Translational Toxicology and Therapeutics

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.

• List of Contributors xixPart 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 11 What Stressors Cause Cancer and When? 3Claude L. Hughes and Michael D. Waters1.1 Introduction 31.1.1 General Information about Cancer 51.1.2 Stressors and Adaptive Responses 81.2 What Stressors Cause Cancer and When? 81.2.1 Mutagenic MOAs 131.2.1.1 DNA Repair 141.2.2 Epigenetic MOAs 161.2.3 Nongenotoxic Carcinogens, ROS, Obesity, Metabolic, Diet, Environment, Immune, Endocrine MOAs 201.2.4 Tumor Microenvironment MOAs 251.3 Relevance of Circulating Cancer Markers 261.4 Potential Cancer Translational Toxicology Therapies 291.4.1 Well-Established/Repurposed Pharmaceuticals 311.4.2 GRAS/GRASE, Diet, and Nutraceuticals 341.4.2.1 Suppression of Cell Proliferation and Induction of Cell Death 351.4.2.2 Anti-Inflammatory Effects: Insights from Various Diseases 361.4.2.3 Upregulation of Tumor Suppressor MicroRNAs 381.4.2.4 Regulation of Oxidative Stress 381.4.2.5 Activation of Signal Transduction Pathways 391.4.2.6 Mitigating Inherited Deleterious Mutations 401.4.2.7 Mitigating Adverse Epigenetic States 421.4.2.8 Paradigm for Study of Cancer Chemoprevention 431.5 Modeling and the Future 47References 512 What Mutagenic Events Contribute to Human Cancer and Genetic Disease? 61Michael D. Waters2.1 Introduction 612.1.1 Childhood Cancer, Developmental Defects, and Adverse Reproductive Outcomes 622.1.2 Newborn Screening for Genetic Disease 622.1.3 Diagnosis of Genetic Disease 632.1.4 Familial and Sporadic Cancer 652.2 Genetic Damage from Environmental Agents 672.3 Testing for Mutagenicity and Carcinogenicity 712.4 Predictive Toxicogenomics for Carcinogenicity 732.5 Germ Line Mutagenicity and Screening Tests 762.6 Reproductive Toxicology Assays in the Assessment of Heritable Effects 802.6.1 Segmented Reproductive Toxicity Study Designs 802.6.2 Continuous Cycle Designs 812.6.2.1 One-Generation Toxicity Study 812.6.2.2 Repeat Dose Toxicity Studies 822.7 Assays in Need of Further Development or Validation 822.7.1 Transgenic Rodent Gene Mutation Reporter Assay 822.7.2 Expanded Simple Tandem Repeat Assay 842.7.3 Spermatid Micronucleus (MN) Assay 852.7.4 Sperm Comet Assay 862.7.5 Standardization of Sperm Chromatin Quality Assays 862.8 New Technologies 872.8.1 Copy Number Variants and Human Genetic Disease 872.8.2 Next-Generation Whole Genome Sequencing 882.8.3 High-Throughput Analysis of Egg Aneuploidy in C. elegans, and Other Alternative Assay Systems 902.9 Endpoints Most Relevant to Human Genetic Risk 912.10 Worldwide Regulatory Requirements for Germ Cell Testing 942.11 Conclusion 95Acknowledgments 96References 963 Developmental Origins of Cancer 111Suryanarayana V. Vulimiri and John M. Rogers3.1 Introduction 1113.2 Current Trends in Childhood Cancer 1123.3 Potential Mechanisms of Prenatal Cancer Induction 1133.4 Ontogeny of Xenobiotic Metabolizing Enzymes and DNA Repair Systems 1133.5 The Developmental Origins of Health and Disease (DOHaD) Theory 1153.6 Epigenetic Regulation during Development 1153.6.1 Critical Periods for Epigenetic Regulation 1163.7 Mechanisms of Cancer in Offspring from Paternal Exposures 1173.8 Parental Exposures Associated with Cancer