Toxic Substances and Human Risk

As society has become increasingly aware of the potential threats to human health due to exposures to toxic chemicals in the environment and the workplace and in consumer products, it has placed increased demands upon the still-fledgling science of toxicology. As is often the case when science is called upon to supply firm answers when pertinent information and fundamental knowledge are lack­ ing, both the scientific and the social issues become confused and new tensions develop. One of the major purposes of this book is to focus on those aspects of the science of toxicology that pertain most to social issues-namely, analysis of risk for purposes of human health protection. Although it is apparent that the discipline of toxicology is not yet prepared to provide firm answers to many questions concerning human risk, it is important that the rigorously derived information be used in the most objective and logical way to yield the closest approximation to the truth. This book is designed to sup­ ply as much guidance for such tasks as is permitted by the current state of our knowledge. Its emphasis is thus placed on interpretation of toxicity data (broadly defined) for assessing risks to human health. In this way, it differs from other basic toxicology texts, most of which emphasize methods for performing studies or describe various toxicological endpoints and classes of toxic agents.

I • Historical Perspectives And General Concepts.- 1 • Introduction.- 2 • Toxicologic Units.- Units Used in Animal Studies.- Units Used to Estimate Acceptable Human Exposure Levels.- Risk Indices Used in Epidemiology.- Appendix: Abbreviations of Toxicological Units.- References.- 3 • Dose-Response Relationships.- Dose-Response Curves.- The Probit Model.- Applications: Therapeutic Index and Margin of Safety.- Exploration of the “Threshold” Region.- Unusual Dose-Response Curves.- Other Dose-Response Models.- Summary and Conclusions.- References.- 4 • Factors Modifying Toxicity.- Species.- Strain.- Age.- Sex.- Nutrition.- Timing.- Lifestyle.- Health Status.- Summary and Conclusions.- References.- 5 • Statistical Interpretation of Toxicity Data.- Statistical Tests for Toxicity.- Estimation of Toxic Effects.- References.- II • Interpretation Of Information From Human Studies.- 6 • Clinical and Epidemiological Studies.- The Principal Types of Human Study.- Limitations of Epidemiological Study Designs.- Conclusion.- References.- 7 • Comprehensive Evaluation of Human Data.- The Nature of Epidemiological Reasoning.- Establishing Causality: Qualitative Aspects of Data Evaluation.- Quantitative Aspects of Data Evaluation.- Conclusions.- References.- III • Interpretation Of in Vivo Experimental Data For Evaluation Of Hazards To Humans.- 8 • Selection of Animal Models for DataInterpretation.- Healthy versus Diseased Animals.- Young, Mature, or Old Animals.- Nutritional Status of Animals.- References.- 9 • Toxicokinetics.- Basic Concepts of Toxicokinetics.- Parameters of First-Order Toxicokinetics.- Correlation of Toxicokinetics and Action.- Toxicokinetics and Toxicology.- A Basic Toxicokinetic Model for Toxicology.- Deduction of Toxicokinetics with Biophasic Steady-State Concentrations of Toxicant.- Toxicokinetics on Chronic Toxicant Administration When Tissues Are Not Equilibrated Instantaneously.- The Time Course of Toxicity on Acute Administration of a Toxicant.- Dose Dependences of Acute Toxicity with Nonsaturable Toxic Receptor Sites.- Dose Dependences of Acute Toxicities with Saturable Toxic Receptor Sites.- Deduction of Pharmacokinetic Properties of a Toxicant from Acute Toxicity Studies.- Critique of Models for Toxicity.- References.- 10 • Approaches to Intraspecies DoseExtrapolation.- Mathematical Models of Dose-Response Relationship.- Comparisons of Specific Models.- Extrapolation of Human Epidemiological Data.- Summary and Conclusions.- References.- 11 • Extrapolation from Animal Data.- Evolutionary Theory As the Practical Basis of Predictive Toxicology.- Guiding Principles for Animal Extrapolation.- Generalizations of Practical Value.- Animal Models for High-Risk Groups.- Quantitative Risk Assessment.- Conclusion.- References.- 12 • Approaches to Route Extrapolation.- The Stokinger-Woodward Approach.- First-Pass Effects.- Summary.- References.- 13 • Application of in Vivo Data onChemical-Biological Interactions.- Metabolism, Detoxification, and Bioactivation.- Use of Covalent Binding Data in Interpreting Results of Toxicity Studies.- Information Necessary for More Predictive Use of Covalent Binding Data in Risk Assessment.- Conclusions.- References.- 14 • Computer-Assisted Prediction of Toxicity.- Cautions Regarding Applicability of Models.- Statistical Methodology.- Estimator for Rat Oral LD50.- Estimator for Probability of Mutagenicity.- Estimator for Probability of Carcinogenicity.- Estimator for Probability of Teratogenicity.- Interspecies and Other Models.- Summary.- References.- IV • Interpretation Of In Vitro Experimental Data For Evaluation Of Hazards To Humans.- 15 • Assessment of the Hazard of Genetic Toxicity.- Terminology.- Human Health Effects Associated with Exposure to Genotoxic Agents.- Methods to Identify the Hazard of Genetic Toxicity.- Assessment of Genetic Risk.- Limitations of Quantitative and Qualitative Extrapolation.- Conclusions.- References.- 16 • Evaluation of Xenobiotic Metabolism.- Categories of Toxic Chemicals.- Metabolic Activation.- Characteristics of Reactive Metabolites.- Strategies for Studying the Reactivity of a Toxic Chemical.- Limitations and Perturbations of the Toxic Response.- The Role of Metabolic Studies in the Evaluation of Toxicity.- Extrapolation from in Vitro Experiments to Living Animals.- Summary.- References.- V • Risk Analysis.- 17 • Exposure Assessment.- Expressions of Exposure.- Conventional Approaches.- An Alternative Approach: “Backward Tracing”.- Example of Backward Tracing: Soaps and Detergents.- Some Observations on Backward Tracing.- References.- 18 • Comprehensive Risk Assessment.- Definitions of Terms.- Analytic Stages.- Defining the Risk Question.- Data Collection.- Evaluation of Individual Studies of Toxicity and Dose Response.- Critical Data Points.- Comprehensive Evaluation of Toxicity Data.- Combining the Evidence.- Other Schemes.- Conclusion.- Human Exposure Assessment.- Risk Characterization.- Selection of Studies and Data Points for Risk Assessment.- Options for Data Selection.- Criteria for Data Selection.- Negative and Presumably Conflicting Data.- Uncertainties Introduced in Data Selection.- Utilization of Selected Data.- Interspecies Extrapolation.- Final Risk Assessment.- References.