Perspectives on Biologically Based Cancer Risk Assessment

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 Ddoes a Biologically Based Model Help Us Understand Interspecies Variability?.- 9.7. What are the Uncertainties Associated with a Biologically Based Model?.- Contributors.