Cancer Risk Assessment: Chemical Carcinogenesis, Hazard Evaluation, and Risk Quantification / Edition 1

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"With a weight-of-the-evidence approach, cancer risk assessment indentifies hazards, determines dose-response relationships, and assesses exposure to characterize the true risk. This book focuses on the quantitative methods for conducting chemical cancer risk assessments for solvents, metals, mixtures, and nanoparticles. It links these to the basic toxicology and biology of cancer, along with the impacts on regulatory guidelines and standards. By providing insightful perspective, Cancer Risk Assessment helps researchers develop a discriminate eye when it comes to interpreting data accurately and separating relevant information from erroneous"--Provided by publisher.

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Editorial Reviews

From the Publisher
"This book aims to inform and to provide interpretive guidance on evaluating toxicological data and understanding the relevance of such data to hazard evaluation and cancer risk estimation." (The British Toxicology Society, 1 November 2011)
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Product Details

  • ISBN-13: 9780470238226
  • Publisher: Wiley
  • Publication date: 7/13/2010
  • Edition number: 1
  • Pages: 832
  • Product dimensions: 6.40 (w) x 9.30 (h) x 1.90 (d)

Meet the Author

CHING-HUNG HSU, PhD, DABT, is a Vice President at TaiGen Biotechnology Co., Ltd. His professional experience includes positions at Merck & Co., Inc., the U.S. Environmental Protection Agency, and the California Environmental Protection Agency. Dr. Hsu earned his BS from the National Taiwan University and PhD from the Massachusetts Institute of Technology. He completed his postdoctoral training at the University of California at Berkeley. Dr. Hsu is board-certified in toxicology by the American Board of Toxicology. He has published numerous professional papers, book chapters, and technical reports. Dr. Hsu serves on the Editorial Board of two international peer-reviewed journals.

TODD STEDEFORD, PhD, JD, DABT, is a Toxicology Advisor and In-house Counsel for a multinational specialty chemical manufacturer. Previously, he was a human health toxicologist with the U.S. Environmental Protection Agency and an adjunct scientist with the Polish Academy of Sciences. Dr. Stedeford is board-certified in toxicology by the American Board of Toxicology and licensed to practice law in the District of Columbia and the State of Louisiana. He has authored over eighty publications including peer-reviewed scientific articles, government health assessments, legal articles, and scientific and legal book chapters.

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Table of Contents



Abbreviations and A Cronyms


Chapter 1 Cancer Risk Assessment Paul Turnham Turnham, Paul 1

1.1 Cancer Risk Assessment 3

1.1.1 Cancer in the United States 3

1.1.2 Historical Perspectives of Cancer Risk Assessment 4

1.1.3 The Defining Steps in Cancer Risk Assessment 9

1.1.4 The Mode of Action (MOA) 11

1.1.5 Accounting for Scientific Uncertainty 11

1.2 The Weight of Evidence (WOE) for Determining Carcinogenicity 12

1.2.1 Epidemiologic Studies 12

1.2.2 Animal Models 14

1.2.3 Weight of the Evidence Descriptors 15

1.3 Risk Assessment in the 21st Century 16

1.3.1 Using the Advances in Molecular and Computational Biology 16

1.3.2 Genetic Susceptibility 17

1.4 Applications in Risk Management 17

1.4.1 Translating Risk Assessment into Risk Management in the United States 17

1.4.2 International Risk Management 18

1.4.3 Risk-Benefit Analysis 19

1.4.4 Risk Acceptance and Risk Communication 20

References 21

Chapter 2 Science Policy and Cancer Risk Assessment Gary E. Marchant Marchant, Gary E. 23

2.1 Introduction 23

2.2 Use of Risk Assessment in Regulatory Decision-Making 24

2.3 Role Of Risk Assessment Guidelines 25

2.4 Data Quality Requirements 28

2.5 Types of Data Used in Risk Assessment 30

2.6 Application of "Conservative" Assumptions and Precaution 33

2.7 Conclusion 34

References 34

Chapter 3 Hazard and Risk Assessment of Chemical Carcinogenicity Within A Regulatory Context Todd Stedeford Stedeford, Todd 37

