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APPENDIX A REVIEW OF SELECTED PRIORITY-SETTING SYSTEMS Initial examination of selected priority-setting schemes revealed that the multiplicity of approaches was more apparent than real. The appearance of dissimilarity arises more from differences in emphasis, or scope, than from differences in basic logic or strategy. Selected for detailed description here are schemes that were thought to make important contributions to the developing science or art of priority-setting. The choices in some cases were related to uniqueness in the treatment of exposure, of toxicity, or of the interaction between the two. A comprehensive list of schemes has been compiled (U.S. Environmental Protection Agency, 1980~. It has been recommended that federal agencies adopt priority-setting systems (Administrative Conference of the United States, 1982~. The Toxic Substances Control Act-Interagency Testing Committee (TSCA-TTC) scheme (Nisbet, 1979) is of particular interest, because it deals with a large part of the universe with which the NTP is concerned. Equally important, it has had to face the test of continued use over several years, and it has been systematically reviewed (Nisbet, 1979~. The schemes of Kornreich et al. (1979 ) and Ross and Lu (1980) are based on a systematic review of a substantial portion of the literature on priority-setting. The Food and Drug Administration (FDA) scheme (U.S. Department of Health and Human Services, 1982) is limited to one route of exposure, but otherwise is comprehensive in its approach. The scheme of Wilhelm (1981) is in large measure a response to what were perceived as deficiencies in the TSCA-ITC system. That of Astill et al. (1981) is designed to function with a sequential testing and feedback strategy. The ranking algorithm of Brown et al. (1980) is based on a simple mathematical model and is designed for multinational application. The proposed cyclic review procedure for FDA (U.S. Department of Health and Human Services, 1982) uses structure-activity considerations to establish initial "levels of concern," which are also found in the decision-tree approach of Cramer, Ford, and Hall (1978~. Gori's scheme (1977) provides a ranking index based on exposure that is complementary to a second scheme that uses structure-activity analysis for assessing possible carcinogenic activity (Dehn and Helmes, 1974~. NATIONAL TOX ICOLOGY PROGRAM The NTP chemical nomination and selection process, as described in the NTP Fiscal 1983 Annual Plan (U.S. Department of Health and Human Services, 1983), is summarized below. 301

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CHEMICAL NOMINATION Member agencies of NTP and other sources (other federal agencies, state agencies, the public, labor, and industry) submit to NTP nominations of chemicals for various types of toxicity testing. Each nomination is expected to include the name of the chemical, the particular toxicity testis) desired, the rationale for the nomination, and the available background data on production, use, exposure, environmental occurrence, and extent of toxicologic characterization. All nominations are considered, however, regardless of the depth of information submitted. Nominations are referred to the NTP chemical selection coordinator for review, to determine which chemicals have been tested, are already on test or scheduled for test, or have been previously considered and rejected for testing by NPT or its predecessors. This may involve preliminary searches of on-line data bases and reference books. The nominations and background information are then forwarded to the chemical-review staff at the National Center for Toxicological Research (NCTR), who examine the available literature, assess the relevant data, and prepare draft executive summaries of the information. (Executive summaries are not prepared for chemicals nominated solely for mutagenicity testing.) Included in each draft executive summary are chemical identification, surveillance index (production, use, occurrence, and analysis), information on toxic effects, and a statement of the source of and reason for nomination. EVALUATION OF NOMINATED CHEMICALS The chemical-review staff sends the draft executive summaries to the Chemical Evaluation Committee (CEC), which is composed of representatives of the Consumer Product Safety Commission (CPSC), Environmental Protection Agency (EPA), FDA, Occupational Safety and Health Administration (OSHA), National Cancer Institute (NCI), National Institute of Environmental Health Sciences (NIEHS), National Institute for Occupational Safety and Health (NIOSH), NCTR, and NTP. Members are requested to search data bases peculiar to their agencies for further information on the nominated chemicals (and structurally related compounds), to improve the evaluation process. The CEC evaluates the summaries and recommends the types of testing to be performed. Primary and secondary reviewers are also assigned to each chemical, after consideration of the nature of exposure, so that appropriate regulatory concerns will be addressed. At the CEC meetings, the primary reviewer for each chemical summarizes the data on that chemical and makes recommendations for testing. The secondary reviewer presents additional information, where available, and also discusses the testing of the compound. After discussion, the CEC votes on the recommended types of testing and assigns priorities for the testing. 302

