Complex Mixtures

Methods for In Vivo Toxicity Testing

Publisher: National Academies Press
ISBN: 9780309037785
eISBN Pdf: 9780309555135
Place of publication: United States
Year of digital publication: 1988
Month: January
Pages: 240
Language: English

Caption

In the laboratory, testing the toxic effects for a single compound is a straightforward process. However, many common harmful substances occur naturally as mixtures and can interact to exhibit greater toxic effects as a mixture than the individual components exhibit separately. Complex Mixtures addresses the problem of identifying and classifying complex mixtures, investigating the effect of exposure, and the research problems inherent in testing their toxicity to human beings. A complete series of case studies is presented, including one that examines the cofactors of alcohol consumption and cigarette smoke.

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

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Complex Mixtures

Methods for In Vivo Toxicity Testing

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