Cancer Risk Assessment

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.

"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)

• PREFACE. CONTRIBUTORS.ABBREVIATIONS AND ACRONYMS.PART I CANCER RISK ASSESSMENT, SCIENCE POLICY, AND REGULATORY FRAMEWORKS.CHAPTER 1 CANCER RISK ASSESSMENT(Elizabeth L. Anderson, Kimberly Lowe, and Paul Turnham).1.1. Cancer Risk Assessment.1.2. The Weight of Evidence (WOE) for Determining Carcinogenicity.1.3. Risk Assessment in the 21st Century.1.4. Applications in Risk Management.References.CHAPTER 2 SCIENCE POLICY AND CANCER RISK ASSESSMENT (Gary E. Marchant).2.1. Introduction.2.2. Use of Risk Assessment in Regulatory Decision-Making.2.3. Role Of Risk Assessment Guidelines.2.4. Data Quality Requirements.2.5. Types of Data Used in Risk Assessment.2.6. Application of "Conservative" Assumptions and Precaution.2.7. Conclusion.References.CHAPTER 3 HAZARD AND RISK ASSESSMENT OF CHEMICAL CARCINOGENICITY WITHIN A REGULATORY CONTEXT (Henk Tennekes, Virginia A. Gretton, and Todd Stedeford).3.1. Overview.3.2. Risk Assessment.3.3. Regulatory Schemes for Industrial Chemicals and Biocides.3.4. Scientific Aspects of Carcinogenic Risk Assessment.3.5. Conclusions.References.CHAPTER 4 USE OF CANCER RISK ASSESSMENTS IN DETERMINATION OF REGULATORY STANDARDS (Robert A. Howd and Anna M. Fan).4.1. Introduction.4.2. Air Standards.4.3. Water Standards.4.4. Food Standards, Pesticide Tolerances, Additives, and Impurities.4.5. Soil Standards.4.6. Consumer Product Standards.4.7. Recent Developments and Future Directions.References.PART II CANCER BIOLOGY AND TOXICOLOGY.CHAPTER 5 THE INTERPLAY OF CANCER AND BIOLOGY (James W. Holder).5.1. Historical Account of Some Important Events in Understanding Cancer.5.2. Recent Foundations of Biological Mechanisms of Cancer.5.3. Cell Biology of Cancer.5.4. Some Final Thoughts on Biology and Cancer.References.CHAPTER 6 CHEMICAL CARCINOGENESIS: A BRIEF HISTORY OF ITS CONCEPTS WITH A FOCUS ON POLYCYCLIC AROMATIC HYDROCARBONS (Stephen Nesnow).6.1. A Brief History of Chemical Carcinogenesis.6.2. James A. and Elizabeth C. Miller and Their Theory of Metabolic Activation.6.3. The Concepts of Initiation, Promotion, and Progression: The Origin of Multistage Carcinogenesis.References.CHAPTER 7 HORMESIS AND CANCER RISKS: ISSUES AND RESOLUTION (Paolo F. Ricci and Edward J. Calabrese).7.1. Introduction.7.2. Evidence for Regulatory Cancer Risk Assessment.7.3. Hormesis and Cancer Risk Assessment: Models.7.4. Conclusions.References.CHAPTER 8 THRESHOLDS FOR GENOTOXIC CARCINOGENS: EVIDENCE FROM MECHANISM-BASED CARCINOGENICITY STUDIES (Shoji Fukushima, Min Wei, Anna Kakehashi, and Hideki Wanibuchi).8.1. Overview.8.2. Introduction.8.3. Low-Dose Carcinogenicity of 2-Amino-3,8-Dimethylimidazo[4,5-f ]-Quinoxaline (MEIQX) in the Rat Liver.8.4. Low-Dose Hepatocarcinogenicity of N-Nitroso Compounds.8.5. Low-Dose Carcinogenicity of 2-Amino-1-methyl-6-phenylimidazo[5,6-b]pyridine (PHIP) in the Rat Colon.8.6. Low-Dose Carcinogenicity of Potassium Bromate, KBrO3 in the Rat Kidney.8.7. Conclusion.References.PART III GENETIC TOXICOLOGY, TESTING GUIDELINES AND REGULATIONS, AND NOVEL ASSAYS.CHAPTER 9 DEVELOPMENT OF GENETIC TOXICOLOGY TESTING AND ITS INCORPORATION INTO REGULATORY HEALTH EFFECTS TEST REQUIREMENTS (Errol Zeiger).9.1. Introduction.9.2. Definitions and Usage.9.3. The Historical Development of Genetic Toxicity Testing.9.4. Types of Available Tests.9.5. Testing Approaches.9.6. Where Are We Now?.9.7. Summary.References.CHAPTER 10 GENETIC TOXICOLOGY TESTING GUIDELINES AND REGULATIONS (Lutz Müller and Hans-Jörg Martus).10.1. Historical Overview of Genotoxicity Testing Guidelines.10.2. Organization for Economic cooperation and Development (OECD) Guidelines for Genotoxicity.10.3. International Conference of Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guidelines for