Thresholds of Genotoxic Carcinogens

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