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Translational Toxicology and Therapeutics

Windows of Developmental Susceptibility in Reproduction and Cancer
1. Aufl.

von: Michael D. Waters, Claude L. Hughes
197,99 €
Verlag:	Wiley
Format:	EPUB
Veröffentl.:	10.11.2017
ISBN/EAN:	9781119023623
Sprache:	englisch
Anzahl Seiten:	784

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Titelbeschreibung

Written by leading research scientists, this book integrates current knowledge of toxicology and human health through coverage of environmental toxicants, genetic / epigenetic mechanisms, and carcinogenicity. <ul> <li>Provides information on lifestyle choices that can reduce cancer risk</li> <li>Offers a systematic approach to identify mutagenic, developmental and reproductive toxicants</li> <li>Helps readers develop new animal models and tests to assess toxic impacts of mutation and cancer on human health</li> <li>Explains specific cellular and molecular targets of known toxicants operating through genetic and epigenetic mechanisms</li> </ul>

Inhaltsverzeichnis

List of Contributors xix Part One Introduction: The Case for Concern about Mutation and Cancer Susceptibility during Critical Windows of Development and the Opportunity to Translate Toxicology into a Therapeutic Discipline 1 1 What Stressors Cause Cancer and When? 3 Claude L. Hughes and Michael D. Waters 1.1 Introduction 3 1.1.1 General Information about Cancer 5 1.1.2 Stressors and Adaptive Responses 8 1.2 What Stressors Cause Cancer and When? 8 1.2.1 Mutagenic MOAs 13 1.2.1.1 DNA Repair 14 1.2.2 Epigenetic MOAs 16 1.2.3 Nongenotoxic Carcinogens, ROS, Obesity, Metabolic, Diet, Environment, Immune, Endocrine MOAs 20 1.2.4 Tumor Microenvironment MOAs 25 1.3 Relevance of Circulating Cancer Markers 26 1.4 Potential Cancer Translational Toxicology Therapies 29 1.4.1 Well-Established/Repurposed Pharmaceuticals 31 1.4.2 GRAS/GRASE, Diet, and Nutraceuticals 34 1.4.2.1 Suppression of Cell Proliferation and Induction of Cell Death 35 1.4.2.2 Anti-Inflammatory Effects: Insights from Various Diseases 36 1.4.2.3 Upregulation of Tumor Suppressor MicroRNAs 38 1.4.2.4 Regulation of Oxidative Stress 38 1.4.2.5 Activation of Signal Transduction Pathways 39 1.4.2.6 Mitigating Inherited Deleterious Mutations 40 1.4.2.7 Mitigating Adverse Epigenetic States 42 1.4.2.8 Paradigm for Study of Cancer Chemoprevention 43 1.5 Modeling and the Future 47 References 51 2 What Mutagenic Events Contribute to Human Cancer and Genetic Disease? 61 Michael D. Waters 2.1 Introduction 61 2.1.1 Childhood Cancer, Developmental Defects, and Adverse Reproductive Outcomes 62 2.1.2 Newborn Screening for Genetic Disease 62 2.1.3 Diagnosis of Genetic Disease 63 2.1.4 Familial and Sporadic Cancer 65 2.2 Genetic Damage from Environmental Agents 67 2.3 Testing for Mutagenicity and Carcinogenicity 71 2.4 Predictive Toxicogenomics for Carcinogenicity 73 2.5 Germ Line Mutagenicity and Screening Tests 76 2.6 Reproductive Toxicology Assays in the Assessment of Heritable Effects 80 2.6.1 Segmented Reproductive Toxicity Study Designs 80 2.6.2 Continuous Cycle Designs 81 2.6.2.1 One-Generation Toxicity Study 81 2.6.2.2 Repeat Dose Toxicity Studies 82 2.7 Assays in Need of Further Development or Validation 82 2.7.1 Transgenic Rodent