3.1 Overview 37

3.2 Risk Assessment 37

3.2.1 Principles of Risk Assessment and Management 38

3.3 Regulatory Schemes for Industrial Chemicals and Biocides 42

3.3.1 The U.S. Toxic Substances Control Act (TSCA) 42

3.3.2 The EU Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) 44

3.3.3 Voluntary Initiatives for Evaluating Industrial Chemicals 45

3.3.4 The U.S. Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) 48

3.3.5 The EU Biocidal Products Directive (BPD) 49

3.4 Scientific Aspects of Carcinogenic Risk Assessment 50

3.4.1 Dose-Response Relationships in Carcinogenesis and Mechanisms of Carcinogenic Action 50

3.4.2 Mathematical Model for Carcinogenic Risk Assessment 60

3.5 Conclusions 61

References 62

Chapter 4 Use of Cancer Risk Assessments In Determination of Regulatory Standards Anna M. Fan Fan, Anna M. 66

4.1 Introduction 66

4.2 Air Standards 70

4.2.1 Scientific Issues 70

4.2.2 Regulatory Considerations 72

4.3 Water Standards 73

4.3.1 Scientific Issues 73

4.3.2 Regulatory Considerations 75

4.4 Food Standards, Pesticide Tolerances, Additives, and Impurities 76

4.4.1 Scientific Issues 76

4.4.2 Regulatory Considerations 77

4.5 Soil Standards 81

4.5.1 Scientific Issues 81

4.5.2 Regulatory Considerations 81

4.6 Consumer Product Standards 82

4.6.1 Scientific Issues 82

4.6.2 Regulatory Considerations 83

4.7 Recent Developments and Future Directions 84

References 87


Chapter 5 The Interplay of Cancer and Biology James W. Holder Holder, James W. 99

5.1 Historical Account of Some Important Events in Understanding Cancer 99

5.1.1 Early Cancer Biology History 99

5.1.2 Near-Recent Cancer Biology History 101

5.2 Recent Foundations of Biological Mechanisms of Cancer 103

5.3 Cell Biology of Cancer 105

5.3.1 In Vitro Systems 105

5.3.2 Programmed Cell Removal 107

5.3.3 Facilitation of Supporting Cells and Cell-to-Cell Communication 113

5.3.4 Clonal Aspects of Carcinogenesis 116

5.3.5 Biology of Inflammation and Cancer 124

5.3.6 Stem Cell Biology and Cancer 130

5.3.7 Specific Biological Growth and Growth Control Gene Sets and Their Pathways 139

5.3.8 Epigenetic Biology and Nuclear Traffic 142

5.3.9 Biological Initiation of Chemical Carcinogenesis 147

5.4 Some Final Thoughts on Biology and Cancer 152

References 155

Chapter 6 Chemical Carcinogenesis: A Brief History Of Its Concepts With A Focus on Polycyclic Aromatic Hydrocarbons Stephen Nesnow Nesnow, Stephen 168

6.1 A Brief History of Chemical Carcinogenesis 168

6.2 James A. and Elizabeth C. Miller and Their Theory of Metabolic Activation 169

6.2.1 Metabolic Activation of PAH and Tumorigenesis 173

6.3 The Concepts of Initiation, Promotion, and Progression: The Origin of Multistage Carcinogenesis 182

References 185

Chapter 7 Hormesis and Cancer Risks: Issues and Resolution Edward J. Calabrese Calabrese, Edward J. 191

7.1 Introduction 191

7.2 Evidence for Regulatory Cancer Risk Assessment 194

7.3 Hormesis and Cancer Risk Assessment: Models 198

7.3.1 Answers to Our Question 201

7.4 Conclusions 203

References 204

Chapter 8 Thresholds for Genotoxic Carcinogens: Evidence from Mechanism-Based Carcinogenicity Studies Hideki Wanibuchi Wanibuchi, Hideki 207

8.1 Overview 207

8.2 Introduction 208

8.3 Low-Dose Carcinogenicity of 2-Amino-3, 8-Dimethylimidazo[4, 5-f]-Quinoxaline (MEIQX) in the Rat Liver 209

8.4 Low-Dose Hepatocarcinogenicity of N-Nitroso Compounds 215

8.5 Low-Dose Carcinogenicity of 2-Amino-1-methyl-6-phenylimidazo[5, 6-b]Pyridine (PHIP) in the Rat Colon 215

8.6 Low-Dose Carcinogenicity of Potassium Bromate, KBrO3 in the Rat Kidney 216

8.7 Conclusion 219

References 220


Chapter 9 Development of Genetic Toxicology Testing and Its Incorporation Into Regulatory Health Effects Test Requirements Errol Zeiger Zeiger, Errol 225

