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1 INTRODUCTION A major function of the National Toxicology Program (NTP) is the selection and testing of chemicals for toxicity. NTP considers chemicals for testing on a continuing basis, as candidates are nominated by the federal agencies served by the programs, by state and local governments, and by academic, industrial, and labor groups. Such candidates are of possible interest to NTP because of their potential for human exposure and possible public-health impact. This portion of the study, the determination of toxicity-testing needs, was undertaken because NTP recognizes that the number of substances, both natural and man-made, in the human environment is large and is increasing with no clear indication of the nature and amount of toxicity information that might be needed on these substances to ascertain potential for adverse effects on human health. It is useful for NTP to know as precisely as practicable the toxicity-testing needs for substances to which humans are potentially exposed. Consequently, NTP asked the National Research Council to address these matters. A major objective of the study was to estimate the amount and type of toxicity testing needed in the defined select universe of substances. To accomplish this objective, three operating goals had to be met by the Committee on Statistical Sampling Methods (commonly called the Committee on Sampling Strategies) and the Committee on Characterization of Status of Toxicity Data Elements for a Select Universe of Compounds (commonly called the Committee on Toxicity Data Elements): · To estimate the proportion of compounds in the select universe on which toxicity data exist. · To estimate the proportion of compounds in the select universe on which toxicity testing has been adequate or that NTP should consider for additional toxicity testing. · To determine the nature of any additional toxicity testing that may be required for particular classes of compounds. The size of the select universe precluded retrieving and evaluating existing toxicity data on all its constitutents to determine the extent to which additional data are needed. To approach an understanding of the status of toxicity information on the select universe, a scheme using carefully conceived sampling techniques, as described in Chapter 2, was developed. A probability sample was extracted from the select universe and later analyzed to learn the extent and quality of toxicity data on substances in the sample. The primary objective of creating the sample 29
was to permit the characterization of the status of toxicity information on chemicals in the sample, the characterization of the quantitative distribution of toxicity data in the sample, and the estimation of the proportions of substances in the select universe on which there are various degrees of toxicity data. This knowledge was then used to estimate the types and amounts of toxicity testing that might be required. The Committee on Sampling Strategies, composed primarily of experts in statistics, was responsible for evaluating sampling methods, for selecting the most appropriate sampling approach to be used in this study, for generating a sample, for assembling the data, and for assisting in the interpretation of the results of sample evaluation. To estimate the percentage of substances that might need further testing, each substance in the final sample was the subject of an exhaustive search for toxicity information, as described in Chapter 3 and in Appendix M. m e Committee on Toxicity Data Elements, composed mainly of experts in the toxicologic sciences, was responsible for establishing criteria by which the toxicity information on chemicals in the sample was to be characterized, for applying the criteria to the sample, and for interpreting the results in relation to the select universe. By blending their expertise, the two committees jointly estimated the toxicity-testing needs of the select universe. The description of toxicity-testing needs includes an estimate of the proportion of the select universe with a degree of information defined later in this report as minimal for the evaluation of possible hazard to human health. m e methods for documentation, protocol evaluation, and testing-need determination used by the committees are presented in this report. These methods were structured and detailed in such a fashion that new information and different judgments can be entered into the process, so that interpretations can be revised. Part 1 of this report, which contains the approaches and procedures used to ascertain the toxicity-testing needs of a select universe of chemical substances, begins with a detailed description of the contents of the select universe as a sampling frame, from which a sample and subsample were drawn. The sampling process is then presented, with particular attention to the choice of sampling method and the sample size. This is followed by an accounting of procedures for data identification, acquisition, and organization, including a description of the operating policies established by the two committees. The organizational framework for the recording and evaluation of data is documented with a consideration of the committees' adopted principles for the evaluative process. The specific standards and process of data evaluation used by the committees are then described. Finally, after a 30
presentation of the statistical techniques used for data interpretation and analysis, the committees explain in detail the results of their findings, with estimates of the quality and quantity of toxicity testing available for the entire select universe and of unmet needs. The report of the Committee on Toxicity Data Elements and the Committee on Sampling Strategies does not include an evaluation of the toxicity itself of the substances examined by the two committees, nor of the predictive power (false-positive and false-negative rates) of tests, the nature of toxicity end points (e.g., the proportion of substances in the select universe that are carcinogenic), or the nature of exposure end points (e.g., the proportion of substances that have high exposure potential). To the extent that it includes an examination of individual substances, it does so only for their usefulness as representatives of a larger population, namely the select universe. The decisions, criteria, and findings of this study were based solely on scientific principles. The study did not include the use of statutory processes of the various federal agencies with regulatory interest in the substances contained in the select universe. The agencies may have regulatory constraints that could alter their use of the information contained in this report; such use would not necessarily be based solely on scientific evaluation. In the detailed explanations of each phase, the committees present their procedures and assumptions with cautionary statements where appropriate, alerting readers to the possibility of misinterpretation. Because the process used by the committees was complex and integrative, readers are advised to note the details and cautionary statements with equal care to safeguard their understanding of the committees' findings 31 .