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INTRODUCTION Human life has always entailed exposure to chemicals. The substances we eat, drink, and breathe are composed of chemicals. The twentieth century has seen substantial growth in the synthesis of new molecules, some of which have proved useful in treating disease, preserving food, and reducing the cost of commodities. The estimates of such substances in the environment range as high as "hundreds of thousands" (NRC, 1975~. In recent decades, there has been widespread concern that synthetic chemical substances--increasing in number and concentrations--and natural substances may adversely affect human health. In response to the concern, such agencies as the Environmental Protection Agency, the Consumer Product Safety Commission, the Occupational Safety and Health Administration, the Food and Drug Administration, and the Department of Agriculture began to monitor the use of chemicals. If one supplements the catalog of man-made substances with the naturally occurring chemicals, such as those which constitute food, the list of substances to which humans are exposed may appear endless. Responding to the Toxic Substances Control Act (TSCA), the Environmental Protection Agency (EPA) has cataloged more than 56,000 substances that are now being manufactured or imported and that enter into various phases of chemical manufacture and formulation in the United States (U.S. Environmental Protection Agency, 1982~. Human exposure to these agents is known only in small measure and must be characterized by inference. me TSCA Inventory excludes some classes of agents that are regulated under other statutes. Humans are exposed to food additives, pharmaceutical agents (prescription and over-the-counter), and cosmetic ingredients, but many are regulated under the Food, Drug, and Cosmetic Act, rather than under TSCA. Recognition of the impact of these and other classes of substances on public health leads society to seek information for determining the magnitude of their potential effects. Such information is based primarily on predictions from results of toxicity studies. The development of a strategy for obtaining appropriate information requires an estimation of the quantity and quality of available toxicity data as criteria for the assessment of human-health hazards, as well as knowledge of the number of substances on which necessary experimental data are not yet available. A characterization of the magnitude of needed testing would inform those who allocate resources for such testing. However, because resources for developing sound scientific bases for identifying public-health hazards are limited, there is a strong impetus to select the most serious problems for immediate attention. Thus, it is important to establish priorities among chemical and physical agents and to select those thought but not proved to have the greatest potential impact on human health. 19
The methods currently used by federal agencies for assigning priorities are diverse. Therefore, it is useful to review existing ranking systems and to develop criteria for a priority-setting framework that acknowledge various needs and assist in ordering them. THE NATIONAL TOXICOLOGY PROGRAM On November 15r 1978J the Secretary of the Department of Health, Education, and Welfare (DHEW) announced the establishment of the National Toxicology Program (NTP) in DHEW (now the Department of Health and Human Services, DHHS) (U.S. Public Health Service, 1979~. The broad goal of NTP is to coordinate DHHS activities in the testing of chemicals of public-health concern and in the development and validation of new and better-integrated test methods. Specific goals of NTP are to extend the toxicologic characterization of chemicals being tested, to increase the rate of chemical testing (within the limits of available resources), and to develop and begin to validate a series of protocols appropriate for regulatory needs. One of its major responsibilities is the development of an information base on the toxic properties of substances that, because of their use or presence in the environment, have a substantial potential for adversely affecting human health. NTP provides access to scientific information about toxic, potentially toxic, and hazardous chemicals. His information is needed by regulatory agencies. It can be used for the prevention of chemically induced disease and for otherwise protecting the health of the American people. The NTP Executive Committee provides linkage between DHHS research agencies and federal regulatory agencies to ensure that toxicologic research and test development under the aegis of NTP are responsive to the needs of those agencies and to the needs of the public. This unique and important aspect of NTP brings together for the first time on a regular and permanent basis the regulatory agencies and the research agencies that are conducting fundamental biomedical research. For further information, the reader is referred to the NTP Annual Plans for fiscal years 1979 through 1982. THE STUDY In September 1980, the National Research Council (NRC) began a 3-year study whose results were intended to assist NTP in carrying out its mission. Broadly defined, the purposes of the study were to characterize the status of toxicity information on substances to which there is known or anticipated human exposure and to develop and validate uniformly applicable and wide-ranging criteria by which to set priorities for research on substances with potentially adverse public-health impact. During the course of this study, NRC transmitted to NTP two interim reports entitled Strategies to Determine Needs and Priorities for 20