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PUBLIC COMMENT A Federal Register notice is published, which lists the chemicals reviewed by the CEC and the recommended types of testing. The notice also solicits comments from interested parties and information on completed, current, and planned testing in the private sector. The list of chemicals is also published in the NTP Technical Bulletin, with a request for comments. These steps are taken to enable other individuals and groups to provide data useful to the chemical evaluation process. PEER REVIEW The revised executive summaries and public comments on the nominated chemicals are forwarded to the NTP Board of Scientific Counselors, which meets to evaluate the data and to make recommendations. CHEMICAL SELECTION The chemical-review staff then incorporates the board's ratings and pertinent public input into final executive summaries, which are submitted to the NTP Executive Committee. That committee decides whether to test, defer, or delete each of the nominated chemicals for the various types of testing. Its decisions are published in the NTP Technical Bulletin. The committee also recommends priorities for testing, test development, and test validation to NTP. After Executive Committee action, the NTP Steering Committee refers the chemicals to one or more of the three organizational units participating in NTP: NIEHS, NIOSH, and NCTR. A chemical manager is then assigned to evaluate the data developed during the NTP chemical evaluation process and other information retrieved from detailed searches of the published literature and from industry. The manager presents a proposal to the Toxicology Design Committee (TDC) either to perform appropriate testing or to delete the chemical from consideration for testing. The TDC, which consists of research scientists from NIEHS and NTP, assesses the proposal and either develops a final protocol for testing or recommends no further testing; the latter recommendation is based on technical difficulties in testing, budgetary reasons, or the existence of adequate outside testing. All chemicals selected through this process are then tested as time and resources permit. The results of testing are reviewed routinely, to determine whether further types of testing are appropriate, and candidates for additional testing are submitted to the NTP chemical nomination and selection process for evaluation and decision-making. 303

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SEQUENTIAL TESTING FOR CHEMICAL RISK ASSESSMENT (ASTILL ET AL. t 1981) This scoring system was developed by the Eastman Kodak Company to ~ the extent of toxicity testing required for production Four categories of information are used to derive a total the basis of which one of four testing levels is recommended. determine chemicals. score, on Available health and environmental data are compiled and rated independently, composite health-effects scores are computed, and the appropriate tests are selected and performed. Results of these tests are then used to revise the ratings. New scores are obtained, and the testing level is revised. This process is repeated until testing information is complete. Thus, the system is dynamic, in that it incorporates a feedback mechanism that allows for continuing review of the testing needs of a specific chemical. This system provides a basis for a multistage screening system. Four categories of information are used: magnitude of human exposure, magnitude of environmental exposure, effects on human health, and effects on the environment. The two magnitude categories have four components each, and the two effects categories have three components each. The four components considered in the rating of the magnitude of human exposure are production volume, number of people exposed, hours per year exposed, and number of population types exposed. Scores for the four components are added to yield a value for the magnitude of exposure. The assessment of health effects considers the LDso, acute effects (reversible and irreversible!, and chronic effects (reversible and irreversible). four categories is scored from 1 Each of the 14 components of the _ _ ~ _ ~ 3, with 3 indicating the most severe or hazardous score. The scores _ to The scores for the two human categories thealth effects and magnitude of human exposure) are summed, as are the scores for the two environmental categories. The resulting scores range from 7 to 21 and are associated with specific testing levels, as follows: Health (or Environmental) Score 7 - 9 10-13 ~ 4 -17 18-21 - Testing Level II III IV The level of testing becomes increasingly specific and sophisticated with increasing score. Level I testing is based on the use of physicochemical evaluation and health screening, as well as acute-toxicity 304

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studies. Although it is not specifically stated, with respect to human data, Level I might include surveillance of morbidity, mortality, and fertility patterns of exposed human populations. Level II testing consists of toxicity tests that are intermediate between acute tests and subahronic feeding studies, whereas Level III testing includes subacute exposure studies. Long-term (or chronic) health effects are evaluated through Level IV testing. The health-effects criteria are not very specific, but readily quantified in an objective and replicable manner. The health-effects criteria and ratings are as follows: LD50, mg/kg Immediate effects Prolonged effects Rating > 500 1 50-500 2 50 3 2 None Reversible Irreversible 3 None 1 Reversible 2 Irreversible 3 This system appears to be efficient, in that it uses a minimum of subjective input (expert opinion or judgment), although such judgment may be used in the review and rating of health effects. This system appears to be practical, in that it facilitates decision-making in an efficient and objective manner. Any compound can be evaluated; in the absence of available data, baseline information is compiled before any testing is done. The baseline information compiled consists of: Quantities manufactured and disposed of. Exposure estimates. Product function and application. Structure-activity correlation. . Literature search. Cancer hazard evaluation. Such baseline information may be sufficiently complete for hazard assessment, particularly if previously published toxicity studies are available. 305

