects 46

References 47

3 Environmental Chemicals Targeting Estrogen Signaling Pathways 51

3.1 Introduction 51

3.1.1 Gonadal Estrogen Function Disruptors 52

3.2 Steroidal Estrogens 54

3.2.1 Physiologic Estrogens 55

3.2.2 17α-Ethinylestradiol (EE2) 55

3.2.3 Phytoestrogens 57

3.2.4 Mycoestrogen – Zearalenone (ZEN) 59

3.3 Nonsteroidal Estrogenic Chemicals 60

3.3.1 Diethylstilbestrol (DES) 60

3.3.2 Organochlorine Insecticides 62

3.3.3 Polychlorinated Biphenyls (PCBs) 65

3.3.4 Alkyphenols 65

3.3.5 Parabens (Hydroxy Benzoates) 73

3.3.6 Sun Screens (Chemical UV Filters) 74

3.4 Metalloestrogens 75

3.4.1 Cadmium (Cd) 76

3.4.2 Lead (Pb) 76

3.4.3 Mercury (Hg) 77

3.4.4 Arsenic (As) 77

3.5 Conclusion and Future Prospects 78

References 78

4 Anti-Androgenic Chemicals 91

4.1 Introduction 91

4.2 Testosterone Synthesis Inhibitors 92

4.2.1 Phthalates 92

4.3 Androgen Receptor (AR) Antagonists 96

4.3.1 Organochlorine (OC) Pesticides 96

4.3.2 Organophosphorus (OP) Insecticides 98

4.3.3 Bisphenol A (BPA) 99

4.3.4 Polybrominated Diphenyl Ethers (PBDEs) 99

4.3.5 Vinclozolin (VZ) 100

4.3.6 Procymidone 101

4.4 AR Antagonists and Fetal Testosterone Synthesis Inhibitors 102

4.4.1 Prochloraz 102

4.4.2 Linuron 103

4.5 Comparative Anti-Androgenic Effects of Pesticides to Androgen Agonist DHT 103

4.6 Conclusions and Future Prospects 103

References 104

5 Thyroid-Disrupting Chemicals 111

5.1 Introduction 111

5.2 Thyroid Synthesis Inhibition by Interference in Iodide Uptake 113

5.2.1 Perchlorate 113

5.3 TH Transport Disruptors and Estrogen Sulfotransferases Inhibitors 114

5.3.1 Polychlorinated Biphenyls (PCBs) 114

5.3.2 Triclosan 116

5.4 Thyroid Hormone Level Disruptors 117

5.4.1 Polybrominated Diphenyl Ethers (PBDEs) 117

5.5 Selective Thyroid Hormone Antagonists 119

5.5.1 Bisphenols 119

5.5.2 Perfluoroalkyl Acids (PFAAs) 120

5.5.3 Phthalates 120

5.6 Conclusions and Future Prospects 121

References 121

6 Activators of PPAR RXR AhR and Steroidogenic Factor 1 126

6.1 Introduction 126

6.2 Peroxisome Proliferator-Activated Receptor (PPAR) Agonists 127

6.2.1 Organotin Antifoulant Biocides 128

6.2.2 Perfluoroalkyl Compounds (PFCs) 130

6.2.3 Phthalates 132

6.3 Aryl Hydrocarbon Receptor (AhR) Agonists 133

6.3.1 Polychlorinated-Dibenzodioxins (PCDDs) and -Dibenzofurans (PCDFs) 133

6.3.2 Coplanar Polychlorinated Biphenyls 135

6.3.3 Substituted Urea and Anilide Herbicides 135

6.4 Steroidogenesis Modulator (Aromatase Expression Inducer) 136

6.4.1 Atrazine 136

6.5 Conclusions and Future Prospects 138

References 139

7 Effects of EDC Mixtures 146

7.1 Introduction 146

7.2 Combined Effect of Exposure to Multiple Chemicals 146

7.3 Mixture Effects of Estrogenic Chemicals 148

7.4 Mixture Effects of Estrogens and Anti-Estrogens 151

7.5 Mixture Effects of Anti-Androgens 152

7.5.1 Anti-Androgens with Common Mechanism of Action 152

7.5.2 Anti-Androgens with Different Modes of Action 154

7.5.3 Chronic Exposure of Low Dose Mixture of Anti-Androgens Versus Acute Exposure to High Dose Individual Compounds 156

7.6 Mixture Effects of Thyroid Disrupting Chemicals 157

7.7 Mixture Effects of Chemicals Acting via AhR 158

7.8 Conclusions and Future Prospects 158

References 161

8 Environmentally Induced Epigenetic Modifications and Transgenerational Effects 166

8.1 Introduction 166

8.2 Regulatory Epigenetic Modifications 168

8.2.1 Methylation of Cytosine Residues in the DNA and Impact on Gene Expression (Transcriptional Silencing) 168

8.2.2 Remodeling of Chromatin Structure through Post-Translational Modifications of Histone Tails (Determinants of Accessibility) 170

