Prepared at the request of the National Toxicology Program, this landmark report reveals that many chemicals used in pesticides, cosmetics, drugs, food, and commerce have not been sufficiently tested to allow a complete determination of their potential hazards. Given the vast number of chemical substances to which humans are exposed, the authors use a model to show how research priorities for toxicity testing can be set.

Contents

• STEERING COMMITTEE ON IDENTIFICATION OF TOXIC AND POTENTIALLY TOXIC CHEMICALS FOR CONSIDERATION BY THE NATIONAL TOXICOLOGY PROGRAM
• COMMITTEE ON STATISTICAL SAMPLING METHODS (Committee on Sampling Strategies)
• COMMITTEE ON CHARACTERIZATION OF STATUS OF TOXICITY DATA ELEMENTS FOR A SELECT UNIVERSE OF COMPOUNDS (Committee on Toxicity Data Elements)
• COMMITTEE ON RESEARCH OF AGENTS POTENTIALLY HAZARDOUS TO HUMAN HEALTH (Committee on Priority Mechanisms)
• BOARD ON TOXICOLOGY AND ENVIRONMENTAL HEALTH HAZARDS
• PREFACE
• ACKNOWLEDGMENTS
• EXECUTIVE SUMMARY
  • Select Universe of Substances
  • Characterizing Toxicity-Testing Needs
  • Quantity and Nature of Testing
  • Quality of Testing
  • Toxicity-Testing Needs
  • Health-Hazard Assessment
  • Interpretation of Physicochemical and Exposure Data
  • Approaches to Priority-Setting
• INTRODUCTION
  • The National Toxicology Program
  • The Study
  • References
• PART 1. TOXICITY-TESTING NEEDS IN THE SELECT UNIVERSE
  • 1. Introduction
  • 2. Sample Selection
    • The Universe and the Sampling Frame
    • Considerations in Developing the Sampling Strategy
    • Sampling Strategy
    • Screening the Sample for Minimal Toxicity Information
  • 3. Operating Policies for Identification, Acquisition, and Organization of Data
    • Restricted-Access or Confidential Information
    • Information on Toxicity in Humans
    • Chemical and Physical Characteristics, Manufacturing Processes, Production Volumes, Intended Uses, and Exposure of Humans
    • Chemical Review Articles
    • Articles in Foreign Languages
    • Substances Structurally Similar to Those in the Sample
  • 4. Data Evaluation
    • The Dossier Concept
    • General Principles for Evaluation of Toxicity-Testing Protocols
    • Consideration of Exposure
    • Purity of Selected Substances
    • Guidelines for Assessing the Quality of Individual Studies
    • Procedures for Evaluation of the Data Base
    • Limitations of the Data Gathering Process
    • Interpretation of Data on Testing Quality
    • Characterizing the Sample and Options for Drawing Inferences to the Select Universe
    • Machine-Readable Files
  • 5. Results
    • Quantity and Nature of Testing
    • Quality of Testing
    • Testing Needs
    • Health-Hazard Assessment
    • Interpretation and Analysis of Physicochemical and Exposure Data
  • 6. Summary and Conclusions
  • References
  • Appendix A Sample of 675 Substances and Subsample of 100 Substances from the ''Select Universe''
  • Appendix B Testing for Various Situations of Chemical Use and General Exposure to Direct and Indirect and Indirect Food Additives (Legend of symbols and reference notations follows )
  • Appendix C Testing for Various Situations of Chemical Use and General Exposure to Oral or Parenteral Drugs or Color Additives for Sutures (Legend for symbols and reference notations follows )
  • Appendix D Testing for Various Situations of Chemical Use and General Exposure to Inhalation and Veterinary Drugs (Legend of symbols and reference notations follows )
  • Appendix E Testing for Various Situations of Chemical Use and General Exposure to Cosmetics and Dermal, Vaginal-Rectal, Over-the-Counter, and Ophthalmic Drugs (Legend of symbols and reference rotations follows )
  • Appendix F Testing for Various Situations of Chemical Use and General Exposure to Pesticides (Legend of symbols and reference notations follows )
  • Appendix G Testing for Various Situations of Chemical Use and General Exposure to Other Marketable Chemicals (Legend of symbols and reference notations follows )
  • Appendix H Reference Protocols for Toxicity Testing
  • Appendix I Reference Protocol Guidelines for Neurobehavioral-Toxicity Tests
  • Appendix J Reference Protocol Guidelines for Genetic-Toxicity Tests
  • Appendix K Conceptual Issues Concerning the Interpretation of Results of Studies of Reproductive and Developmental Toxicity
  • Appendix L Major Components of A Dossier
  • Appendix M Procedures, Rationale, and Results of Data Identification and Acquisition
• PART 2. SETTING PRIORITIES FOR TOXICITY TESTING
  • 1. Introduction
  • 2. Decision of the Priority-Setting System
    • Goal of Priority-Setting
    • Chemicals Considered
    • Structure of the System
    • Analysis of Information
    • Assessment and Decision-Making
    • Design Factors
  • 3. Briefly Following a Chemical Through an Illustrative System
    • Stage 1
    • Stage 2
    • Stage 3
    • Stage 4
  • 4. Detailed Description of the Operation of an Illustrative System
    • Introduction
    • Elements of Design
    • Stage 1
    • Stage 2
    • Stage 3
    • Stage 4
  • 5. Future Development, Implementation, and Refinement of the System
    • Development
    • Implementation
    • Further Refinement
    • Evaluation
    • Possible New Data Elements
  • 6. Conclusions and Recommendations
  • References
  • Appendix A Review of Selected Priority-Setting Systems
  • Appendix B Mathematical Modeling of the Priority-Setting Process and Resulting Decision Rules
  • Appendix C Expert Judgment and the Treatment of Uncertainty
  • Appendix D The Analysis of Structure-Activity Relationships in Selecting Potentially Toxic Compounds for Testing
  • Appendix E Costs of Misclassification
  • Appendix F Differences Between Part 1 and Part 2

The work on which this publication is based was performed pursuant to Contract NO1-ES-0-0008 with the National Toxicology Program.

NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance.

This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine.

The National Research Council was established by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy's purposes of furthering knowledge and of advising the federal government. The Council operates in accordance with general policies determined by the Academy under the authority of its congressional charter of 1863, which establishes the Academy as a private, nonprofit, self-governing membership corporation. The Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in the conduct of their services to the government, the public, and the scientific and engineering communities. It is administered jointly by both Academies and the Institute of Medicine. The National Academy of Engineering and the Institute of Medicine were established in 1964 and 1970, respectively, under the charter of the National Academy of Sciences.