in Offspring 1183.8.1 Radiation 1183.8.2 Diethylstilbestrol 1193.8.3 Tobacco Smoke 1203.8.4 Pesticides 1223.8.5 Arsenic 1233.9 Models for the Developmental Origins of Selected Cancers 1243.9.1 Breast Cancer 1243.9.2 Leukemia 1273.10 Public Health Agencies’ Views on Prenatal Exposures and Cancer Risk 1293.10.1 The United States Environmental Protection Agency (US EPA) 1293.10.2 The California Environmental Protection Agency (CalEPA) 1313.10.3 Washington State Department of Ecology (WA DoE) 1333.11 Conclusions 134Acknowledgment 135References 1354 The Mechanistic Basis of Cancer Prevention 147Bernard W. Stewart4.1 Introduction 1474.2 A Mechanistic Approach 1474.2.1 Specifying Carcinogens 1484.2.2 Cancer Risk Factors Without Carcinogen Specification 1484.3 Preventing Cancer Attributable to Known Carcinogens 1494.3.1 Involuntary Exposure 1494.3.1.1 Infectious Agents 1494.3.1.2 Occupation 1504.3.1.3 Drugs 1514.3.1.4 Pollution 1524.3.1.5 Dietary Carcinogens 1524.3.2 Tobacco Smoking 1534.3.2.1 Measures to Limit Availability and Promotion 1544.3.2.2 Product Labeling, Health Warnings, and Usage Restrictions 1544.3.2.3 Smoking Cessation 1554.3.3 Alcohol Drinking 1554.3.4 Solar and Ultraviolet Radiation 1564.4 Prevention Involving Complex Risk Factors 1574.4.1 Workplace Exposures 1574.4.2 Diet and Overweight/Obesity 1574.5 Prevention Independent of Causative Agents or Risk Factors 1584.5.1 Screening 1584.5.2 Chemoprevention 1594.6 Conclusion 160References 160Part Two Exposures that Could Alter the Risk of Cancer Occurrence, and Impact Its Indolent or Aggressive Behavior and Progression Over Time 1715 Diet Factors in Cancer Risk 173Lynnette R. Ferguson5.1 Introduction 1735.2 Obesity 1745.3 Macronutrients 1755.3.1 Protein 1765.3.2 Lipids 1775.3.3 Carbohydrates 1785.4 Micronutrients 1815.4.1 Vitamins 1815.4.2 Minerals 1845.5 Phytochemicals 1845.5.1 Phytoestrogens 1855.5.2 Other Phytochemicals 1865.6 Conclusions 188References 1886 Voluntary Exposures: Natural Herbals, Supplements, and Substances of Abuse – What Evidence Distinguishes Therapeutic from Adverse Responses? 199Eli P. Crapper, Kylie Wasser, Katelyn J. Foster, and Warren G. Foster6.1 Introduction 1996.1.1 Alcohol 2006.1.2 Cigarette Smoking 2016.1.3 Herbals and Supplements 2026.1.3.1 Melatonin 2026.1.3.2 Resveratrol 2046.1.3.3 Dong Quai 2056.1.3.4 Eleutherococcus 2066.1.3.5 Saw Palmetto 2066.1.3.6 Stinging Nettle 2076.2 Summary and Conclusions 207References 2077 Voluntary Exposures: Pharmaceutical Chemicals in Prescription and Over-the-Counter Drugs – Passing the Testing Gauntlet 213Ronald D. Snyder7.1 Introduction 2137.2 Testing of New Drug Entities for Genotoxicity 2147.3 Relationship between Genotoxicity Testing and Rodent Carcinogenicity 2177.4 Can Drug-Induced Human Cancer Be Predicted? 