Gene Mutation Reporter Assay 82 2.7.2 Expanded Simple Tandem Repeat Assay 84 2.7.3 Spermatid Micronucleus (MN) Assay 85 2.7.4 Sperm Comet Assay 86 2.7.5 Standardization of Sperm Chromatin Quality Assays 86 2.8 New Technologies 87 2.8.1 Copy Number Variants and Human Genetic Disease 87 2.8.2 Next-Generation Whole Genome Sequencing 88 2.8.3 High-Throughput Analysis of Egg Aneuploidy in C. elegans, and Other Alternative Assay Systems 90 2.9 Endpoints Most Relevant to Human Genetic Risk 91 2.10 Worldwide Regulatory Requirements for Germ Cell Testing 94 2.11 Conclusion 95 Acknowledgments 96 References 96 3 Developmental Origins of Cancer 111 Suryanarayana V. Vulimiri and John M. Rogers 3.1 Introduction 111 3.2 Current Trends in Childhood Cancer 112 3.3 Potential Mechanisms of Prenatal Cancer Induction 113 3.4 Ontogeny of Xenobiotic Metabolizing Enzymes and DNA Repair Systems 113 3.5 The Developmental Origins of Health and Disease (DOHaD) Theory 115 3.6 Epigenetic Regulation during Development 115 3.6.1 Critical Periods for Epigenetic Regulation 116 3.7 Mechanisms of Cancer in Offspring from Paternal Exposures 117 3.8 Parental Exposures Associated with Cancer in Offspring 118 3.8.1 Radiation 118 3.8.2 Diethylstilbestrol 119 3.8.3 Tobacco Smoke 120 3.8.4 Pesticides 122 3.8.5 Arsenic 123 3.9 Models for the Developmental Origins of Selected Cancers 124 3.9.1 Breast Cancer 124 3.9.2 Leukemia 127 3.10 Public Health Agencies’ Views on Prenatal Exposures and Cancer Risk 129 3.10.1 The United States Environmental Protection Agency (US EPA) 129 3.10.2 The California Environmental Protection Agency (CalEPA) 131 3.10.3 Washington State Department of Ecology (WA DoE) 133 3.11 Conclusions 134 Acknowledgment 135 References 135 4 The Mechanistic Basis of Cancer Prevention 147 Bernard W. Stewart 4.1 Introduction 147 4.2 A Mechanistic Approach 147 4.2.1 Specifying Carcinogens 148 4.2.2 Cancer Risk Factors Without Carcinogen Specification 148 4.3 Preventing Cancer Attributable to Known Carcinogens 149 4.3.1 Involuntary Exposure 149 4.3.1.1 Infectious Agents 149 4.3.1.2 Occupation 150 4.3.1.3 Drugs 151 4.3.1.4 Pollution 152 4.3.1.5 Dietary Carcinogens 152 4.3.2 Tobacco Smoking 153 4.3.2.1 Measures to Limit Availability and Promotion 154 4.3.2.2 Product Labeling, Health Warnings, and Usage Restrictions 154 4.3.2.3 Smoking Cessation 155 4.3.3 Alcohol Drinking 155 4.3.4 Solar and Ultraviolet Radiation 156 4.4 Prevention Involving Complex Risk Factors 157 4.4.1 Workplace Exposures 157 4.4.2 Diet and Overweight/Obesity 157 4.5 Prevention Independent of Causative Agents or Risk Factors 158 4.5.1 Screening 158 4.5.2 Chemoprevention 159 4.6 Conclusion 160 References 160 Part Two Exposures that Could Alter the Risk of Cancer Occurrence, and Impact Its Indolent or Aggressive Behavior and Progression Over Time 171 5 Diet Factors in Cancer Risk 173 Lynnette R. Ferguson 5.1 Introduction 173 5.2 Obesity 174 5.3 Macronutrients 175 5.3.1 Protein 176 5.3.2 Lipids 177 5.3.3 Carbohydrates 178 5.4 Micronutrients 181 5.4.1 Vitamins 181 5.4.2 Minerals 184 5.5 Phytochemicals 184 5.5.1 Phytoestrogens 185 5.5.2 Other Phytochemicals 186 5.6 Conclusions 188 References 188 6 Voluntary Exposures: Natural Herbals, Supplements, and Substances of Abuse – What Evidence Distinguishes Therapeutic from Adverse Responses? 