Pharmaceuticals.10.4. International Workshop on Genotoxicity Tests (IWGT).10.5. The International Program on Chemical Safety (IPCS) Under the Auspices of the World Health Organization (WHO).10.6. In Vitro Testing.10.7. In Vivo Testing.10.8. European Union Guideline for Testing of Chemicals Under the Registration, Evaluation, Authorization and Restriction of Chemical (REACH).10.9. Specialty Guidelines for Genotoxicity: Genotoxic Impurities in Pharmaceuticals.10.10. The Quintessence for Regulatory Assessment: In Vivo Testing for Risk Assessment.10.11. Summary and Outlook.References.CHAPTER 11 IN VITRO GENOTOX ASSAYS (David Kirkland and David Gatehouse).11.1. Introduction.11.2. In Vitro Metabolic Activation.11.3. In Vitro Tests for Gene Mutation in Bacteria.11.4. In Vitro Tests for Gene Mutation in Mammalian Cells.11.5. In Vitro Tests for Chromosome Damage in Mammalian Cells.11.6. The In Vitro Micronucleus Test.11.7. In Vitro Test for Unscheduled DNA Synthesis in Rat Hepatocytes.11.8. In Vitro Comet Assay.11.9. Strengths and Limitations.References.CHAPTER 12 IN VIVO GENOTOXICITY ASSAYS (Véronique Thybaud).12.1. Introduction.12.2. Parameters and Criteria for Valid In Vivo Genotoxicity Assays and Implications for Experimental Design.12.3. In Vivo Genotoxicity Assays Required in the Standard Battery of Tests.12.4. In Vivo Genotoxicity Assays Used Mainly as Complementary or Follow-Up Tests.12.5. Conclusion and Perspectives.References.PART IV ASSESSING THE HUMAN RELEVANCE OF CHEMICAL-INDUCED TUMORS.CHAPTER 13 FRAMEWORK ANALYSIS FOR DETERMINING MODE OF ACTION AND HUMAN RELEVANCE (R. Julian Preston).13.1. Introduction.13.2. Framework Analysis: Mode of Action and Key Events.13.3. Framework Analysis: Human Relevance.13.4. Future Directions.References.CHAPTER 14 EXPERIMENTAL ANIMAL STUDIES AND CARCINOGENICITY (Mary Elizabeth (Bette) Meek).14.1. Introduction.14.2. Current Status of Hazard Testing for Cancer for Regulatory Risk Assessment.14.3. Application in Risk Assessment.14.4. Evolution of Testing Strategies.14.5. Discussion: Closing the GAP Between Hazard Testing and Risk Assessment.References.CHAPTER 15 CANCER EPIDEMIOLOGY (Herman J. Gibb and Jessie P. Buckley).15.1. Introduction.15.2. Considerations for the Epidemiologic Study of Cancer.15.3. Epidemiologic Study Methods.15.4. Evaluation of Studies and Their Results.15.5. Substances Causally Associated with Cancer.15.6. Future for Cancer Epidemiology.References.CHAPTER 16 RODENT HEPATOCARCINOGENESIS (James E. Klaunig).16.1. Introduction.16.2. Mechanisms of Action of Hepatic Carcinogens.16.3. Human Relevance Framework.16.4. Summary.References.CHAPTER 17 MODE OF ACTION ANALYSIS AND HUMAN RELEVANCE OF LIVER TUMORS INDUCED BY PPARa ACTIVATION (J. Christopher Corton).17.1. Overview.17.2. Introduction.17.3. Mode of Action Analysis in the EPA Risk Assessment Framework.17.4. Relevance of PPARá Activator-Induced Rodent Liver Tumor Response to Humans.References.CHAPTER 18 ALPHA2U-GLOBULIN NEPHROPATHY AND CHRONIC PROGRESSIVE NEPHROPATHY AS MODES OF ACTION FOR RENAL TUBULE TUMOR INDUCTION IN RATS, AND THEIR POSSIBLE INTERACTION (Edward A. Lock and Gordon C. Hard).18.1. Introduction.18.2. Chemicals that Increase the Incidence of Renal Tubule Tumors in Male Rats by an á2u-Globulin Mode of Action.18.3. Chemicals Increasing the Incidence of Renal Tumors Through Exacerbation of Spontaneous Chronic Progressive Nephropathy (CPN).18.4. Chemicals Increasing RTT Incidence Through a Mode of Action Involving Exacerbation of CPN.18.5. Examples Where the á2u-Globulin and Exacerbated CPN Modes of Action May Be Acting in Concert.18.6. Relevance of Rat á2u-Globulin Nephropathy and CPN to Humans.References.CHAPTER 19 URINARY TRACT CALCULI AND BLADDER TUMORS (Samuel M. Cohen, Lora L. Arnold, and Shugo Suzuki).19.1. Introduction.19.2. Direct and Indirect Formation of Urinary Solids.19.3. Urinary Factors