2187.5 What Can Rodent Carcinogenicity Tell Us about Human Cancer Risk? 2207.6 Genotoxicity Prediction Using “Traditional” In Silico Approaches 2227.7 Covalent versus Noncovalent DNA Interaction 2237.8 Use of New Technologies to Predict Toxicity and Cancer Risk: High-Throughput Methods 2247.9 Transcriptomics 2257.10 Single-Nucleotide Polymorphisms (SNPs) 2267.11 Conclusions 227Appendix A 228References 2538 Children’s and Adult Involuntary and Occupational Exposures and Cancer 259Annamaria Colacci and Monica Vaccari8.1 Introduction 2598.2 Occupational Exposures and Cancer 2628.2.1 Occupational Cancer in the Twenty-First Century 2628.2.2 Past and Present Occupational Exposure to Asbestos 2638.2.3 Toxicology of Fibers: What We Have Learned from the Asbestos Lesson 2658.2.3.1 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 2688.2.4 Occupational Exposures and Rare Tumors 2708.3 Environmental Exposures and Cancer 2718.3.1 Environmental Exposures and Disease: Is This the Pandemic of the Twenty-First Century? 2718.3.2 The Complexity of Environmental Exposures 2728.3.3 Environmental Impact on Early Stages of Life: Are Our Children at Risk? 2748.3.4 Environmental Endocrine Disruptors: The Steps Set Out to Recover Our Stolen Future 2778.3.5 From Occupational to Environmental Exposures: Asbestos and Other Chemicals of Concern 2798.3.5.1 Asbestos 2798.3.5.2 Arsenic and Arsenic Compounds 2808.3.5.3 Phthalates 2828.3.5.4 Pesticides 2838.3.5.5 Mycotoxins 2868.3.6 Air Pollution and Airborne Particulate Matter: The Paradigmatic Example of Environmental Mixtures 2888.3.6.1 Characteristics of PM and PM Exposures 2898.3.6.2 PM Exposures and Cancer 2918.3.6.3 Possible Mechanisms of PM Toxicity 2938.3.6.4 The Role of PM Exposures in the Fetal Origin of the Disease 2948.4 Conclusions and Future Perspectives 296References 299Part Three Gene–Environment Interactions 3179 Ethnicity, Geographic Location, and Cancer 319Fengyu Zhang9.1 Introduction 3199.2 Classification of Cancer 3209.2.1 Classification by Histology 3209.2.2 Classification by Primary Location 3229.3 Ethnicity and Cancer 3239.3.1 Cancer Death and Incidence 3239.3.2 Site-Specific Cancer Incidence 3269.3.3 Site-Specific Cancer Incidence between the United States and China 3289.4 Geographic Location and Cancer 3319.4.1 Mapping Human Diseases to Geographic Location 3319.4.2 Geographic Variation and Cancer in the United States 3329.5 Ethnicity, Geographic Location, and Lung Cancer 3349.5.1 Ethnic Differences 3349.5.2 Geographic Variation 3359.5.3 Individual Risk Factors 3359.6 Common Cancers in China 3389.6.1 Liver Cancer 3399.6.1.1 Geographic Variation 3399.6.1.2 Urban Residence and Sex 3409.6.1.3 Hepatitis B Virus Infection 3409.6.1.4 Familial Aggregation and Genetic Variants 3419.6.2 Gastric Cancer 3429.6.2.1 H. pylori 3429.6.2.2 Familial Aggregation 3439.6.2.3 Genetic Susceptibility Factors 3439.6.3 Esophageal Cancer 3449.6.3.1 Geographic Variation 3449.6.3.2 Viral Infections 3449.6.3.3 Familial Aggregation 3459.6.3.4 Genetic Susceptibility Factors 3459.6.4 Lung Cancer 3469.6.5 Genetic Susceptibility Factors 3479.6.6 Cervical Cancer 3489.7 Cancer Risk Factors and Prevention 3489.7.1 Environmental Chemical Exposure 3489.7.2 Infectious Agents 3499.7.3 Psychosocial Stress and Social Network 3499.7.4 The Developmental Origin of Adult-Onset Cancer 3509.7.5 Cancer Prevention and Intervention 351References 35310 Dietary/Supplemental Interventions and Personal Dietary Preferences for Cancer: Translational Toxicology Therapeutic Portfolio for Cancer Risk Reduction 363Sandeep Kaur, Elaine Trujillo, and Harold Seifried10.1 Introduction 36310.2 Gene Expression and Epigenetics 36410.3 Environmental Lifestyle Factors Affecting Cancer Prevention and Risk 36610.3.1 Obesity 