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INTRODUCTION The information available on the potential toxicity of most chemicals is scanty, and the resources available for toxicity testing do not suffice to test all chemicals for every possible health effect. Hence, a priority-setting system is needed for selecting substances to be tested and selecting tests with which to evaluate them. Because of limitations in available data and methods, the priority-setting system must be designed to operate in the presence of considerable uncertainty. The Committee on Priority Mechanisms has sought to develop a priority-setting approach applicable to the large number of chemicals of potential concern with respect to human health. The approach, which is drawn from systems analysis and decision theory, is based on the thesis that the rationale of any priority-setting system should be explicit, open to inspection, and scientifically defensible. In view of the rapidity with which the art of toxicity testing is evolving, the committee does not propose a particular priority-setting scheme now, but rather suggests an approach for designing a system that can keep pace with advances in the field. The approach is presented in this report largely in conceptual form, although examples are given to illustrate how it could be applied to the selection of chemicals for carcinogenicity testing. Testing priorities have traditionally been assigned on the basis of expert judgment, which is now supplemented with a variety of analytic, data-based techniques, such as scoring systems. The committee believes that this basic pattern should continue, with further improvement in techniques that allow expert judgment to be most effective. The committee recognized that no priority system, scheme, or procedure can be perfect, because the knowledge needed for unerring selection of the most important chemicals and tests is the same as the knowledge resulting from a complete and accurate testing program for all chemicals, which would of course make priority-setting unnecessary. The priority-setting system and the testing program form a continuum whose overall objective is to yield the most information about the overall hazards of chemicals. Given a goal for the priority-setting system, the committee needed to decide whether improvements over current procedures for selecting chemicals for testing were possible. It concluded that improvements were possible--at least at the margin--by injecting additional systematic information-gathering and -processing procedures. Because the total number of chemicals far exceeds the number that can be evaluated in depth at any one time, the committee's approach seeks to arrive at the combination of information-gathering procedures that, for a given investment of resources, will yield the most useful toxicity data 205
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on the universe of chemicals to be considered. To enable the entire select universe of chemicals to be scanned for compounds that may warrant testing, a multistage scheme is presented for consideration; it begins with automated processing of machine-retrievable data and proceeds through successive stages to costlier procedures that depend on expert judgment. A model is presented to illustrate how the performance of this four-stage priority-setting system can be optimized by selecting the most effective set of decisions for a given investment of resources. Lack of knowledge about the effectiveness of toxicity testing, the extent and distribution of toxic properties among chemicals, or the exposure to chemicals hinders the design of an optimal system. However, the report shows not only how a priority-setting scheme might operate with incomplete and uncertain information, but also how to determine what information is most needed to improve the system itself. The work of the committee is presented as a review of the elements of systems analysis as applied to priority-setting for toxicity testing in Chapter 2. These principles are applied to an illustrative system in Chapter 4. An explanation of the operation of the illustrative system is presented in Chapter 3, and suggestions for implementation are presented in Chapter 5. The committee believes that a fully developed version of the outlined system not only is a plausible extension of current practice, but also would provide at least marginal improvements over existing priority- setting procedures toward the goal defined earlier. Obviously, it might not provide improvements toward other goals, but it should not impede them. Even at the margin, the improvements would probably easily justify the costs of developing, implementing, and operating the system. However, the implementation of these concepts in the illustrative system or one of similar scope would require adjustments in the established patterns of thinking about testing priorities. Specifically, full application of the proposed analytic techniques will require that each information-gathering procedure be described quantitatively with respect to its ability to identify and to characterize potentially toxic chemicals. This requirement is not readily fulfilled in our present state of knowledge. Hence, efforts toward further quantification of the performance characteristics of toxicologic methods would be essential to full implementation of the priority-setting approach proposed herein. For this reason, the approach can be pursued initially on a pilot scale, with further implementation depending on the development and availability of the necessary data. The committee believes that it should be possible to institute changes in current procedures gradually, without irreversibly committing resources to the novel features of its suggestions. 206
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