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Thresholds of Genotoxic Carcinogens


Author: Takehiko NohmiShoji Fukushima

Publisher: Academic Press

Publish Date: 25th May 2016

ISBN-13: 9780128018033

Pages: 224

Language: English



Thresholds of Genotoxic Carcinogens: From Mechanisms to Regulation brings together current opinion and research activities from Japan, the US, and Europe on the subject of genotoxic thresholds. In regulation, it is an adage that genotoxic carcinogens have no thresholds for action, and that they impose cancer risk on humans even at very low levels. This policy is frequently called into question as humans possess a number of defense mechanisms including detoxication, DNA repair, and apoptosis, meaning there is a threshold at which these genotoxic carcinogens take action.The book examines these potential thresholds, describing the potential cancer risks of daily low-level exposure, the mechanisms involved (such as DNA repair, detoxication, translesion DNA synthesis), chemical and statistical methods of analysis, and the ways in which these may be utilized to inform policy. Thresholds of Genotoxic Carcinogens: From Mechanisms to Regulation is an essential reference for any professional researchers in genetic toxicology and those involved in toxicological regulation.

Table of Contents

List of Contributors Preface Chapter 1. Qualitative and Quantitative Assessments on Low-Dose Carcinogenicity of Genotoxic Hepatocarcinogens: Dose–Response for Key Events in Rat Hepatocarcinogenesis Abstract Introduction Qualitative and Quantitative Analyses on Low-Dose Carcinogenicity of 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline in the Rat Liver Qualitative and Quantitative Analyses on Low-Dose Hepatocarcinogenicity of 2-Amino-3-methylimidazo[4,5-f]quinoline in the Rat Liver Qualitative and Quantitative Analysis on Low-Dose Hepatocarcinogenicity of N-nitrosodiethylamine in the Rat Liver Discussion References Chapter 2. Thresholds for Hepatocarcinogenicity of DNA-Reactive Compounds Abstract Introduction Dose–Effect Studies of Initiation of Liver Carcinogenesis Conclusions Relevance to Humans References Chapter 3. Interaction of Low-Dose Radiation and Chemicals in Cancer Risk Abstract Epidemiological Analysis of Cancer Risk Interaction of Radiation and Other Carcinogens Data From Animal Experiments Conclusion Acknowledgments References Chapter 4. Possible Mechanisms Underlying Genotoxic Thresholds: DNA Repair and Translesion DNA Synthesis Abstract Introduction Challenges in Identification of Genotoxicity of Chemicals Possible Mechanisms Underlying Genotoxic Thresholds Significance of DNA Repair Mechanisms in the Suppression of Mutagenesis and Tumorigenesis in Mammals TLS as a Critical Factor for Mutagenesis Future Perspectives Acknowledgments References Chapter 5. DNA Repair and Its Influence on Points of Departure for Alkylating Agent Genotoxicity Abstract Introduction The Paradigm Shift in Response to Low Doses of Alkylating Agents Alkylating Agent Mechanism of Action DNA Repair of Alkyl Adducts: Potential Influences on PoDs Mechanistic Evidence Supporting a PoD for EMS Mechanistic Evidence Supporting a PoD for ENU Mechanistic Evidence Supporting a PoD for MMS Mechanistic Evidence Supporting a PoD for MNU Concluding Remarks References Chapter 6. The Role of Endogenous Versus Exogenous DNA Damage in Risk Assessment Abstract Introduction Aldehydes Alkylating Agents Oxidative Stress Ionizing Radiation Quantifying Complex Dose–Response Relationships to Support Risk Assessments Conclusion References Chapter 7. Thresholds of Toxicological Concern for Genotoxic Impurities in Pharmaceuticals Abstract Introduction Genotoxic and Nongenotoxic Carcinogens Thresholds of Chemical Genotoxicity Risk Management for Genotoxic Carcinogens Risk Assessment and Control of Genotoxic Impurities in Pharmaceuticals Conclusion References Chapter 8. Practical Thresholds in the Derivation of Occupational Exposure Limits (OELs) for Carcinogens Abstract Introduction Derivation of Occupational Exposure Limits for Carcinogenic Substances Concept of the German DFG (MAK (Maximale Arbeitsstoffkonzentration) Commission) Discourse and Further Development in Europe The Concept of SCOEL Recent Examples of Carcinogens With a Practical Threshold Assigned by SCOEL Conclusions Abbreviations References Chapter 9. Experimental Design and Statistical Analysis of Threshold Studies Abstract Introduction No-Observed Genotoxic Effect Level Dose–Response Modeling Interpolation and Extrapolations Goodness of Fit Issues: Acceptance and Rejection of Models BMD Approach Mathematical Modeling for the BMD Software Conclusions Acronyms References Chapter 10. Nrf2 as a Possible Determinant of the Threshold for Carcinogenesis Abstract Introduction The Regulation of Gene Expression by Nrf2 The Susceptibility of Nrf2 Knockout Mice to Xenobiotics The Carcinogenicity and Mutagenicity of Xenobiotics in Nrf2 Knockout Mice Human Carcinogenesis in Regard to Nrf2 Activity Do Nrf2 and Nrf2-Regulating Genes Contribute to the Creation of a Threshold to Carcinogenesis? Conclusion Abbreviations References Chapter 11. Assessment of Nongenotoxic Mechanisms in Carcinogenicity Test of Chemicals; Quinone, Quinone Imine, and Quinone Methide as Examples Abstract Quercetin Eugenol and Methyleugenol Phenacetin and Acetaminophen Menadione Ethoxyquin General Discussion for All the Chemicals Shown References Chapter 12. Mode of Action and Assessment of Human Relevance for Chemical-Induced Animal Tumors Abstract Introduction Importance of Mode of Action (MOA) Analyses for Chemical-Induced Animal Tumors and Assessment of Human Relevance Based on MOA Human Relevance of the Constitutive Androstane Receptor (CAR) Activator-Induced Liver Tumors in Rodents Based on MOA Human Relevance of the Mutagen-Induced Tumors in Rodents Based on Threshold Future Prospects of the Mechanistic Research in Genotoxic and Nongenotoxic Tumor Inducers References Index