36610.3.2 Weight Loss 36810.3.3 Physical Activity 36910.4 Dietary Patterns 37010.5 Complementary and Integrative Oncology Interventions/Restorative Therapeutics 37310.6 Special and Alternative Diets 37710.7 Popular Anticancer Diets 37810.7.1 Macrobiotic Diet 37810.7.2 The Ketogenic Diet 38210.7.3 Fasting Diet 38310.8 Conclusion 384Acknowledgment 384References 38511 Social Determinants of Health and the Environmental Exposures: A Promising Partnership 395Lauren Fordyce, David Berrigan, and Shobha Srinivasan11.1 Introduction 39511.1.1 Conceptual Model 39711.1.2 Difference versus Disparity 39811.2 Social Determinants of Health 39911.2.1 Race/Ethnicity 39911.2.2 Social Determinants of Health: “Place” and Its Correlates 40211.2.3 Gender and Sexuality 40511.3 Conclusions: Social Determinants of Health and Windows ofSusceptibility 407Acknowledgments 408References 408Part Four Categorical and Pleiotropic Nonmutagenic Modes of Action of Toxicants: Causality 41512 Bisphenol A and Nongenotoxic Drivers of Cancer 417Natalie R. Gassman and Samuel H. Wilson12.1 Introduction 41712.2 Dosing 42012.3 Receptor-mediated Signaling 42112.4 Epigenetic Reprogramming 42212.5 Oxidative stress 42412.6 Inflammation and Immune Response 42512.7 BPA-Induced Carcinogenesis 42612.8 Fresh Opportunities in BPA Research 428References 42913 Toxicoepigenetics and Effects on Life Course Disease Susceptibility 439Luke Montrose, Jaclyn M. Goodrich, and Dana C. Dolinoy13.1 Introduction to the Field of Toxicoepigenetics 43913.1.1 The Epigenome 44013.1.2 Epigenetic Marks are Heritable and Reversible 44013.1.3 DNA Methylation 44113.1.4 Histone Modifications and Chromatin Packaging 44213.1.5 Noncoding RNAs 44313.1.6 Key Windows for Exposure-Related Epigenetic Changes 44313.1.7 Evaluation of Environmentally Induced Epigenetic Changes in Animal Models and Humans 44413.2 Exposures that Influence the Epigenome 44413.2.1 Air Pollution 44513.2.2 Metals 44713.2.3 Endocrine Disrupting Chemicals (EDCs) 44813.2.4 Diet 45113.2.5 Stress 45313.3 Intergenerational Exposures and Epigenetic Effects 45413.4 Special Considerations and Future Directions for the Field of Toxicoepigenetics 45613.4.1 Tissue Specificity 45613.4.2 The Dynamic Nature of DNA Methylation 45813.5 Future Directions 45913.6 Conclusions 460Acknowledgments 461References 46114 Tumor-Promoting/Associated Inflammation and the Microenvironment: A State of the Science and New Horizons 473William H. Bisson, Amedeo Amedei, Lorenzo Memeo, Stefano Forte, and Dean W. Felsher14.1 Introduction 47314.2 The Immune System 47514.2.1 Innate Immune Response 47514.2.2 Adaptive Immune Response 47814.3 Prioritized Chemicals 48214.3.1 Bisphenol A 48214.3.2 Polybrominated Diphenyl Ethers 48314.3.3 4-Nonylphenol 48514.3.4 Atrazine 48514.3.5 Phthalates 48614.4 Experimental Models of Carcinogenesis through Inflammation and Immune System Deregulation 48714.5 Antioxidants and Translational Opportunities 49314.6 Tumor Control of the Microenvironment 495Acknowledgments 497References 49715 Metabolic Dysregulation in Environmental Carcinogenesis and Toxicology 511R. Brooks Robey15.1 Introduction 51115.2 Metabolic Reprogramming and Dysregulation in Cancer 51315.2.1 Carbohydrate Metabolism in Cancer 51515.2.2 Lipid Metabolism in Cancer 51915.2.3 