Perspectives on Biologically Based Cancer Risk Assessment: 23 - Rilegato

Rilegato

ISBN 10: 0306461080 ISBN 13: 9780306461088

Casa editrice: Springer-Verlag GmbH, 1999

Riassunto

This text includes a comprehensive updated analysis of cancer risk assessment procedures, with particular attention to biologically-based modelling. The presented arguments include the basic assumptions of cancer risk assessment methods, their biological basis and theoretical background, the relevant data sources, the multistage models (including the two-stage and clonal expansion models and pharmacokinetic models), and the relevant biomarkers, together with fundamental statistical considerations and selected case studies and examples of practical applications. The uncertainty of assessment and the practical use of the proposed methods are suggested. The book examines in detail the updated biologically-based carcinogenic risk assessment procedures together with the usually employed procedures, as well as background information on which they are based. It also proposes new ideas and methods in this field. Furthermore, it includes criteria and methods for practical application and use of the examined procedures.

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Contenuti

1. Introduction.- 1.1. Dose-Response Assessment in Nato Countries.- 1.1.1. European Community.- 1.1.1.1. European Union.- 1.1.1.2. The Netherlands.- 1.1.1.3. United Kingdom.- 1.1.1.4. Germany.- 1.1.1.5. Denmark.- 1.1.1.6. Norway.- 1.1.1.7. Other countries.- 1.1.1.8. Concluding remarks.- 1.1.2. United States.- 1.1.2.1. Use of Dose-Response Assessment.- 1.1.2.2. Evolution of Dose-Response Assessment.- 1.1.3. Differences between the United States and European Countries.- 1.2. Future Directions in Dose-Response Assessment.- 1.3. Brief Considerations on Some Commonly Used Parameters.- 1.3.1. Variation in Carcinogenic Potency and in Parameters Adopted for Carcinogen Regulation.- 1.3.2. Toxicity Data and Carcinogenic Potencies: Correlation between Parameters Adopted for Risk Assessment.- 1.3.3. The Linearized Multistage Model and Benchmark Dose (BD) Approaches: Dose-Response Analysis May Provide a Unique Framework for Both the Carcinogenic and Noncarcinogenic Procedures.- 1.4. Structure of this Report.- 1.5. References.- 2. The Biological Basis of Cancer.- 2.1. Introduction.- 2.2. Cell Proliferation.- 2.3. Cell Proliferation and Mutation.- 2.4. Differences in Susceptibility.- 2.5. Mechanisms of Inhibition in Mutagenesis and Carcinogenesis.- 2.5.1. Introduction.- 2.5.2. Inhibition in Mutagenesis and Carcinogenesis.- 2.5.3. Extracellular Inhibition.- 2.5.4. Intracellular Inhibition.- 2.5.5. Inhibitors of Cancer Initiation.- 2.5.6. Inhibitors of Tumor Promotion and Progression.- 2.5.7. Dual Effects of Inhibitors.- 2.6. References.- 3. Sources of Data For Cancer Risk Assessment.- 3.1. Introduction.- 3.2. In Vitro and Short Term Testing.- 3.3. Trends in Animal Toxicology Testing.- 3.4. Cell Proliferation.- 3.4.1. Quantitative Methods and Data Sources.- 3.4.1.1. Direct Measurements of Cell Division.- 3.4.1.2. Serum Biomarkers of Cellular Proliferation.- 3.4.1.3. Cell kinetics of EAF.- 3.5. Sources of Toxicokinetic Data.- 3.5.1. Introduction.- 3.5.2. Model Parameters.- 3.5.2.1. Physiologic.- 3.5.2.2. Biochemical.- 3.5.3. Toxicokinetic Data.- 3.6. Inter- and Intra-Species Variability.- 3.6.1. Variability in Genetic Damage.- 3.6.2. The Parallelogram Model.- 3.7. References.- 4. Use of Biochemical and Molecular Biomarkers For Cancer Risk Assessment in Humans.- 4.1. Introduction.- 4.2. The Initiatory Complex and its Modulators.- 4.2.1. Biomarkers of Exposure.- 4.2.1.1. The External Dose.- 4.2.1.2. The Internal Dose.