Thresholds of Genotoxic Carcinogens

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.

• Unites an international team of experts to provide a balanced overview of the current opinion on thresholds of genotoxic carcinogens
• Provides all the information readers need to determine a safe threshold for potential genotoxic carcinogens
• Includes information on the mechanisms of genotoxic carcinogens and how these can inform regulation
• Serves as an essential reference for any professional researchers in genetic toxicology and those involved in toxicological regulation

Researchers in genetic toxicology, genetic toxicologists working in pharmaceuticals, foods, agricultural pesticides and cosmetics, regulatory toxicologists, risk assessors

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