Protein Metabolism in Cancer 52115.3 Moonlighting Functions 52315.4 Cancer Metabolism in Context 52315.4.1 The Gestalt of Intermediary Metabolism 52315.4.2 Cancer Tissues, Cells, and Organelles as Open Systems 52715.4.3 The Endosymbiotic Nature of Cancer 52715.4.4 Catabolic and Anabolic Support of Cell Proliferation 52815.4.5 Cancer Heterogeneity 52915.4.6 Phenotypic Relationships between Cancer Cells and Their Parental Cell Origins 53215.4.7 Evolutionary Perspectives of Metabolic Fitness and Selection in Cancer Development 53315.5 Dual Roles for Metabolism in Both the Generation and Mitigation of Cellular Stress 53615.5.1 Metabolism and Oxidative Stress 53715.5.2 Metabolism and Hypoxic Stress 53915.5.3 Nutritional Stress and Metabolism 53915.5.4 Metabolism and Physical Stress 54015.5.5 Metabolism and Other Forms of Cellular Stress 54115.6 Models of Carcinogenesis 54115.6.1 Traditional Multistage Models of Cancer Development 54215.6.2 Role of Replicative Mutagenesis in Cancer Development 54315.6.3 Acquired Mismatch Model of Carcinogenesis 54315.7 Potential Metabolic Targets for Environmental Exposures 54615.7.1 Conceptual Overview of Potential Metabolic Targets 54615.7.2 Identification of Key Targetable Contributors to Metabolic Dysregulation and Selection 54915.7.2.1 Glycolysis 55515.7.2.2 Lipogenesis, Lipolysis, and the PPP 55515.7.2.3 Citric Acid Cycle 55615.7.2.4 Organizational or Compartmental Targets 55615.7.2.5 Metabolite Transport Mechanisms 55715.7.2.6 Signal Transduction Effectors 55815.8 Metabolic Changes Associated with Exposures to Selected Agents 55915.8.1 Selected Agents Classified by the World Health Organization’s International Agency for Research on Cancer (IARC) 55915.8.1.1 IARC Group 1 (Carcinogenic to Humans) 56015.8.1.2 IARC Group 2A (Probably Carcinogenic to Humans) 56415.8.1.3 IARC Group 2B (Possibly Carcinogenic to Humans) 56515.8.1.4 Other Agents 56515.8.2 Environmentally Relevant Combinatorial Exposures 56715.8.2.1 Occupational and Common Environmental Exposures 56715.8.2.2 Environmentally Relevant Low-Dose Combinatorial Exposures 56815.8.2.3 The Halifax Project 57015.9 A Conceptual Overview of Traditional and Emerging Toxicological Approaches to the Problem of Cancer Metabolism: Implications for Future Research 57115.9.1 General Experimental Considerations in the Study of Metabolism In Vitro 57115.9.2 Systems Biology and Current Approaches to In Vitro Toxicology Screening 57315.10 The Nosology of Cancer and Cancer Development 57715.11 Discussion 579Acknowledgments 583References 583Part Five Biomarkers for Detecting Premalignant Effects and Responses to Protective Therapies during Critical Windows of Development 60716 Circulating Molecular and Cellular Biomarkers in Cancer 609Ilaria Chiodi, A. Ivana Scovassi, and Chiara Mondello16.1 Introduction 60916.2 Proteins in Body Fluids: Potential Biomarkers 61016.2.1 Diagnostic Protein Biomarkers 61216.2.2 Prognostic Protein Biomarkers 61316.2.3 Protein Biomarkers of Drug Response 61516.3 Circulating Cell-Free Nucleic Acids 61516.3.1 Circulating Cell-Free Tumor DNA 61616.3.1.1 Cf-DNA Integrity, Microsatellite Instability, and LOH 61716.3.1.2 Tumor-Specific Genetic Alterations 61716.3.1.3 Tumor Genetic Alterations and Therapy Resistance 61916.3.1.4 Tumor