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This scheme has been evaluated by the authors with a wide range of industrial chemicals, although the specifics of evaluation are not provided. A RANKING ALGORITHM FOR EEC WATER POllUTANTS (BROWN ET AL., 1980) The purpose of this scheme is to rank, for possible regulatory action, water pollutants as potential hazards to humans and to aquatic organisms. The scheme considers about 1,500 compounds used in countries of the European Economic Community and suspected of entering rivers. The algorithm is based on a simplified mathematical model relating production and use of a chemical to its occurrence in drinking water and in food of freshwater origin. Standard assumptions are made as to intake of fish and water; daily maximal and annual average intakes through ingestion are calculated. The amount of a chemical estimated to reach the water is calculated by multiplying production by the fraction that reaches the water; the fraction is estimated on the basis of manufacturing practices and the chemical's use. A typical dilution volume of the chemical is estimated from its half-life in water and from river-flow data. Estimated concentrations are used to calculate human exposure from consuming drinking water and freshwater fish. A concentration factor is used to calculate ingestion from consumption of f ish, assuming typical diets. The list of 1, 500 chemicals was reduced to about 1,400 when mercury and cadmium compounds were eliminated because they were already controlled by the EEC and persistent synthetic substances (mainly plastic materials) were eliminated because, although objectionable in water, they are not toxic. For the remaining 1,400 compounds, production and consumption data are obtained, and all those estimated to be produced at under 100 metric tons per year are eliminated. The remaining 426 compounds are then processed through a screening algorithm based on production, environmental half-life, and acute-toxicity factors. Some elements of toxicity testing for human health are applied in this scheme. The acute-mammalian-effect dose is represented by the lowest reported lethal oral dose for humans. If this information is not available, the lowest oral LD50 value for other mammalian species is used. If no oral LD50 value is available, the lowest LD50 value for the dermal or inhalation route is applied. If no LD50 values have been reported at all, the lowest lethal dose for the oral, dermal, or inhalation route is used. If no acute-lethality data are available, an estimate is devised on the basis of comparison with other compounds in the same chemical class. If a reasonable estimate cannot be made this way, the default entry "unknown" is used in the program. 306

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Chronic mammalian effects are also used when available. If the data file indicates that carcinogenicity, mutagenicity, or teratogenicity information is available, it is factored into the algorithm. If a chemical exhibits all three effects, only one is entered, preferably carcinogenicity. The chronic-mammalian-effect dose is the lowest dose that caused the reported effect. ESTIMATION OF TOXIC HAZARD--A DECISION TREE APPROACH (CRAMER ET AL., 1978) This scheme ranks food chemicals in three classes of concern for toxicity testing on the basis of chemical structure and oral-toxicity data. It is applied to structurally defined organic and organometallic compounds. Polymers and inorganic compounds are excluded. By answering a series of questions about chemical structure, the operator of the system follows a decision tree until the chemical considered falls into Class I (low concern), Class II (moderate concern), or Class III (serious concern). In each class, chemicals are ranked by comparison witn no-observed-effect doses. The data on no-effect doses were derived from literature values based on short-term or chronic studies. Class I substances are those whose structures and toxicity data, when combined with low human exposure, suggest low priority for investigation. Class III substances are those whose structures and toxicity data would not permit presumptions of safety and which thus require the highest priority for investigation. Class II substances are intermediate between Classes I and III. High exposures to substances in any class would increase the priority for investigation or testing. The number of chemicals found to be in Class II is not large. The tabulation of compounds in classes, with the exception of compounds with no-effect exposures above 500 mg/kg of body weight per day, is restricted to toxicity tests in which the next higher feeding exposure above the no-effect exposure is no more than 5 times the no-effect exposure. It was the general intent of the authors that the most toxic substances in Class I (low concern) should have a no-effect exposure in animal tests at or above SO mg/kg of body weight per day. This exposure, subjected to a safety factor of 100, corresponds to human exposure at approximately 25 mg/day. Use of this procedure requires knowledge of chemical structure and reasonably accurate estimates of human intake. The authors made it clear that chemical structure is to be used only as a guideline for testing decisions and that such use of structure-activity analysis is intended as a guide to the acquisition of data, not as a substitute for data. 307