199 Eli P. Crapper, Kylie Wasser, Katelyn J. Foster, and Warren G. Foster 6.1 Introduction 199 6.1.1 Alcohol 200 6.1.2 Cigarette Smoking 201 6.1.3 Herbals and Supplements 202 6.1.3.1 Melatonin 202 6.1.3.2 Resveratrol 204 6.1.3.3 Dong Quai 205 6.1.3.4 Eleutherococcus 206 6.1.3.5 Saw Palmetto 206 6.1.3.6 Stinging Nettle 207 6.2 Summary and Conclusions 207 References 207 7 Voluntary Exposures: Pharmaceutical Chemicals in Prescription and Over-the-Counter Drugs – Passing the Testing Gauntlet 213 Ronald D. Snyder 7.1 Introduction 213 7.2 Testing of New Drug Entities for Genotoxicity 214 7.3 Relationship between Genotoxicity Testing and Rodent Carcinogenicity 217 7.4 Can Drug-Induced Human Cancer Be Predicted? 218 7.5 What Can Rodent Carcinogenicity Tell Us about Human Cancer Risk? 220 7.6 Genotoxicity Prediction Using “Traditional” In Silico Approaches 222 7.7 Covalent versus Noncovalent DNA Interaction 223 7.8 Use of New Technologies to Predict Toxicity and Cancer Risk: High-Throughput Methods 224 7.9 Transcriptomics 225 7.10 Single-Nucleotide Polymorphisms (SNPs) 226 7.11 Conclusions 227 Appendix A 228 References 253 8 Children’s and Adult Involuntary and Occupational Exposures and Cancer 259 Annamaria Colacci and Monica Vaccari 8.1 Introduction 259 8.2 Occupational Exposures and Cancer 262 8.2.1 Occupational Cancer in the Twenty-First Century 262 8.2.2 Past and Present Occupational Exposure to Asbestos 263 8.2.3 Toxicology of Fibers: What We Have Learned from the Asbestos Lesson 265 8.2.3.1 Mechanism and Mode of Action of Asbestos and Asbestos-Like Fibers in Carcinogenesis: The Role of Inflammation and Immune System to Sustain the Cancer Process 268 8.2.4 Occupational Exposures and Rare Tumors 270 8.3 Environmental Exposures and Cancer 271 8.3.1 Environmental Exposures and Disease: Is This the Pandemic of the Twenty-First Century? 271 8.3.2 The Complexity of Environmental Exposures 272 8.3.3 Environmental Impact on Early Stages of Life: Are Our Children at Risk? 274 8.3.4 Environmental Endocrine Disruptors: The Steps Set Out to Recover Our Stolen Future 277 8.3.5 From Occupational to Environmental Exposures: Asbestos and Other Chemicals of Concern 279 8.3.5.1 Asbestos 279 8.3.5.2 Arsenic and Arsenic Compounds 280 8.3.5.3 Phthalates 282 8.3.5.4 Pesticides 283 8.3.5.5 Mycotoxins 286 8.3.6 Air Pollution and Airborne Particulate Matter: The Paradigmatic Example of Environmental Mixtures 288 8.3.6.1 Characteristics of PM and PM Exposures 289 8.3.6.2 PM Exposures and Cancer 291 8.3.6.3 Possible Mechanisms of PM Toxicity 293 8.3.6.4 The Role of PM Exposures in the Fetal Origin of the Disease 294 8.4 Conclusions and Future Perspectives 296 References 299 Part Three Gene–Environment Interactions 317 9 Ethnicity, Geographic Location, and Cancer 319 Fengyu Zhang 9.1 Introduction 319 9.2 Classification of Cancer 320 9.2.1 Classification by Histology 320 9.2.2 Classification by Primary Location 322 9.3 Ethnicity and Cancer 323 9.3.1 Cancer Death and Incidence 323 9.3.2 Site-Specific Cancer Incidence 326 9.3.3 Site-Specific Cancer Incidence between the United States and China 328 9.4 Geographic Location and Cancer 331 9.4.1 Mapping Human Diseases to Geographic Location 331 9.4.2 Geographic Variation and Cancer in the United