Toxicity Testing. The first report, Volume 1: Design, was delivered in October 19 81, and the second , Volume 2. Development, in October 1982. report of the entire 3-veer Effort. enc~c~mn^.~.~. Thus volume, the final _ much of the information contained in the two interim reports. The study, called "Identification of Toxic and Potentially Toxic Chemicals for Consideration by the National Toxicology Program," was undertaken by three committees: the Committee on Statistical Sampling Methods (commonly called the Committee on Sampling Strategies), the Committee on Characterization of Status of Toxicity Data Elements for a Select Universe of Compounds (commonly called the Committee on Toxicity Data Elements), and the Committee on Research of Agents Potentially Hazardous to Human Health (commonly called the Committee on Priority Mechanisms). These committees received guidance and coordination from the Steering Committee on Identification of Toxic and Potentially Toxic Chemicals for Consideration by the National Toxicology Program. The committees completed five major tasks during the first year: (1) They identified a "select universe" of 65,725 substances chosen because of their potential for human exposure and their ready accessibility through computerized lists. This universe contains pesticides and inert ingredients of pesticide formulations, cosmetic ingredients, drugs and excipients in drug formulations, food additives, and other chemicals in commerce as listed in the TSCA Inventory. (2) Hey developed and applied a procedure to obtain a representative sample of 675 substances from the select universe and, from this, a subsample of 100 substances. (3) They established criteria by which to judge the quality of individual toxicity studies and of toxicity data bases on individual substances in the subsample, to determine their suitability for assessing hazards to human health. (4) Hey analyzed previously developed priority-setting approaches. (5) They described performance criteria that might be part of a comprehensive approach to setting priorities for toxicity testing. During the second year, the Committee on Toxicity Data Elements completed most of its evaluation of the data base on each of the 100 substances in the subsample. It determined in detail the adequacy of testing protocols for all toxicity studies that, according to the standards adopted, it considered necessary for conducting a health-hazard assessment. me committee formulated operating policies pertaining to the usefulness of information not generally available to the public, the role of human toxicity information, and the extent to which information on chemical mixtures should be used. To facilitate the achievement of its objectives, the committee developed procedures for document control (i.e., data identification, acquisition, and organization) and for evaluation of data (including committee decisions and comments from ; I;; Al'=1 ~mm; ~ ~ ~ ~_~\ .~^V6~8 ~VlIUI11~= Ills. Standardization of format, content, and method of reporting was also established. The Committee on Sampling Strategies selected a method for estimating the population percentages from the sample, developed procedures for combining results from sample and subsample analyses, and produced statistical summaries of the results of analyses. . 21
The Committee on Priority Mechanisms sought to develop criteria for a priority-setting approach that could function effectively with either long or short lists of substances. To accomplish this, the committee identified methods for assessing toxicity and exposure, so that they could be used in developing priority-setting criteria. It then designed and refined a model for the selection of methods believed to be important in setting priorities, elucidated performance characteristics at various stages of the priority-setting system, indicated how they may be applied, and determined the relative roles of expert judgment and the more mechanized aspect of the priority-setting approach. In this final report, the Committee on Sampling Strategies and the Committee on Toxicity Data Elements describe in detail the criteria they used to determine the status of testing quality and their collective judgment on the testing needs for substances in the select universe. The Committee on Priority Mechanisms presents a framework that could be used for decision-making to set priorities for research on substances with a potential for adverse public-health impact. The report summarizes the work of the first 2 years and presents the final results of the study. However, readers may wish to refer to Volumes 1 and 2 for greater detail of the design and development of the study. Although the work of all the committees was related, each group concentrated on the issues that were relevant to its specific charge. The report is therefore in two parts: the first part was the responsibility of and describes the work of the Committee on Sampling Strategies and the Committee on Toxicity Data Elements, and the second part, the work of the Committee on Priority Mechanisms. The committees had the opportunity to read and comment on each other's part of the report, but each part should be considered the independent product of group that prepared it. REFERENCES National Research Council, Gb~mmittee for the Working Conference on Principles of Protocols for Evaluating Chemicals in the Environment. 1975. Principles for Evaluating Chemicals in the Environment. Washington, D.C.: National Academy of Sciences. 454 pp. U.S. Environmental Protection Agency. 1982. Toxic Substances Control Act Chemical Substances Inventory. Cumulative Supplement II. Washington, D.C.: U.S. Government Printing Office. 950 pp. U.S. Public Health Service (DHHS). 1979. National Toxicology Program Annual Plan for FY 1980. Washington, D.C.: U.S. Government Printing Office. 117 pp. 22