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