States 332 9.5 Ethnicity, Geographic Location, and Lung Cancer 334 9.5.1 Ethnic Differences 334 9.5.2 Geographic Variation 335 9.5.3 Individual Risk Factors 335 9.6 Common Cancers in China 338 9.6.1 Liver Cancer 339 9.6.1.1 Geographic Variation 339 9.6.1.2 Urban Residence and Sex 340 9.6.1.3 Hepatitis B Virus Infection 340 9.6.1.4 Familial Aggregation and Genetic Variants 341 9.6.2 Gastric Cancer 342 9.6.2.1 H. pylori 342 9.6.2.2 Familial Aggregation 343 9.6.2.3 Genetic Susceptibility Factors 343 9.6.3 Esophageal Cancer 344 9.6.3.1 Geographic Variation 344 9.6.3.2 Viral Infections 344 9.6.3.3 Familial Aggregation 345 9.6.3.4 Genetic Susceptibility Factors 345 9.6.4 Lung Cancer 346 9.6.5 Genetic Susceptibility Factors 347 9.6.6 Cervical Cancer 348 9.7 Cancer Risk Factors and Prevention 348 9.7.1 Environmental Chemical Exposure 348 9.7.2 Infectious Agents 349 9.7.3 Psychosocial Stress and Social Network 349 9.7.4 The Developmental Origin of Adult-Onset Cancer 350 9.7.5 Cancer Prevention and Intervention 351 References 353 10 Dietary/Supplemental Interventions and Personal Dietary Preferences for Cancer: Translational Toxicology Therapeutic Portfolio for Cancer Risk Reduction 363 Sandeep Kaur, Elaine Trujillo, and Harold Seifried 10.1 Introduction 363 10.2 Gene Expression and Epigenetics 364 10.3 Environmental Lifestyle Factors Affecting Cancer Prevention and Risk 366 10.3.1 Obesity 366 10.3.2 Weight Loss 368 10.3.3 Physical Activity 369 10.4 Dietary Patterns 370 10.5 Complementary and Integrative Oncology Interventions/Restorative Therapeutics 373 10.6 Special and Alternative Diets 377 10.7 Popular Anticancer Diets 378 10.7.1 Macrobiotic Diet 378 10.7.2 The Ketogenic Diet 382 10.7.3 Fasting Diet 383 10.8 Conclusion 384 Acknowledgment 384 References 385 11 Social Determinants of Health and the Environmental Exposures: A Promising Partnership 395 Lauren Fordyce, David Berrigan, and Shobha Srinivasan 11.1 Introduction 395 11.1.1 Conceptual Model 397 11.1.2 Difference versus Disparity 398 11.2 Social Determinants of Health 399 11.2.1 Race/Ethnicity 399 11.2.2 Social Determinants of Health: “Place” and Its Correlates 402 11.2.3 Gender and Sexuality 405 11.3 Conclusions: Social Determinants of Health and Windows of Susceptibility 407 Acknowledgments 408 References 408 Part Four Categorical and Pleiotropic Nonmutagenic Modes of Action of Toxicants: Causality 415 12 Bisphenol A and Nongenotoxic Drivers of Cancer 417 Natalie R. Gassman and Samuel H. Wilson 12.1 Introduction 417 12.2 Dosing 420 12.3 Receptor-mediated Signaling 421 12.4 Epigenetic Reprogramming 422 12.5 Oxidative stress 424 12.6 Inflammation and Immune Response 425 12.7 BPA-Induced Carcinogenesis 426 12.8 Fresh Opportunities in BPA Research 428 References 429 13 Toxicoepigenetics and Effects on Life Course Disease Susceptibility 439 Luke Montrose, Jaclyn M. Goodrich, and Dana C. Dolinoy 13.1 Introduction to the Field of Toxicoepigenetics 439 13.1.1 The Epigenome 440 13.1.2 Epigenetic Marks are Heritable and Reversible 440 13.1.3 DNA Methylation 441 13.1.4 Histone Modifications and Chromatin Packaging 442 13.1.5 Noncoding RNAs 443 13.1.6 Key Windows for Exposure-Related Epigenetic Changes 443 13.1.7 Evaluation of Environmentally Induced Epigenetic Changes in Animal Models and