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AN AUTOMATIC PROCEDURE FOR ASSESSING POSSIBLE C - CIN~ENIC ACTIVITY OF CHEMICALS PRIOR TO TESTING - ( DEHN AND HELMES, 1 9 7 4 ) This scheme uses structure-activity relationships to predict carcinogenesis. mere is no exposure element. The corresponding exposure element has been described by Gori (1977~. me procedure incorporates the collective knowledge of a panel of experts and attempts to automate the key features of that knowledge to select candidate compounds for carcinogenicity testing. The basis of the procedure is an activity tree constructed so that more specific details of chemical structure (as related to carcinogenicity) are applied at each decision point in the tree. This subdivision of structures continues until an end group (called a node) containing compounds of closely related chemical structure is identified. An estimate is then made of the probability that the chemicals in a node are carcinogenic and of the relative potency of each. Reflecting the expertise of the panel, construction of the tree concentrates on the following groups of chemicals: naturally occurring substances; nitroso, hydrazino, and ado compounds; polycyclic aromatic hydrocarbons; aromatic amines; and inorganic compounds. Although structure-activity relationships can be useful in setting priorities for carcinogenicity testing, the accuracy of analysis of such relationships in predicting carcinogenicity has not been verified. If the decision tree could be compared with test data generated since the scheme was completed, its utility could be better assessed. Exceptions within a given node (i.e., negative compounds within a carcinogenic chemical class) are extremely instructive and should serve as a cautionary guide when one attempts to apply analysis of structure-activity relationships in too broad a manner. TOXICOLOG ICAL PRI NCIPLES FOR THE SAFETY OF DIRECT FOOD ADDITIVES AND COLOR ADDITIVES USED IN FAD (U. S . DEPARTMENT OF HEALTH AND HORN SERVICES, 1982) This scheme was developed to establish priorities (and extent) for toxicity testing of direct food additives. Chemicals are divided into three categories of suspicion based on structure-activity considerations by following a short decision tree. A suspicion category is combined with exposure information to define a level of concern (I, II, or III). Once the level of concern is determined, tests may be required. Results of tests already done are placed in three categories (well done; not well enough done, but usable to some degree as a "core" test; and unusable). On the basis of this further information, additional testing may be required. 308

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Toxicity is not estimated quantitatively, so there is no quantitative assessment of uncertainty for it. There is judgmental consideration of uncertainty (specification error) in the evaluation of toxicity tests in the literature. There is a discussion of tests for each level of concern and for various combinations of concern and test information. RANKING OF ENVIRONMENTAL CONTAMINANTS FOR BIOASSAY PRIORITY (GORI, 1977) The purpose of this scheme is to estab~ ish, on the basis of exposure ~ a priority ranking for chemicals to be tested in a carcinogenicity bioassay. All chemicals in commerce are considered by the scheme. Total intake of a chemical by a given route is estimated for all members of a population group with similar exposures, and intake is then summed over population groups and sources of exposure. Intake by route is combined with probability of carcinogenicity and expected potency to produce a ranking index that, in theory, reflects the expected annual number of cancer cases. The scheme depends on the quantitative prediction of carcinogenic activity from structure-activity comparisons (see Dehn and Helmes, 1974~. This requires the identification of substructures, derived from known carcinogens, to which activity indexes can be attached--a process that requires expert opinion. A chemical of unknown carcinogenic potential is then inspected for such substructures, and an activity value is ascertained on the basis of their presence. Exposure assessment takes account of chemical production and use, but not disposal or discharges explicitly. Although it may not be clear from the text, the scheme estimates an uncertainty factor or confidence range for every variable. One notes and keeps track of the route of exposure and maintains an "audit trail" to the information in the data base. Deriving an exposure estimate for a chemical might require up to a person-day of effort, on the average. Considerable subjective input is required. PRIORITY-SETTING OF TOXIC SUBSTANCES FOR GUIDING MONITORING PROGRAMS (KORNREICH ET AL., 1979) This system, prepared for the Office of Technology Assessment by Clement Associates, is designed to compile a priority list for selecting potentially toxic chemicals for monitoring in food. 309