- 4.2.1.3. The Biologically Effective Dose.- 4.2.1.4. Interaction with Relevant Macromolecules.- 4.2.1.5. Cytogenetic Biomarkers of Early Effects.- 4.2.1.6. Discussion about the Biomarkers of Exposure.- 4.2.2. Biomarkers of Individual Susceptibility.- 4.2.2.1. Phase I Enzymes and Related Markers.- 4.2.2.2. Phase II Enzymes.- 4.2.3. DNA Repair and its Variability.- 4.2.3.1. Assessment of DNA Repair.- 4.2.3.2. Mismatch Repair, Microsatellite Instability and Mutator Phenotype.- 4.2.3.3. Other Genetic Instability Syndromes.- 4.2.3.4. Restatement of the DNA Repair Problem.- 4.2.4. Exogenous Nutritional Factors.- 4.3. The Determinants of the Clonal Expansion of the Initiated Cells.- 4.3.1. Basic Mechanisms.- 4.3.2. Cell Cycle Control Mechanisms.- 4.3.2.1. p53.- 4.3.2.2. The Rb tumour suppressor gene.- 4.3.2.3. The myc Oncogene.- 4.3.2.4. Low Molecular Weight Regulatory Proteins.- 4.3.3. Growth Factors, Growth Factor Receptors and Signal Transduction Pathways.- 4.3.3.1. Growth Factors and Receptors.- 4.3.3.2. Growth Factor Receptors.- 4.3.4. Signal Transduction Pathways.- 4.3.4.1. Transmembrane Receptors with Intrinsic TRK Activity.- 4.3.4.2. Receptors with Seven Transmembrane-spanning Domains.- 4.3.4.3. Cytoskeletal Signal Transduction Pathways.- 4.3.5. The Outcome: The Clonal Expansion of the Initiated Cells.- 4.3.5.1. Proliferation.- 4.3.5.2. Apoptosis.- 4.4. Adjuvant Determinants of the Clonal Expansion.- 4.4.1. Oxidative Damage and its Repair.- 4.4.1.1. Identification of Oxidative Damage.- 4.4.1.2. Thymine Glycol and Thymidine Glycol.- 4.4.1.3. 8-Hydroxydeoxyguanosine (8OHdG).- 4.4.1.4. ADPRT.- 4.4.1.5. Others.- 4.4.2. Intercellular Communication.- 4.4.3. Intercellular Adhesion.- 4.4.4. Cell-Surface Structures.- 4.4.5. Miscellaneous Determinants.- 4.4.5.1. Immune Status.- 4.4.5.2. Nutritional Status.- 4.5. Conclusion.- 4.6. Acknowledgments.- 4.7. References.- 5. The Multistage Model of Carcinogenesis: A Critical Review of its Use.- 5.1. Introduction.- 5.2. Historical Antecedents of the Multistage Model.- 5.3. The Armitage-Doll Multistage Model.- 5.4. Derivation, Rationale and Mathematical Form of the Model.- 5.5. The “Linearized Multistage Model”.- 5.6. Time-Dependent Non-Constant Exposure Patterns: Their Influence on Multistage-Derived Risk Estimates.- 5.7. Consideration of Pharmakokinetics in Multistage Modeling.- 5.8. The Problem of Multiple Exposure: Multistage Carcinogenesis Theory and Additive and Multiplicative Models.- 5.9. Critical Review of the Model.- 5.10. Discussion.- 5.11. References.- 6. Biologically Based Models of Carcinogenesis.- 6.1. Introduction.- 6.2. A Brief History of Biologically-Based Cancer Models.- 6.3. Two-Mutation Clonal Expansion Model.- 6.4. Modes of Action of Carcinogens.- 6.5. Quantitative Formulation of the Model.- 6.5.1. The Probability of Tumor.- 6.5.1.1. Solution for Piecewise Constant Parameters.- 6.5.1.2. Identifiability of Model Parameters.- 6.6. Likelihood Construction and Estimation.- 6.7. Quantitative Analysis of Intermediate Lesions.- 6.7.1. Modeling Initiation and Promotion of EAF.- 6.7.2. Gompertz Growth.- 6.7.3. Statistical Analysis.- 6.7.4. Joint Analysis of Premalignant and Malignant Lesions.- 6.8. Toxicokinetics in Biologically Based Risk Assessment.- 6.8.1. Physiologically-based Toxicokinetic Models in Risk Assessment.- 6.8.2. Multistage Modeling.- 6.8.3. Biologically-based Risk Assessment.- 6.8.4. Model Development and Parameterization.- 6.9. Interspecies Extrapolation.- 6.9.1. Scaling Physiologic and Metabolic PBTK Model Parameters.- 6.9.2. Discussion of Allometric Scaling.- 6.9.3. Choice of a Dose Surrogate.- 6.9.4. Interspecies Extrapolation of Toxicokinetics.- 6.10. Implications for Low-Dose Extrapolation.