Influencing the Formation of Urinary Solids.19.4. Collection of Urine for Detection of Urinary Solids.19.5. Interspecies Comparison of Urine Composition.19.6. Urinary Solid Carcinogenesis in Rodents.19.7. Epidemiology.19.8. Risk Assessment.References.PART V METHODS FOR INFORMING CANCER RISK QUANTIFICATION.CHAPTER 20 (Q)SAR ANALYSIS OF GENOTOXIC AND NONGENOTOXIC CARCINOGENS: A STATE-OF-THE-ART OVERVIEW (Yin-tak Woo and David Y. Lai).20.1. Introduction.20.2. Overview of (Q)SAR Analysis and Modeling.20.3. Mechanism-Based SAR Analysis of Chemical Carcinogens, Fibers, and Particles/Nanoparticles.20.4. Uses of (Q)SAR in Cancer Hazard/Risk Assessment and Brief Overview of Predictive Systems/Softwares.20.5. Future Perspectives.References.CHAPTER 21 PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELS IN CANCER RISK ASSESSMENT (Mathieu Valcke and Kannan Krishnan).21.1. Introduction.21.2. PBPK Modeling: Characteristics and Approaches.21.3. PBPK Models in Cancer Risk Assessment.21.4. PBPK Models in Cancer Risk Assessment: Case Studies.21.5. Concluding Remarks.References.CHAPTER 22 GENOMICS AND ITS ROLE IN CANCER RISK ASSESSMENT (Banalata Sen, Douglas C. Wolf, and Vicki Dellarco).22.1. Introduction.22.2. "-Omics" Technologies.22.3. Genomics and the New Risk Assessment Paradigm.22.4. Case Studies.22.5. Use of Genomics in Predictive Toxicology.22.6. Conclusions.References.CHAPTER 23 COMPUTATIONAL TOXICOLOGY IN CANCER RISK ASSESSMENT (Jerry N. Blancato).23.1. Introduction.23.2. Risk Assessment: Historical Perspective.23.3. Enhancements in Quantitative Risk Assessment.23.4. Computational Toxicology and Future Risk Assessments.23.5. Conclusion.References.PART VI GENERAL APPROACHES FOR QUANTIFYING CANCER RISKS.CHAPTER 24 LINEAR LOW-DOSE EXTRAPOLATIONS (Michael Dourson and Lynne Haber).24.1. Introduction.24.2. Historical.24.3. Issues Related to Extrapolation from Experimental Data.24.4. Conclusion.References.CHAPTER 25 QUANTITATIVE CANCER RISK ASSESSMENT OF NONGENOTOXIC CARCINOGENS (Rafael Meza, Jihyoun Jeon, and Suresh H. Moolgavkar).25.1. Introduction.25.2. Some Examples and Applications.25.3. Concluding Remarks.References.CHAPTER 26 NONLINEAR LOW-DOSE EXTRAPOLATIONS (Ari S. Lewis and Barbara D. Beck).26.1. Introduction.26.2. Mechanistic Aspects of Nonlinear Carcinogenesis.26.3. DNA-Reactive Carcinogens and Nonlinearity.26.4. Nonmutagenic Carcinogens and Nonlinearity.26.5. Cancer Risk Assessment.26.6. Nonlinearity Principles into Practice.26.7. Summary and Conclusion.References.CHAPTER 27 CANCER RISK ASSESSMENT: MORE UNCERTAIN THAN WE THOUGHT (Edmund A. C. Crouch).27.1. Introduction.27.2. Summary of Previous Analyses.27.3. Selection of Carcinogenicity Measure—The CD10.27.4. The Variation of CD10 Within a Species.27.5. Extrapolation of the Median CD10 Between Species.27.6. Extrapolation of the IntraSpecies Variation in CD10.27.7. Conclusions.27.8. Appendix.References.CHAPTER 28 COMBINING NEOPLASMS FOR EVALUATION OF RODENT CARCINOGENESIS STUDIES (Amy E. Brix, Jerry F. Hardisty, and Ernest E. McConnell).28.1. Introduction.28.2. Rationale for Combining Neoplasms.28.3. Usefulness of Differentiating Benign from Malignant Neoplasms and of Subclassifying Neoplasms.28.4. Criteria for Combining Neoplasms.28.5. Summary.References.CHAPTER 29 CANCER RISK BASED ON AN INDIVIDUAL TUMOR TYPE OR SUMMING OF TUMORS (Andrew G. Salmon and Lindsey A. Roth).29.1. Introduction.29.2. Summing of Tumors of Related Types.29.3. Summing of Unrelated Tumor Types.29.4. Example: 1,3-Butadiene.29.5. Conclusions.References.CHAPTER 30 EXPOSURE RECONSTRUCTION AND CANCER RISK ESTIMATE DERIVATION (Shannon Gaffney, Jennifer Sahmel, Kathryn D. Devlin, and Dennis J. Paustenbach).30.1. Introduction.30.2. Exposure Reconstruction Methodology.30.3. Application of Estimated Historical Exposure Values to Cancer Risk Estimates.30.4. Summary.References.INDEX.