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The criteria used in developing 32 existing priority lists of toxic chemicals are examined, and criteria developed for ranking chemicals on the basis of their likelihood of endangering human health through contamination of the food supply. Three preliminary lists of possible food contaminants (organic substances, inorganic substances, and radionuclides) are compiled. Data on each chemical on these lists are assembled and used to assign scores to each chemical for various factors. Scores for the factors are combined, and the combined scores are used for ranking the chemicals on the three lists. Selection criteria include both exposure and toxicity factors. Weights are assigned to reflect the relative importance of each criterion and to allow the total score to be a measure of the overall propensity of a chemical to contaminate foods. The individual score for each factor is _ _ _ and the weighted scores are added. The total exposure score and the total biologic score are each adjusted to a maximum of 50 points and summed to allow for a possible total of 100 points. multiplied by the assigned weight, This system is designed to use quantitative information, with considerable reliance on expert opinion for the assigning of scores. For toxicity factors, a score of 0 is assigned for negative results and for absence of data. No cost estimates are given for this system, which was intended for one-time, rather than repeated, use. RANKING CHEMICALS FOR TESTING: A PRIORITY-SETTING EXERCISE UNDER THE TOXIC SUBSTANCES CONTROL ACT - (NISBET, 1979) This scoring system was developed to set priorities for testing chemicals under the authority of the Toxic Substances Control Act. The scheme is intended for application to chemicals in commerce that are not covered by other statutes. Drugs, cosmetics, food additives, and pesticides are excluded, unless they also have other uses. Also excluded are chemicals with an annual production volume of 1,000 lb or less. The system is intended for chemicals already in commerce at the time of compilation of the TSCA Inventory, which now defines "old" chemicals for the purposes of the statute. Because the Inventory did not exist when the first testing recommendations were required by the statute, the system was originally applied to a list of chemicals derived from lists of chemicals of high production volume or previously reported toxicity. Thus, the initial "universe" of chemicals was limited to chemicals already identified as of potential concern or nominated for inclusion by Interagency Testing Committee (ITC) members or other experts. Of 24 priority lists reviewed, 19 were used as a basis for the initial compilation of compounds. Noncommercial chemicals were then eliminated. 310

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Chemicals that were not on the U.S. ITC list were designated to be eliminated from the list, but were screened initially and were included if nominated by the expert panel. Later screening evaluated use and eliminated substances already regulated under some statute other than the TSCA. These initial screening steps resulted in a list of approximately 900 chemicals for scoring. ITC divided the scoring process into two discrete phases--potential exposure and biologic effects. Screening and scoring of biologic effects were postponed until potential exposure was evaluated. _ following factors were used in the first stage of exposure scoring: General population exposure--number of people exposed, frequency of exposure, exposure intensity, and penetrability. Quantity released into and persistence in the environment. Production volume. Occupational exposure. Some 330 chemicals were then selected from the list for biologic scoring. The TSCA requires that ITC give priority to compounds that are known or thought to cause or contribute to cancer, gene mutations, or birth defects. Seven factors were selected for scoring on biologic activity: Carcinogenicity. Mutagenicity. Teratogenicity. . Acute toxicity. Other toxic effects. Ecologic effects.* Bioaccumulation. Because ITC seeks to identify chemicals that require testing, rather than simply scoring compounds for known biologic activity, it was decided that the biologic scoring system should have two independent components--a measure of known biologic activity and a measure of the need for further testing. These components provided the basis for the biologic scoring system, as follows: *Note that this scheme and its variants (Nisbet, 1979; Ross and Lu, 1980) are designed to set priorities among chemicals for potential effects on the environment, as well as on human health. 311

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It is probable that further scrutiny would follow a classification of a chemical as a medium carcinogen; the assignment of 49 units for the cost of regulatory error may overstate the cost of this misclassificat- ion. With further scrutiny, there is some chance that the chemical in question would be correctly classified, with eventually a lower cost to society. The cost of this scrutiny in further testing might be $100,000 - 500,000 (less than if the chemical had been classified as high). Thus, if the chemical is truly nontoxic, but is misclassified as medium, the cost of the mistake might be a little more than 0.1 unit ($100,000), suggested in Table E-2. Thus, we modify the costs of a regulatory error when a chemical is classified as a medium carcinogen, as shown in Table E-3. Thus far, exposure has been assumed to be known and to be proportional to production. Exposure has been estimated to range over about 6 orders of magnitude. Furthermore, exposure often is fairly independent of production. Taking into account a range of 6 orders of magnitude in exposure and a range of 7 orders of magnitude in toxic potency, a hazard index of the product of toxicity and exposure would range over 13 orders of magnitude. At the same time, the link between regulatory action and hazard classification becomes more complicated and more diffuse. A more complicated example of misclassification occurs when a chemical is correctly classified as having medium toxicity, but erroneously classified as having high exposure when in fact it has low exposure. Is the chemical likely to be regulated on the basis of this misclassification? Hardly. Before regulation, its exposure is likely to be studied more carefully and (it is hoped) sufficiently well to correct the misclassification of exposure. Because the exposure category is 3 orders of magnitude wide, this discovery is fairly likely. Thus, the main cost of classifying exposure too highly is the extra cost (ultimately found to be unnecessary) of learning that the chemical belongs in a lower exposure category. Now consider a chemical, correctly classified as high in toxicity, but erroneously classified as having low exposure when it actually has high exposure. Would such a chemical receive no further attention, on the basis of its erroneous exposure classif ication? Once a chemical is classified as having high toxic potency, it would receive further attention, even if currently classified as having low exposure. With the further attention, the erroneous classification of exposure would have a good chance of being correctd. The main cost of this misclassification is not the cost of research on exposure, which is warranted in this case, but the cost arising from the chance that the error in exposure would not be corrected through investigation. Similar reasoning applies in the case of a chemical correctly classified as being medium in toxicity, but misclassified as to exposure. Too high a classification of exposure leads to unnecessary research on exposure, whereas too low a classif ication leads to a chance that research will not correct the error. Chemicals classif fed as having medium toxicity are assumed to receive further attention. 372