9.1 Introduction 225

9.2 Definitions and Usage 226

9.3 The Historical Development of Genetic Toxicity Testing 227

9.4 Types of Available Tests 228

9.5 Testing Approaches 229

9.6 Where Are We Now? 232

9.7 Summary 235

References 235

Chapter 10 Genetic Toxicology Testing Guidelines and Regulations Hans-Jorg Martus Martus, Hans-Jorg 238

10.1 Historical Overview of Genotoxicity Testing Guidelines 238

10.2 Organization for Economic cooperation and Development (OECD) Guidelines for Genotoxicity 243

10.3 International Conference of Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guidelines for Pharmaceuticals 243

10.4 International Workshop on Genotoxicity Tests (IWGT) 248

10.5 The International Program on Chemical Safety (IPCS) Under the Auspices of the World Health Organization (WHO) 249

10.6 In Vitro Testing 250

10.6.1 In Vitro Tests 250

10.6.2 Evaluation of In Vitro Testing Results 250

10.6.3 Follow-Up to In Vitro Testing 250

10.7 In Vivo Testing 251

10.7.1 Follow-Up to In Vivo Testing 251

10.7.2 Straegy for Germ Cell Testing 251

10.8 European Union Guideline for Testing of Chemicals Under the Registration, Evaluation, Authorization and Restriction of Chemical (REACH) 252

10.9 Specialty Guidelines for Genotoxicity: Genotoxic Impurities in Pharmaceuticals 256

10.10 The Quintessence for Regulatory Assessment: In Vivo Testing for Risk Assessment 258

10.10.1 Choice of In Vivo Test 261

10.10.2 Evaluation of In Vivo Results 263

10.11 Summary and Outlook 264

References 265

Chapter 11 In Vitro Genotox Assays David Gatehouse Gatehouse, David 273

11.1 Introduction 272

11.2 In Vitro Metabolic Activation 273

11.3 In Vitro Tests for Gene Mutation in Bacteria 273

11.4 In Vitro Tests for Gene Mutation in Mammalian Cells 276

11.5 In Vitro Tests for Chromosome Damage in Mammalian Cells 279

11.6 The In Vitro Micronucleus Test 280

11.7 In Vitro Test for Unscheduled DNA Synthesis in Rat Hepatocytes 283

11.8 In Vitro Comet Assay 284

11.9 Strengths and Limitations 285

References 286

Chapter 12 In Vivo Genotoxicity Assays Veronique Thybaud Thybaud, Veronique 289

12.1 Introduction 289

12.1.1 Endpoints Used for In Vivo Genetic Toxicology Assays 289

12.1.2 Contribution of In Vivo Genetic Toxicology Assays to Risk Assessment 291

12.2 Parameters and Criteria for Valid In Vivo Genotoxicity Assays and Implications for Experimental Design 292

12.3 In Vivo Genotoxicity Assays Required in the Standard Battery of Tests 303

12.3.1 Mammalian Erythrocyte Micronucleus Test 304

12.3.2 Bone Marrow Chromosome Aberration Test 308

12.4 In Vivo Genotoxicity Assays Used Mainly as Complementary or Follow-Up Tests 310

12.4.1 The Comet Assay 311

12.4.2 DNA Adducts 314

12.4.3 Unscheduled DNA Synthesis Test in Liver Cells 324

12.4.4 Sister-Chromatid Exchange Assay 326

12.4.5 Gene Mutation Assays 328

12.5 Conclusion and Perspectives 344

References 345


Chapter 13 Framework Analysis For Determining Mode Of Action and Human Relevance R. Julian Preston Preston, R. Julian 363

13.1 Introduction 363

13.2 Framework Analysis: Mode of Action and Key Events 364

13.2.1 Definitions 364

13.2.2 An Overview of the Framework for Analyzing Mode of Action 365

13.2.3 Framework for Assessing Human Relevance of Animal MOA 365

13.2.4 Establishing and Applying Key Events in Support of MOA 367

13.3 Framework Analysis: Human Relevance 372

13.4 Future Directions 375

References 376

Chapter 14 Experimental Animal studies and Carcinogenicity Mary Elizabeth (Bette) Meek Meek, Mary Elizabeth (Bette) 378