Humans 444 13.2 Exposures that Influence the Epigenome 444 13.2.1 Air Pollution 445 13.2.2 Metals 447 13.2.3 Endocrine Disrupting Chemicals (EDCs) 448 13.2.4 Diet 451 13.2.5 Stress 453 13.3 Intergenerational Exposures and Epigenetic Effects 454 13.4 Special Considerations and Future Directions for the Field of Toxicoepigenetics 456 13.4.1 Tissue Specificity 456 13.4.2 The Dynamic Nature of DNA Methylation 458 13.5 Future Directions 459 13.6 Conclusions 460 Acknowledgments 461 References 461 14 Tumor-Promoting/Associated Inflammation and the Microenvironment: A State of the Science and New Horizons 473 William H. Bisson, Amedeo Amedei, Lorenzo Memeo, Stefano Forte, and Dean W. Felsher 14.1 Introduction 473 14.2 The Immune System 475 14.2.1 Innate Immune Response 475 14.2.2 Adaptive Immune Response 478 14.3 Prioritized Chemicals 482 14.3.1 Bisphenol A 482 14.3.2 Polybrominated Diphenyl Ethers 483 14.3.3 4-Nonylphenol 485 14.3.4 Atrazine 485 14.3.5 Phthalates 486 14.4 Experimental Models of Carcinogenesis through Inflammation and Immune System Deregulation 487 14.5 Antioxidants and Translational Opportunities 493 14.6 Tumor Control of the Microenvironment 495 Acknowledgments 497 References 497 15 Metabolic Dysregulation in Environmental Carcinogenesis and Toxicology 511 R. Brooks Robey 15.1 Introduction 511 15.2 Metabolic Reprogramming and Dysregulation in Cancer 513 15.2.1 Carbohydrate Metabolism in Cancer 515 15.2.2 Lipid Metabolism in Cancer 519 15.2.3 Protein Metabolism in Cancer 521 15.3 Moonlighting Functions 523 15.4 Cancer Metabolism in Context 523 15.4.1 The Gestalt of Intermediary Metabolism 523 15.4.2 Cancer Tissues, Cells, and Organelles as Open Systems 527 15.4.3 The Endosymbiotic Nature of Cancer 527 15.4.4 Catabolic and Anabolic Support of Cell Proliferation 528 15.4.5 Cancer Heterogeneity 529 15.4.6 Phenotypic Relationships between Cancer Cells and Their Parental Cell Origins 532 15.4.7 Evolutionary Perspectives of Metabolic Fitness and Selection in Cancer Development 533 15.5 Dual Roles for Metabolism in Both the Generation and Mitigation of Cellular Stress 536 15.5.1 Metabolism and Oxidative Stress 537 15.5.2 Metabolism and Hypoxic Stress 539 15.5.3 Nutritional Stress and Metabolism 539 15.5.4 Metabolism and Physical Stress 540 15.5.5 Metabolism and Other Forms of Cellular Stress 541 15.6 Models of Carcinogenesis 541 15.6.1 Traditional Multistage Models of Cancer Development 542 15.6.2 Role of Replicative Mutagenesis in Cancer Development 543 15.6.3 Acquired Mismatch Model of Carcinogenesis 543 15.7 Potential Metabolic Targets for Environmental Exposures 546 15.7.1 Conceptual Overview of Potential Metabolic Targets 546 15.7.2 Identification of Key Targetable Contributors to Metabolic Dysregulation and Selection 549 15.7.2.1 Glycolysis 555 15.7.2.2 Lipogenesis, Lipolysis, and the PPP 555 15.7.2.3 Citric Acid Cycle 556 15.7.2.4 Organizational or Compartmental Targets 556 15.7.2.5 Metabolite Transport Mechanisms 557 15.7.2.6 Signal Transduction Effectors 558 15.8 Metabolic Changes Associated with Exposures to Selected Agents 559 15.8.1 Selected Agents Classified by the World Health Organization’s International Agency for Research on Cancer (IARC) 559 15.8.1.1 IARC Group 1 (Carcinogenic to Humans) 560 15.8.1.2 IARC Group 2A (Probably Carcinogenic to Humans) 564 15.8.1.3 IARC Group 2B (Possibly Carcinogenic to Humans) 565 15.8.1.4 Other Agents 565 15.8.2 Environmentally Relevant Combinatorial Exposures 567 15.8.2.1 Occupational and Common Environmental Exposures 567 15.8.2.2 Environmentally Relevant Low-Dose Combinatorial Exposures 568 15.8.2.3 The Halifax Project 570 15.9 A Conceptual Overview of Traditional and Emerging Toxicological Approaches to the Problem of Cancer Metabolism: Implications for Future Research 571 15.9.1 General Experimental Considerations in the Study of Metabolism In Vitro 571 15.9.2 Systems Biology and Current Approaches to In Vitro Toxicology Screening 573 15.10 The Nosology of Cancer and Cancer Development 577 15.11 Discussion 579 Acknowledgments 583 References 583 Part Five Biomarkers for Detecting Premalignant Effects and Responses to Protective Therapies during Critical Windows of Development 607 16 Circulating Molecular and Cellular Biomarkers in Cancer 609 Ilaria Chiodi, A. Ivana Scovassi, and Chiara Mondello 16.1 Introduction 609 16.2 Proteins in Body Fluids: Potential Biomarkers 610 16.2.1 Diagnostic Protein Biomarkers 612 16.2.2 Prognostic Protein Biomarkers 613 16.2.3 Protein Biomarkers of Drug Response 615 16.3 Circulating Cell-Free Nucleic Acids 615 16.3.1 Circulating Cell-Free Tumor DNA 616 16.3.1.1 Cf-DNA Integrity, Microsatellite Instability, and LOH 617 16.3.1.2 Tumor-Specific Genetic Alterations 617 16.3.1.3 Tumor Genetic Alterations and Therapy Resistance 619 16.3.1.4 Tumor Epigenetic Alterations: DNA Methylation 620 16.3.2 Circulating Cell-Free RNA 621 16.3.2.1 Circulating Cell-Free microRNA 621 16.4 Extracellular Vesicles: General Features 624 16.4.1 Classification of EVs 624 16.4.2 EVs and Cancer 625 16.4.3 EVs as Mediators of Cell-To-Cell Communication 627 16.5 Circulating Tumor Cells 628 16.5.1 Two-Step Processing of Blood Samples: Enrichment and Identification of Circulating Tumor Cells 628 16.5.1.1 CTC Number as a Cancer Biomarker 630 16.5.2 Characterization of CTCs 630 16.5.2.1 Molecular Characterization of CTCs 630 16.5.2.2 Functional Characterization of CTCs 632 16.5.3 Single CTCs versus CTC Clusters 634 16.5.4 In Hiding Before Getting Home, the Long Journey of CTCs 635 16.6 Conclusions 635 References 637 17 Global Profiling Platforms and Data Integration to Inform Systems Biology and Translational Toxicology 657 Barbara A. Wetmore 17.1 Introduction 657 17.2 Global Omics Profiling Platforms 659 17.2.1 Genomics 659 17.2.2 Epigenomics 661 17.2.3 Transcriptomics 662 17.2.4 Proteomics 665 17.2.5 Metabolomics 668 17.3 High-Throughput Bioactivity Profiling 669 17.3.1 High-Throughput Bioactivity and Toxicity Screening 669 17.3.2 In Vitro–In Vivo Extrapolation 671 17.4 Biomarkers 672 17.5 Exposomics 673 17.6 Bioinformatics to Support and Data Integration and Multiomics Efforts 674 17.7 Data Integration: Multiomics and High-Dimensional Biology Efforts 676 17.8 Conclusion 679 References 679 18 Developing a Translational Toxicology Therapeutic Portfolio for Cancer Risk Reduction 691 Rebecca Johnson and David Kerr 18.1 Introduction 691 18.2 The Identification of Novel Predictors of Adverse Events 693 18.2.1 Candidate Gene Studies 693 18.2.2 Genome-wide Associations 694 18.2.3 Next-Generation Sequencing 695 18.3 