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TABLE E-3 Cost of Regulatory Error in Terms of Social Benefit per Average Chemical under Market Conditions, b (qm) Cost, biqm) Estimated t1 t2 t3 Toxicity 0 0.05 99 tl t 0~4 0 25 -2 t3 le O O e 95 0 373

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Further attention is more likely to be devoted to these chemicals than in the previous case, because less attention will probably be devoted to a chemical classified as having medium than high toxic potency. Taking these ideas into account, we might arrive at a table of regulatory error, R(t,t), as shown in Table E-4. The underlined numbers correspond to medium exposure and correspond to the entries of Table E-3, with some modification. The obvious thing to note in Table E-4 is the large range in the costs of false-negatives, which appear above and to the right of the diagonal whose values are zeroes. This range is due to the range of 13 orders of magnitude in hazard. The range of regulatory false-positives is about 7 orders of magnitude, which is less than the range in hazard because of the way false-positive and false-negative costs are defined, in comparison with benefit, bigm). However, the range is still enormous. Moreover, the cost of the largest false-negative (99,999) is enormous, compared with the cost of the largest false-positive (0.8), and probably much larger than most people would think realistic. What might lead to overstating these ranges? Consideration of the answers to this question leads to examination of two assumptions: exposure is proportional to production, and a classification of medium toxicity leads to some control. These assumptions may decrease the differences between false-negatives and false-positives. The "average" chemical is assumed to have market-determined production, qm, with a net benefit, balm). Consider what happens when qm also ranges over 6 orders of magnitude and, with it, net benefit. In the simplest case, exposure is proportional to production, and regulation follows directly from classification. The matrix of error costs is similar to Tables E-2 and E-3, where the variation in bum) and qm, from high to low production, scales everything up and down. An overestimate of exposure is also a mistake in overestimating balm), and these mistakes cancel out, as long as costs of mistakes are expressed in terms of b~qm). In another simple case, benefit, biqm), and production, qm, are fixed and exposure still varies over 6 orders of magnitude. This case is shown in Table E-4. A more realistic case has costs of regulatory error intermediate between the values for the extreme cases shown in Table E-4. The main reason for the high relative cost of the largest false-negative in Table E-2 (99) is the assumption that there should be some regulatory control for medium carcinogens. The control considered was a restriction of production to about 50% of that determined by the market. With the typical concavity of the benefit curve (which follows from typical supply-and-demand schedules) and the range of 3 orders of magnitude in toxic potency, this led to the asymmetric structure of Table E-2. 374

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TABLE E-4 Expected Cost of Regulatory Error, as Modif fed by Expected Reaction to Misclassif icationa True Classification Estimated Classif i- eltl e2t1 e3t1 elt2 e2t2 3 2 cation elt3 e2t3 e3t3 eltlO0 0. 05 0 0. OS 99 0.05 99 99, 999 e2t e3t1 e t0.70.7 1- 2 0 00. 05 0 0. 05 99 0. 05 99 99, 999 0 00 0 0.05 99 0.05 99 99, 999 0.7 0 0.40 40 0.5 40 40, 000 e2t2 0 ~ 7 0 7 0 7 0 ~ 20 10 0. 5 10 10, 000 e3t2 0 7 0~7 0.7 0.20.1 0 0.5 5 5,000 elt3 0.8 0.8 0.8 0.40.4 0.2 0 2 200 e t 0.8 0.8 0.S 0.4 0.4 0.2 0.1 0 100 2 3 e3t3 0.8 0.8 0.8 0.4 0.4 0.2 .0_1 0.1 0 - exposure class; t = toxicity class. Subscripts: 1 = low or non-; 2 = medium; 3 - high. Underlined numbers correspond to medium exposure and correspond to entries of Table E-3, with some modification. 375