8.2.3 Regulation of Gene Expression by Noncoding RNAs 173

8.2.4 DNA Demethylation 174

8.2.5 Assays for Epigenetic Modification 175

8.3 Epigenetic Dysregulation Effects of Endocrine Disruption 176

8.3.1 Bisphenol A (BPA): A Case Study 177

8.3.2 DEHP 179

8.4 Environmental Epigenetic Effects of Heavy Metals Exposure 179

8.4.1 Cadmium 180

8.4.2 Arsenic 180

8.4.3 Nickel 180

8.4.4 Lead 181

8.5 Transgenerational Inheritance of Environmentally Induced Epigenetic Alterations 181

8.5.1 DES 182

8.5.2 Vinclozolin 183

8.5.3 Methoxychlor 185

8.5.4 BPA 185

8.5.5 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) 185

8.6 Transgenerational Actions of EDCs Mixture on Reproductive Disease 186

8.7 Conclusions and Future Prospects 187

References 188

Part II Removal Mechanisms Of Edcs Through Biotic And Abiotic Processes 195

9 Biodegradations and Biotransformations of Selected Examples of EDCs 197

9.1 Introduction 197

9.2 Natural and Synthetic Steroidal Estrogens 199

9.2.1 17β-Estradiol and Estrone 199

9.2.2 17α-Ethynylestradiol 202

9.3 Alkylphenols 205

9.3.1 4-n-Nonylphenol (4-NP1) 205

9.3.2 4-tert-Nonylphenol Isomer 4-(1-Ethyl-1,4-Eimethylpentyl) Phenol (NP112) 208

9.3.3 4-tert-Nonylphenol Isomer 4-[1-Ethyl-1,3-Dimethylpentyl] Phenol (4-NP111) 210

9.3.4 4-n- and 4-tert-Octylphenols 212

9.3.5 Bisphenol A 214

9.4 Phthalates 220

9.4.1 Di-n-butyl Phthalate (DBP) 221

9.4.2 n-Butyl Benzyl Phthalate (BBP) 222

9.4.3 Di-(2-ethylhexyl) Phthalate (DEHP) 223

9.4.4 Di-n-octyl Phthalate (DOP) 226

9.5 Insecticides 226

9.5.1 Methoxychlor 226

9.6 Fungicides 228

9.6.1 Vinclozolin 228

9.6.2 Procymidone 231

9.6.3 Prochloraz 232

9.7 Herbicides 232

9.7.1 Linuron 232

9.7.2 Atrazine 233

9.8 Polychlorinated Biphenyls (PCBs) 236

9.9 Polybrominated Diphenyl Ethers (PBDEs) 238

9.9.1 2,2’,4,4’ -Tetrabromodiphenyl Ether (BDE-47) 238

9.9.2 2,2’,4,4’,5-Penta-bromodiphenyl Ether (BDE-99) 243

9.9.3 3,3’,4,4’,5,5’,6,6’-Decabromodiphenyl Ether (BDE-209) 243

9.10 Triclosan 245

9.11 Conclusions and Future Prospects 245

References 246

10 Abiotic Degradations/Transformations of EDCs Through Oxidation Processes 254

10.1 Introduction 254

10.2 Natural and Synthetic Estrogens 256

10.2.1 17β-Estradiol (E2) and Estrone (E1) 256

10.2.2 17α-Ethinylestradiol (EE2) 260

10.3 Bisphenol A 260

10.3.1 Chlorination with HOCl 263

10.3.2 Catalytic Oxidation with H2O2 263

10.3.3 Oxidation with KMnO4 266

10.3.4 Oxidation with MnO2 267

10.3.5 Treatment with Zero-Valent Aluminum 267

10.3.6 Ozonation 267

10.3.7 Fenton Reaction 270

10.3.8 Photolytic and Photocatalytic Degradation 272

10.4 4-Octylphenol and 4-Nonylphenol 272

10.4.1 Chlorination 272

10.4.2 Ozonation 274

10.4.3 Photocatalytic Degradation 274

10.5 Parabens 274

10.5.1 Ozonation 276

10.5.2 Photocatalytic Degradation 276

10.6 Phthalates – Photocatalytic Degradation 276

10.6.1 Dibutyl Phthalate (DBP) 277

10.6.2 n-Butyl Benzylphthalate 277

10.6.3 Di(2-Ethylhexyl)phthalate (DEHP) 279

10.7 Linuron 279

10.7.1 Treatment with O3 UV and UV/O3 279

10.8 Atrazine 281

10.8.1 Fenton Reaction 281

10.8.2 Reaction with Ozone Ozone/H2O2 and Ozone/OH Radicals 282

10.8.3 Treatment with δ-MnO2 282

10.8.4 Reductive Dechlorination 282

10.8.5 Photocatalytic Degradation 282

10.9 Polybrominated Diphenyl Ether (PBDE) Flame Retardants 282

10.9.1 Photochemical Degradation 282

10.9.2 TiO2-Mediated Photocatalytic Debromination 284

10.9.3 Zero-Valent Iron Reductive Debromination 285

10.10 Triclosan 285

10.10.1 Clorination with HOCl 285

10.10.2 Oxidation with KMnO4/MnO2 286

10.10.3 Ozonation 286

10.10.4 Photochemical Transformation 286

10.11 PFOA and PFOS 289

10.11.1 Modified Fenton Reaction 289

10.11.2 Sonochemical Degradation 289

10.11.3 Photocatalytic Reaction 289

10.12 Conclusions 289

References 290

Part III Screening And Testing For Potential Edcs Implications For Water Quality Sustainability Policy And Regulatory Issues And Green Chemistry Principles In The Design Of Safe Chemicals And Remediation Of Edcs 297

