Complex Mixtures -- Copyright -- Preface -- Contents -- Executive Summary -- 1 Introduction -- DEFINITIONS -- STRUCTURE OF THE REPORT -- 2 Concepts for Analyzing Human Exposure to Complex Chemical Mixtures -- GENERAL CONCEPTS -- Dose and Dose Surrogates -- Indicators of Exposure to Complex Mixtures as Dose Surrogates -- Effects of Matrix and Physical State on Dose -- Factors Influencing Relationships Between Exposure and Dose -- EFFECT OF POPULATION AND EXPOSURE COMPLEXITY ON QUALITATIVE ASSESSMENT -- Complexity of Exposure -- Complexity of Populations -- Interactive Effects of Multiple Exposures -- Complexity of Health Effects -- CONSIDERATIONS IN QUANTITATION OF HUMAN EXPOSURES IN EPIDEMIOLOGIC STUDIES -- Ambient Exposure -- Concentrations in Air, Water, and Food -- Biologic Sampling Data -- Exposure Histories -- Some Statistical Issues in Quantitation of Exposure -- PREDICTIVE VALUE OF LABORATORY STUDIES FOR HUMAN EFFECTS OF ENVIRONMENTAL EXPOSURES -- Exposure as a Variable -- Complexity of the Agent as a Variable -- Limitations of Animal Models -- Tosicokinetics -- SUMMARIES OF EXAMPLES OF HUMAN EXPOSURES TO COMPLEX CHEMICAL MIXTURES -- Sulfur Dioxide and Suspended Particulate Matter -- Lead and Nutritional Factors-Effects on Blood Pressure -- Radon Daughters and Cigarette Smoke -- Asbestos Exposure and Cigarette-Smoking -- Cigarette-Smoking and Alcoholic-Beverage Consumption as Risk Factors in the Etiology of Oral Cancer -- Trihalomethanes and Other Byproducts of Chlorination in Drinking Water -- Coke-Oven Emissions -- Coal-Mine Dust -- REFERENCES -- 3 Testing Strategies and Methods -- PROBLEM AND QUESTION DEFINITION -- Questions Related to Effects -- Questions Related to Causative Agents -- Questions Related to Predictability -- STRATEGIES -- Strategies Related to Effects -- Tier Testing -- Screening Studies -- Matrix Testing.

Battery Approach -- Comparative-Potency Approach -- Strategies Related to Causative Agents -- Bioassay-Directed Fractionation -- Pairing -- Chemical Search -- Effect Search -- Bioassay Identification -- Strategies Related to Predictability and Models -- Testing Mixture Components -- Mechanistic Studies and Models for Interactions -- Empirical Models -- Aquatic Test Systems -- INTEGRATION OF STRATEGIES -- COMPLEXITY OF MIXTURE -- Knowledge of Constituents and Effects -- Problems or Questions in Relation to Strategies -- Formulation of Overall Strategy -- REFERENCES -- 4 Sampling and Chemical Characterization -- CLASSIFICATION -- SAMPLING -- Collection Strategy -- Exposure -- Meteorology -- Temporal Factors -- Spatial Considerations -- Collection Procedure -- Gases and Aerosols -- Aqueous Materials -- Nonaqueous Materials -- Solids and Sediments -- Maintenance of Sample Integrity -- Storage -- Preparation for Assay -- Quality Assurance -- ANALYSIS -- Chemical Classification -- General Considerations in Fractionation of Complex Mixtures -- Requirements for Analysis -- Separation and Preliminary Examination -- Extraction and Concentration -- Separation -- Liquid-Liquid Partitioning -- Chromatographic Separation -- Chemical Analyses -- REFERENCES -- 5 Interpretation and Modeling of Toxicity-Test Results -- INTRODUCTION -- What to Test? Whole Mixtures Versus Separate Components of Mixtures -- Implications for Strategies -- Evaluation of Mixture Components -- Expectation of Additivity at Low (Response) Doses -- Evaluation of Composite Mixture -- COMPARATIVE EVALUATION -- PHARMACOKINETIC MODELS -- EXPERIMENTAL DESIGN -- Identification of Toxic Agents -- Response-Surface Analysis -- Designs for Predicting Low-Dose Risks -- Designs for Initiation-Promotion Studies -- Practical Implications for Experimental Design -- FUTURE DIRECTIONS -- Cancer Models.

Developmental Effects and Other Noncancer End Points -- Statistical Approaches for Situations with No Preferred Dose-Response Model -- Empirical Modeling of the Toxicity of Mixtures -- Pharmacokinetics -- Design of Experiments -- Strategy Definition -- REFERENCES -- Appendixes -- A Origins of Complex Mixtures -- Combustion and Distillation Products -- Fossil Fuels -- Coal -- Petroleum -- Oil Shale -- Synthetic Fuels -- Vegetable Sources -- Synthetic Materials -- Noncombusted Materials -- Coal Dust -- Oil Shale -- Waste -- Water -- References -- B Case Studies Establishing Active Agents and/or Interactions in Complex Mixtures -- Sulfur Dioxide and Suspended Particulate Matter -- Lead and Nutritional Factors-Effects on Blood Pressure -- Radon Daughters and Cigarette Smoke -- Asbestos Exposure and Cigarette-Smoking -- Cigarette-Smoking and Alcoholic-Beverage Consumption -- Trihalomethanes and Other Byproducts of Chlorination in Drinking Water -- Coke-Oven Emissions -- Coal-Mine Dust -- References -- C Case Studies on Strategies for Testing the Toxicity of Complex Mixtures -- Cigarette-Smoke Toxicity -- Fire Atmospheres -- Hexacarbon Neuropathy -- References -- D Predicting the Joint Risk of a Mixture in Terms of the Component Risks -- Expressing Joint Risks in Terms of Component Risks -- Illustrative Examples -- Mixtures of More Than Two Chemicals -- Additional Research -- Summary -- Reference -- E Cancer Models -- Implications of the Multistage Model -- Derivation of the Multistage Model that Accounts for Exposure to Multiple Carcinogenic Agents -- Illustrative Multistage Model That Results in Synergistic Effect -- Estimation of Largest Synergistic Effect Detectable in 2 × 2 Balanced-Design Experiment -- Estimation of Joint Effects of Environmental Exposure with Previously Derived Numerical Model.

Practical Implications Discernible from Numerical Investigation of Generalized Multistage Model -- Effect of Background Tumor Rate on Additivity Assumption -- Additivity of Excess Risks At Low Doses -- Multistage Model -- Additive-Background Models -- Mixed-Background Models -- Multiplicative-Risk Models -- Prediction of Risk at Low Doses -- Summary -- References -- F Developmental Toxicology -- Statistical Methods for Developmental Toxicology Data -- Dose-Response Models for Developmental Effects -- Limitations and Advantages of Procedures That Use Developmental End Points -- Summary -- References -- G Empirical Modeling of the Toxicity of Mixtures -- Analysis of an Inhalation Experiment on Rats -- A Generalized Class of Noninteracting Models -- Simple Additive Model -- Generalized Additive Model -- Quasibiologic Models -- Summary -- References -- Index.