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But there is another, probably more realistic, scenario in which chemicals classified as of medium toxicity may be subjected to some control. For the same production, more careful handling and use might halve exposure at a management cost that is low relative to the benefit. To have some control for medium toxicity, it is not necessary to posit c2(q) with a slope of about 10% of that of bigm) (see Figure E-4. Suppose the slope of c2(q) is only 1% of that of balm), instead of 10~. This assumption implies very little restriction in production, but it could imply large reductions in exposure per unit of production by restricting use and adopting stringent handling requirements. With this change, we can revise Table E-2 to Table E-5. Again, consider the cost of various cases of misclassification: ~ R(tlt3~. Because high toxicity is 1,000 times more than medium toxicity, the slope of c3(q) is only 10 times that of balm). Classifying a chemical as nontoxic when it has a high toxicity leads to a false-negative regulatory cost of lOb~qm) - bigm) = Album) (upper right corner of Table E-5 in terms of benefit from production set by market conditions). ~ R(tlt2~. If a chemical is classified as nontoxic when it is actually medium, it is possible to halve the exposure at a small cost (say, 0.1%), relative to b~qm). The cost of regulatory error is [b~q ~ = c2(qr) - O.Ollb~qm) - b~qm) - cfqm)~. Because c2(qr) is half c2(qm), the cost of this false-negative is 0.004 unit of balm). O R(t2t3~. If society acts directly on a chemical classified as medium when it is actually high, the benefit is bum) - c3(qr) - O.OOlbigm), or balm) - 5 - 0.001 balm). With correct information, the chemical would be banned, with zero benefit. So the cost of this false-negative is O - (-3.999) = 3.999. R(t2tl). If a chemical is classified as medium when it is actually nontoxic, the benef it is b (qm) - O . OOlb (qm); it could have been bm. The cost of this false-positive is 0.001. 0 R(t3t2~. If a chemical is classified as of high toxicity when it is actually medium, it is banned, with zero benefit, whereas we could have halved the exposure, at production qm, with a benefit of bum) - c2(qr) - 0.001 bum) = 1 - 0.005 - 0.001 = 0.994b~qm). The cost of this false-positive is 0.994biqm). R(t3tl). If a chemical is classified as highly toxic when it is actually nontoxic, it is banned, with zero benefit, whereas we could have had the benefit, berm), with no health cost. Therefore, the cost of this false-negative is b(gm) - 0 = balm). 376

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TABLE E-5 Cost of Regulatory Error Due to Misclassification of Toxicity in Terms of Social Benef it under Market Conditions, b (qm) Cost, bedim) t1 t2 t3 Estimated toxicity t1 00.004 9 t2 0.0010 3999 t3 10.994 0 377

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Table E-5 was Maculated on the assumption that exposure (unless separately controlled) is proportional to production and b~qm) is proportional to qm. Now we can take into account the idea that exposure and production are not always proportional. Suppose that for high-exposure chemicals the proportionality between exposure and production is twice that for medium-exposure chemicals, and suppose further that for medium-exposure chemicals the proportionality between exposure and production i s twice that for low-exposure chemicals. In other words, high-production chemicals tend to cost less per pound, and the assumption is that the market benefit per pound of production volume is half that for medium-production chemicals and one-fourth that for low- production chemicals. This assumption leads to Table E-6. The false- negative section (upper right portion) is revised, but the false-positive portion is unchanged. Most of the false-positive costs are associated with research to develop a chemical before it is regulated, and these costs are limited to 1 unit; the total benefit having been foregone, the chemical is erroneously banned. It is difficult to assess regulatory costs resulting from misclassification of a chemical with regard to exposure or toxicity. But, although the above analysis can be refined, some features of the structure of error costs are discernible. It seems reasonable for the costs in the upper right portion to be asymmetrically larger than those in the lower left portion--perhaps as much as 20 times as large. This indicates that the social cost of underregulating a chemical is much greater than that of overregulation. Exposure clarification is clearly important, but it does not play a role entirely symmetric with that of toxicity classification, as the simple concept, "hazard equals exposure times toxicity," might suggest. The reason for the asymmetry is that exposure tends to be proportional to the benefit of a chemical, whereas toxic potency is an inherent property of a chemical and does not vary with production, benefit, or exposure. An implication of this difference is that, for a given health effect, information on toxic potency is permanent or changes only as science improves, whereas correct information on exposure is more dynamic and changes as production responds to market changes and technologic advances. 378