Proof of Principle Toxgnostics 696 18.4 Proposed Protocol 698 18.4.1 Integration within Randomized Control Trials 698 18.4.2 Biobanking and Future-Proofing Samples 699 18.4.3 Data Protection and Full Consent 702 18.4.4 The Need for a Collaborative Approach 703 18.4.5 Open Access to Results 704 18.4.6 Translation from Bench to Bedside 705 18.5 Fiscal Matters 706 18.6 The Future of Toxgnostics 706 References 707 19 Ethical Considerations in Developing Strategies for Protecting Fetuses, Neonates, Children, and Adolescents from Exposures to Hazardous Environmental Agents 711 David B. Resnik and Melissa J. Mills 19.1 Introduction 711 19.2 What Is Ethics? 712 19.2.1 Some Fundamental Ethical Values 712 19.2.1.1 Benefits and Costs 712 19.2.1.2 Individual Rights and Responsibilities 713 19.2.1.3 Justice 713 19.2.2 Value Conflicts and Ethical Decision-Making 713 19.3 Ethical Considerations for Strategies Used to Protect Fetuses, Neonates, Children, and Adolescents from Exposures to Harmful Environmental Agents 715 19.3.1 Education 715 19.3.2 Testing/Screening/Monitoring 717 19.3.3 Worker Protection 720 19.3.4 Government Regulation 722 19.3.5 Taxation 725 19.3.6 Civil Liability 726 19.3.7 Criminal Liability 729 19.4 Research with Human Participants 730 19.4.1 Return of Individualized Research Results 732 19.4.2 Protecting Privacy and Confidentiality 733 19.4.3 Interventional Studies 734 19.4.4 Intentional Exposure Studies 736 19.4.5 Protecting Vulnerable Participants 739 19.5 Conclusion 742 References 742 Index 751

Autorenportrait

MICHAEL D. WATERS, PhD, is an independent consultant with over 40 years of toxicology and toxicogenomics research experience at the EPA, at NIH/NIEHS and in the private sector. He has held adjunct professorships in toxicology and pharmacology at both the University of North Carolina and Duke University. CLAUDE L. HUGHES, MD, PhD, is an Executive Director in the Therapeutic Science and Strategy Unit at QuintilesIMS. He is also an Adjunct Professor at North Carolina State University, and Wake Forest University as well as a Consulting Professor at Duke University Medical Center.

Back cover copy

Translational toxicology aims to identify applicable therapeutics that can safely and effectively mitigate potential harm from natural as well as anthropogenic environmental exposures. Written by leading research scientists, Translational Toxicology and Therapeutics: Windows of Developmental Susceptibility in Reproduction and Cancer integrates toxicology and human health through coverage of environmental toxicants, genetic / epigenetic mechanisms, and carcinogenicity. The disciplines of toxicology and therapeutics are linked, relating toxicant exposure and genetic and epigenetic mechanisms to human health and development. The chapters explain specific cellular and molecular targets of known toxicants and offer a systematic approach to identify mutagenic, reproductive, and developmental toxicants. Coverage features discussion about cancer and mutation causes, toxicant exposures, gene-environment interactions, toxicant modes-of-action, and therapeutic strategies to reduce cancer risk. Readers can use this information to develop new animal models and tests to assess toxic impacts – specifically mutation and cancer – on human health.