- 6.11. References.- 7. Statistical Issues in the Application of Multistage and Biologically Based Models.- 7.1. Introduction.- 7.2. Characterization Of Models.- 7.2.1. Model Components.- 7.2.2. Model Comparison.- 7.2.3. Low Dose.- 7.3. Statistical Inference.- 7.3.1. Available Data and Parameter Estimation.- 7.3.2. Comparing Low-Dose Extrapolations from Different Models: A Simulation Study.- 7.3.3. Design of the Simulation Study.- 7.3.3.1. Data Generation.- 7.3.3.2. Estimation of Parameters.- 7.3.4. Simulation Results.- 7.3.4.1. Parameter Estimates.- 7.3.4.2. Estimates of Additional Risk.- 7.3.4.3. The Direction of Error.- 7.3.4.4. Goodness of Fit as a Criterion for Model Choice.- 7.4. Design Considerations for Low-Dose Problems.- 7.5. Sensitivity Analysis and Physiologically Based Toxicokinetic Modeling.- 7.5.1. Current Methodology.- 7.5.2. Physiologically Based Toxicokinetic Model Sensitivity Analysis.- 7.6. Discussion.- 7.7. References.- 8. Informative Case Studies.- 8.1. Radon, Cigarette Smoke, and Lung Cancer: The Colorado Plateau Uranium Miners’ Cohort.- 8.2. Modeling Colon Cancer.- 8.2.1. How Many Rate-limiting Events for Colon Cancer?.- 8.2.2. Analysis of Colon Cancer Data in Patients with FAP.- 8.3. Quantitative Analysis of Enzyme Altered Foci (EAF).- 8.3.1. Effects of PCBs on the Initiation and Promotion of EAF.- 8.3.2. Effects of Chronic Administration of N-nitrosomorpholine on Liver EAF and Hepatocellular Carcinoma (HCC).- 8.4. The Role of Cell Proliferation in Urinary Bladder Carcinogenesis.- 8.5. N-Nitrosomorpholine: Comparison of Multistage Model and Two-Event Clonal Expansion Model.- 8.6. Calculation of Tetrachloroethylene Risk Estimates.- 8.6.1. Classical Risk Assessment Methodology.- 8.6.1.1. Interspecies Extrapolation.- 8.6.1.2. Dose-Response Relation in Animals.- 8.6.1.3. Calculation of Administered Dose in Humans.- 8.6.1.4. Classical Calculation of Human Risk.- 8.6.2. Toxicokinetic Risk Assessment Methodology.- 8.6.2.1. Interspecies Extrapolation.- 8.6.2.2. Dose-Response Relation in Mice.- 8.6.2.3. Calculation of Effective Dose in Humans.- 8.6.2.4. Toxicokinetic Calculation of Human Risk.- 8.6.3. Biologically Based Risk Assessment Methodology.- 8.6.3.1. Dose-Response Relation in Mice.- 8.6.3.2. Calculation of Human Risk.- 8.6.4. Comparison of Human Risk Estimates.- 8.7. Considerations for Benzene Toxicokinetic Extrapolation.- 8.7.1. Methods.- 8.7.1.1. Experimental Data.- 8.7.1.2. Model.- 8.7.1.3. Extrapolation.- 8.7.1.4. Extrapolated Model Predictions.- 8.7.2. Results and Discussion.- 8.7.2.1. Extrapolated Model Predictions.- 8.8. References.- 8.9. Appendix A.- 9. Conclusions and Recommendations.- 9.1. Introduction.- 9.2. What does Each Source of Experimental Data Contribute to our Knowledge and Ability to Model?.- 9.3. What Kinds of Information are Needed to Develop a Biologically Based Model?.- 9.4. How does Linearity Enter into Empirical Models and Biologically Based Models?.- 9.5. How does a Biologically Based Model Help Us Understand Intraspecies Variability?.- 9.6. How D does a Biologically Based Model Help Us Understand Interspecies Variability?.- 9.7. What are the Uncertainties Associated with a Biologically Based Model?.- Contributors.

Product Description

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Dettagli dell'edizione

• Editore: Springer-Verlag GmbH
• Data di pubblicazione: 1999
• Lingua: Inglese
• ISBN 10: 0306461080
• ISBN 13: 9780306461088
• Rilegatura: Copertina rigida
• Numero di pagine: 336
• Redattore: Cogliano Vincent James, Zapponi Giovanni A., Luebeck E. Georg
• Contatto del produttore: ProductSafety@springernature.com; ProductSafety@springernature.com; ; Poststr. 9; Darmstadt; 64293; Germania