Epigenetic Alterations: DNA Methylation 62016.3.2 Circulating Cell-Free RNA 62116.3.2.1 Circulating Cell-Free microRNA 62116.4 Extracellular Vesicles: General Features 62416.4.1 Classification of EVs 62416.4.2 EVs and Cancer 62516.4.3 EVs as Mediators of Cell-To-Cell Communication 62716.5 Circulating Tumor Cells 62816.5.1 Two-Step Processing of Blood Samples: Enrichment and Identification of Circulating Tumor Cells 62816.5.1.1 CTC Number as a Cancer Biomarker 63016.5.2 Characterization of CTCs 63016.5.2.1 Molecular Characterization of CTCs 63016.5.2.2 Functional Characterization of CTCs 63216.5.3 Single CTCs versus CTC Clusters 63416.5.4 In Hiding Before Getting Home, the Long Journey of CTCs 63516.6 Conclusions 635References 63717 Global Profiling Platforms and Data Integration to Inform Systems Biology and Translational Toxicology 657Barbara A. Wetmore17.1 Introduction 65717.2 Global Omics Profiling Platforms 65917.2.1 Genomics 65917.2.2 Epigenomics 66117.2.3 Transcriptomics 66217.2.4 Proteomics 66517.2.5 Metabolomics 66817.3 High-Throughput Bioactivity Profiling 66917.3.1 High-Throughput Bioactivity and Toxicity Screening 66917.3.2 In Vitro–In Vivo Extrapolation 67117.4 Biomarkers 67217.5 Exposomics 67317.6 Bioinformatics to Support and Data Integration and Multiomics Efforts 67417.7 Data Integration: Multiomics and High-Dimensional Biology Efforts 67617.8 Conclusion 679References 67918 Developing a Translational Toxicology Therapeutic Portfolio for Cancer Risk Reduction 691Rebecca Johnson and David Kerr18.1 Introduction 69118.2 The Identification of Novel Predictors of Adverse Events 69318.2.1 Candidate Gene Studies 69318.2.2 Genome-wide Associations 69418.2.3 Next-Generation Sequencing 69518.3 Proof of Principle Toxgnostics 69618.4 Proposed Protocol 69818.4.1 Integration within Randomized Control Trials 69818.4.2 Biobanking and Future-Proofing Samples 69918.4.3 Data Protection and Full Consent 70218.4.4 The Need for a Collaborative Approach 70318.4.5 Open Access to Results 70418.4.6 Translation from Bench to Bedside 70518.5 Fiscal Matters 70618.6 The Future of Toxgnostics 706References 70719 Ethical Considerations in Developing Strategies for Protecting Fetuses, Neonates, Children, and Adolescents from Exposures to Hazardous Environmental Agents 711David B. Resnik and Melissa J. Mills19.1 Introduction 71119.2 What Is Ethics? 71219.2.1 Some Fundamental Ethical Values 71219.2.1.1 Benefits and Costs 71219.2.1.2 Individual Rights and Responsibilities 71319.2.1.3 Justice 71319.2.2 Value Conflicts and Ethical Decision-Making 71319.3 Ethical Considerations for Strategies Used to Protect Fetuses, Neonates, Children, and Adolescents from Exposures to Harmful Environmental Agents 71519.3.1 Education 71519.3.2 Testing/Screening/Monitoring 71719.3.3 Worker Protection 72019.3.4 Government Regulation 72219.3.5 Taxation 72519.3.6 Civil Liability 72619.3.7 Criminal Liability 72919.4 Research with Human Participants 73019.4.1 Return of Individualized Research Results 73219.4.2 Protecting Privacy and Confidentiality 73319.4.3 Interventional Studies 73419.4.4 Intentional Exposure Studies 73619.4.5 Protecting Vulnerable Participants 73919.5 Conclusion 742References 742Index 751

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