14.1 Introduction 378

14.2 Current Status of Hazard Testing for Cancer for Regulatory Risk Assessment 379

14.2.1 The Combined Chronic/Cancer Bioassay in Rats and Mice 379

14.2.2 Perinatal Carcinogenicity Studies 382

14.2.3 Limited In Vivo Studies 382

14.3 Application in Risk Assessment 383

14.3.1 Hazard Identification 383

14.3.2 Hazard Characterization 386

14.3.3 Dose-Response Analyses; Selection of Points of Departure 388

14.4 Evolution of Testing Strategies 390

14.5 Discussion: Closing the GAP Between Hazard Testing and Risk Assessment 391

References 393

Chapter 15 Cancer Epidemiology Jessie P. Buckley Buckley, Jessie P. 397

15.1 Introduction 397

15.2 Considerations for the Epidemiologic Study of Cancer 398

15.2.1 Demographics 398

15.2.2 Other Variables 400

15.3 Epidemiologic Study Methods 403

15.3.1 Types of Epidemiologic Studies 403

15.3.2 Meta-analysis and Case Reports 407

15.4 Evaluation of Studies and Their Results 407

15.4.1 Quality of Studies 407

15.4.2 Determining Causal Association 408

15.5 Substances Causally Associated with Cancer 411

15.6 Future for Cancer Epidemiology 414

15.6.1 The Effect of Exposure at Different Ages 414

15.6.2 Molecular Epidemiology 415

15.6.3 Infectious Agents 415

References 416

Chapter 16 Rodent Hepatocarcinogenesis James E. Klaunig Klaunig, James E. 419

16.1 Introduction 419

16.1.1 Initiation 420

16.1.2 Promotion 422

16.1.3 Progression 422

16.2 Mechanisms of Action of Hepatic Carcinogens 423

16.2.1 Genotoxic Agents 424

16.2.2 Nongenotoxic Mechanisms of Action 425

16.3 Human Relevance Framework 434

16.4 Summary 435

References 435

Chapter 17 Mode of Action Analysis and Human Relevance of Liver Tumors Induced by PPARα Activation J. Christopher Corton Corton, J. Christopher 439

17.1 Overview 439

17.2 Introduction 440

17.3 Mode of Action Analysis in the EPA Risk Assessment Framework 441

17.3.1 Summary of the Mode of Action and Human Relevance of Liver Tumors Induced by PPARα Activation 441

17.3.2 Detailed Evaluation of the Rodent Mode of Action 443

17.4 Relevance of PPARα Activator-Induced Rodent Liver Tumor Response to Humans 467

References 467

Chapter 18 Alpha2u-Globulin Nephropathy and Chronic Progressive Nephropathy As Modes of Action For Renal Tubule Tumor Induction In Rats, and Their Possible Interaction Gordon C. Hard Hard, Gordon C. 482

18.1 Introduction 482

18.2 Chemicals that Increase the Incidence of Renal Tubule Tumors in Male Rats by an α2u-Globulin Mode of Action 483

18.3 Chemicals Increasing the Incidence of Renal Tumors Through Exacerbation of Spontaneous Chronic Progressive Nephropathy (CPN) 489

18.4 Chemicals Increasing RTT Incidence Through a Mode of Action Involving Exacerbation of CPN 491

18.5 Examples Where the α2u-Globulin and Exacerbated CPN Modes of Action May Be Acting in Concert 493

18.6 Relevance of Rat α2u-Globulin Nephropathy and CPN to Humans 495

References 496

Chapter 19 Urinary Tract Calculi and Bladder Tumors Shugo Suzuki Suzuki, Shugo 501

19.1 Introduction 501

19.2 Direct and Indirect Formation of Urinary Solids 502

19.3 Urinary Factors Influencing the Formation of Urinary Solids 505

19.4 Collection of Urine for Detection of Urinary Solids 507

19.5 Interspecies Comparison of Urine Composition 508

19.6 Urinary Solid Carcinogenesis in Rodents 508

19.7 Epidemiology 510

19.8 Risk Assessment 511

References 512


Chapter 20 (Q)Sar Analysis of Genotoxic and Nongenotoxic Carcinogens: A State-Of-The-Art-Overview David Y. Lai Lai, David Y. 517

20.1 Introduction 517

20.2 Overview of (Q)SAR Analysis and Modeling 518

20.2.1 Types of (Q)SAR 518

20.2.2 Criteria for Assessing Validity and Scientific Soundness of (Q)SAR 519

20.2.3 Difficulties of (Q)SAR Modeling/Prediction of Chemical Carcinogens 520

20.2.4 Importance of Mechanistic Understanding 520

20.3 Mechanism-Based SAR Analysis of Chemical Carcinogens, Fibers, and Particles/Nanoparticles 521

20.3.1 Basic Principles 521

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