11 Screening and Testing Programs for EDCs 299

11.1 Introduction 299

11.2 Endocrine Disruptor Screening Program (EDSP) 300

11.2.1 EDSP Tier 1 301

11.2.2 EDSP Tier 2 302

11.3 Assays for the Detection of Chemicals that Alter the Estrogen Signaling Pathway 304

11.3.1 The ER Binding Assay (USEPA OPPTS 890.1250) 304

11.3.2 ERα Transcriptional Activation Assay (USEPA OPPTS 890.1300; OECD 455) 304

11.3.3 Aromatase Assay (USEPA OPPTS 890.1200) 306

11.3.4 In vivo Uterotrophic Bioassay in Rodents (USEPA OPPTS 890.1600; OECD 440) 307

11.3.5 Pubertal Female Rat Assay (USEPA OPPTS 890.1450) 308

11.3.6 Twenty-One-Day Fish Reproduction Assay (USEPA OPPTS 890.1350; OECD 229) 308

11.4 Assays for the Detection of Chemicals that Alter the Androgenic Signaling Pathway 308

11.4.1 AR Binding Assay (Rat Prostate Cytosol) (USEPA OPPTS 890.1150) 309

11.4.2 H295R Steroidogenesis Assay (USEPA OPPTS 890.1550) 309

11.4.3 Hershberger Bioassay in Rats for Androgenicity (USEPA OCSPP 890.1400; OECD 441) 309

11.4.4 Pubertal Male Rat Assay (USEPA OPPTS 890.1500) 310

11.4.5 Strengths and Limitations of Assays for Interference with Androgen Action 310

11.5 Assays for the Detection of Chemicals that Alter the HPT Axis 311

11.5.1 Amphibian Metamorphosis Assay (OPPTS 890.1100) 311

11.5.2 Strengths and Limitations of Thyroid Disrupting Chemical Assays 311

11.6 The USEPA’s EDSP21 Work Plan 312

11.6.1 The USEPA ToxCast Program 313

11.6.2 Tox21 HTS Programs 314

11.7 Conclusions and Future Prospects 316

References 317

12 Trace Contaminants: Implications for Water Quality Sustainability 320

12.1 Introduction 320

12.2 Trace Contaminants Sources in Water 321

12.3 Wastewater Reclamation Processes 323

12.3.1 Primary Treatment: Sedimentation/Coagulation 323

12.3.2 Secondary Treatment: Removal by Physical Methods or Biological Process 324

12.3.3 Tertiary Treatment: Redox Processes 325

12.4 Indirect Water Reuse Systems 326

12.4.1 Removal of Trace Contaminants for Potable Water Reuse Applications 326

12.5 Leaching of Contaminants in Water – the Case of Bottled Water 327

12.6 Water Quality Sustainability and Health Effects 328

12.7 Toxicological Implications 329

12.8 Regulatory Structures to Maintain Water Quality 330

12.9 Conclusions and Future Prospects 331

References 333

13 Policy and Regulatory Considerations for EDCs 339

13.1 Introduction 339

13.2 Regulating Paradigm Shift in Conventional Toxicology 340

13.2.1 Downward Movement of Safe Thresholds 341

13.2.2 Nonmonotonic Low-Dose Effects (Nonthreshold substances) 341

13.2.3 Sensitivity of Development Periods 342

13.2.4 Cumulative Exposures to Multiple EDCs (Exposures can be Additive) 342

13.2.5 Long Latency Between Exposure and Effect (Delayed Effects) 343

13.3 Policy Options for EDC Regulation 344

13.3.1 Scientific Uncertainty and Precautionary Policy 344

13.3.2 Shifting the Burden of Proving Safe Products 345

13.3.3 Need to Broaden the Risk Assessment 346

13.3.4 Cutting-Edge Bioassays Showing Developmental Endpoints 346

13.4 Controversy on Regulatory Framework for EDCs 348

13.4.1 Diversity of Viewpoints of the Risk Assessors and the Endocrine Scientists 348

13.4.2 A Debate on EU Regulatory Framework for EDCs 350

13.5 Conclusions and Future Prospects 351

References 353

14 Green Chemistry Principles in the Designing and Screening for Safe Chemicals and Remediation of EDCs 357

14.1 Introduction 357

14.2 Benign by Design Chemicals 358

14.3 Chemical Endocrine Disruption Screening Protocol 361

14.3.1 Tiered Protocol for Endocrine Disruption 361

14.4 Green Oxidative Remediation of EDCs 363

14.4.1 Catalytic Oxidation Processes 364

14.5 Conclusions and Future Prospects 366

References 368

Index 371