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TABLE E-6 Regulatory Error Due to Misclassif ication of Exposure and Toxicity True Classif ication Estimated Classifi cation1 12tle3t1 elt2 e2t2 e3t2 elt3e2t3e3t3 eltl000 0,002 0.004 0.008 4.5918 e2tl000 0.002 0.004 0.008 4.5918 e3t1 0 0 0 0.0015 0.003 0.006 4.5 8 16 elt2 e2~2 0.7 0.7 0.7 0.7 0.7 0.7 0.2 0 0.01 0.04 4 8 00.012 4 8 3t2 0 7 0.7 0.7 0.20.101.8 3 6 elt3 e2t3 0.8 0.8 0.8 0.4 0.4 0.200.01 0.05 0.8 0.8 0.8 0.4 0.4 0.20.10 0.01 e3t3 0.8 0.8 0.8 0.4 0.4 0. 2 0.1 0.1 0 a e = exposure class; t = toxicity class. non-; 2 = moderate; 3 = high. 379 Subscripts: 1 = low or

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APPENDIX F DIFFERENCES BETWEEN PART 1 AND PART 2 The stated objectives of the Committee on Sampling Strategies and the Committee on Toxicity Data Elements differed from those of the Committee on Priority Mechanisms. Accordingly, the concepts and practices used by the committees to achieve the two objectives were different: The study included an examinination of the extent of toxicity testing of chemicals to which humans are exposed and methods of selecting chemicals for testing. The committees were thus assigned different aspects of the same problem: evaluating toxicity testing for chemicals of concern to NTP. The Committees on Toxicity Data Elements and Sampling Strategies devised a method to assess the current state of toxicity information used to determine health hazard and to estimate additional needs for toxicity testing. The Committee on Priority Mechanisms developed a design approach for priority-setting systems and applied that approach to a demonstration system for the select universe defined by the Committee on Toxicity Data Elements. The Committee on Toxicity Data Elements identified a list of test types that served as a basis for examining the adequacy of past toxicity testing and estimating current testing needs. The committees acknowledge that under a variety of conditions it would not be necessary for all such tests to be done. For example, although it is useful to have information on chronic toxicity for a specific substance, the presence of positive data from a well-conducted subahronic study might obviate the development of any further information on chronic exposure. A need would still remain to establish a mechanism for deciding which tests and which substances should be examined and which ones would be given a higher priority. The Committee on Priority Mechanisms examined this issue. The select universe defined by the Committee on Toxicity Data Elements was fixed once the sample was taken so that, after sample analysis, useful estimates for the universe could be made. The universe of substances that the Committee on Priority Mechanisms considered, however, by definition is constantly expanding as more substances with a potential for human exposure are identified. Working documents developed and used by the Committee on Toxicity Data Elements were designed to assess the status and quality of toxicity-testing information. The dossier concept adopted by the Committee on Priority Mechanisms is intended to provide an assessment of exposure and toxicity. The approach of the Committee on Sampling Strategies and the Committee on Toxicity Data Elements results in an estimation of toxicity-testing frequency, adequacy, and needs based on a retrospective analysis of existing information. The approach of the Committee on Priority Mechanisms results in a priority-setting framework that could be useful in determining which chemicals to test and which tests would yield the most informative data. 381

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me select universe of chemicals used in this study contained, by design, substances with a potential for human exposure. A sample was drawn from this select universe by the Committee on Sampling Strategies for use by the Committee on Toxicity Data Elements in its determination of toxicity-testing needs. Although the degree of potential human exposure was used in the determination of testing needs, it was not a determinant in selecting the sample of substances. In contrast, the Committee on Priority Mechanisms suggests procedures that use information on the degree of potential human exposure early in the chemical selection process. For each substance in its sample, the Committee on Toxicity Data Elements searched comprehensively for and nonselectively used all . . . . . . . . . . . . . . . ~ information that might assist It In aetermlnlog the testing neeas For that substance. The Committee on Priority Mechanisms was selective in applying information to each of the various stages of its priority- setting system. Analysis of information was approached differently in each activity. The purpose of the Committee on Toxicity Data Elements was to determine the type and quality of available data, rather than review existing assessments of toxicity. These determinations were based on the expert judgment of committee members. The Committee on Priority Mechanisms devised an approach to making assessments of public-health concern as part of a system to select chemicals for testing. This approach explicitly provides for estimating the degree of uncertainty in the assessment. Finally, the Committee on Toxicity Data Elements and the Committee on Sampling Strategies examined available information to determine whether there is enough to conduct at least partial health-hazard assessments. The Committee on Priority Mechanisms provides a framework for using the information to conduct such assessments. 382