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3 BRIEFLY FOLLOWING A CHEMICAL TH ROUGH AN I LLUSTRATIVE SYSTEM This chapter presents a simplified overview of the operation of an illustrative priority-setting system. It assumes that the system has been fully designed and implemented and is ready for operation. Although it uses the decision rules from an optimization model, it does not attempt to show how those rules were derived (see Appendix B). As currently envisioned, the principal operations of the system occur in three stages (Stages 1, 2, and 3), with successively increasing costs per chemical processed and decreasing number of chemicals needing scrutiny. This chapter also discusses the formation of the universe of chemicals of concern (Stage 0) and the actual testing of chemicals (Stage 4~. Figures 3 through 5 illustrate the steps in each stage. The reader is encouraged to refer to the figures while reading the text. The system can treat a chemical only if it is in the universe of chemicals of interest (or is nominated for Stage 3 by an agency or individual). The universe must be assembled as a list containing unique identifiers for each chemical, such as its number in the CAS Registry. me universe is made up of several lists, the largest and most accessible of which is the select universe compiled by the Committee on Sampling Strategies. Other sources are the environment (which could be characterized in the sampling programs of EPA); food ingredients, including natural constituents, contaminants, and conversion products (which might be available from lists maintained by FDA); and the growing group of chemicals on which premanufacturing notices have been filed with EPA. The additional lists must be acquired or constructed, and identifiers and associated data added; then these new lists must be merged with the existing lists by eliminating duplication and sorting the chemicals into the order in which they will be maintained on the master list. To illustrate the operation of the remaining stages, it is useful to have an example chemical, rather than dealing in the abstract with an unlimited range of possibilities. We have chosen bisphenol A as our example chemical, although at some places in our analysis we have speculated about its properties to create the best illustration. STAGE 1 Bisphenol A is identified by its CAS Registry number, 80057. This number links the priority-setting system with the various automated data bases on which it depends. In Stage 1, only a few fragments of information can feasibly be retrieved and processed. Among them are the following: 227

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STAGE DATA INPUTS DATA PROCESSING DECISIONS OUTPUTS CSS Select Universe Pre-Manufacturing Notices Environmental Occurrence Food I ngredients, etc. :-:~:-:-:-:-:-:~:-:~:~:~:-:~:~:~:-:~: - ~ ..................................... ~ Cunmjpvelrese ..... , .................. :~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~: .............. - ................................... .............. ~ ~ - .~................ ................. ~.~.~. - .~.~. - .~.~.~.. - - ~ ................ :--~-~------~-~-~-~----~-.-.-.-.-. ............. :~:~:~:~:. ~ ....~. - .~. - .-.~. - . - .~. - . - - - :-:-:-:~:-:-:-:-:-:-:-:-:-:-:-::::: ............. :.:~:~:~:. ::::::::::::::::::::::::::::::::::::: Computer Computer Bisphenol A t ................... :-:~:-:-:-:-:-:~:~:~:~:-:-:-:-:-:-: .. OC :~: . ~- . .................................... :-:-:-:-:~:-:-:-:-:-:-:-:-:-:-:-:~:~: .............. ~ .................. :-:-:-:-:~:-:-:~:-:-:-:-:-:~:-:-:-:-: :-:-:-:~:~:-:-:~:-:-:-:~ ................. .~...~............................ ,.................. ~- Eliminate Dupl icates Sort Universe of Chemicals FIGURE 3 Stage 1 of illustrative system. 228 TSCA Inventory CTDE Data Base RTECS, EMIC, ETIC SANSS _ _ _ _ _ _ _ _ _ _ _ _ _ _ _-_ Computer ~1 STAGE 1 Compile Data - Production Volume Use Class Toxic Effects Reported Toxic Class (SAR) Decision Rules Stage 1 Processor L M H :-:-: :-:-: :-:-: _ ._....~. Computer L M H _ ...-~ .-~ Exposure Toxicity CAS 80057 Bisphenol A Prod:>10 Use: Cosmetics - Effects: M UT, ETA, TE R SAR Class: Neuro, Skin, Pulmonarv Micro Dossier

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~r>~ `'.~ Exposure Needs and Sources Toxicity Needs and Sources ~ 1 Exposure Toxicity Staff Staff Data Bases Compilations Reviews l Literature Staff ll Exposure Toxicity Staff Staff FIGURE 4 Stage 2 of illustrative system. 229 STAGE 2 Uses Chem Interm Fungicide Nail Polish Fate Solid I nsol H 2O Sol var organics Acute LD50 4000+2000 mg/kg Sensitizer Tera 1500~500 mg/kg Marc Mutagen Bioassay Indef. Neuro Phenol (subst) ~ Mini Dossier 1 Confidence Le e L;. M H 7~ . ..~:~: , .~.~. l . :.:.:. l _ or :~:: _~ e __ EM H Exposu re Tox icity CA R l , 1, ~ a~ :. Decision: .. Rules :~:~:~:~:~:~:~:~:~:~:~:~:~: l ~ 111 ~1 Stage 2 Processor L M H Exposure Toxicity CAS 80057 - +, + Bisphenol A Uses Toxicity Fate | Mini Dossier

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Exposure Needs and Sources Toxicity Needs and Sources ~ 1 ~ ~ I lid ~::' Committee of Exposure Experts Exposure Toxicity Staff Staff i FIGURE 5 Stages l ~ Specialized Data Bases Computer Literature Search Secondary Literature Primary Literature Literature Staff Dossier CAS 80057 Bisphenol A Conf idence L M H Exposure Level L M H . . . . .... ,.. .... :-:-:- :-:-: 1~:-:~: :~.. . ~ ~ :::., am.- ..-.-. ...~.. I ...... ...... .:. A... :~:~: X :::. _ _ ~ IM H Committee of Toxicity Experts Toxicity R EPRO ~ NTP Scientific and Policy Review R EPRO Bisphenol A - _ \ / -(~ - - 11 Dossier 3 and 4 of illustrative system. 230 STAGE 3 , I STAGE 4 ~ 1 fertility Assessment by Continuous Breeding Evaluation of Results Fungicide, wheat & oats Indirect food additive (packaging) Anti-corrosive for Coatings Flame Retardants Dental Fillings 203,000 Workers Exposed Teratogenicity Inadequate Sperm Abnormalities No Convincing Evidence for Carcinogenicity [. Rules L ~ | ~ ~Hi 111 ' M :.:.:: : ::.: X H a ~ .. ~............................. Stage 3 Processor I L M Hi 1 L M H Exposure Toxicity 1 Reassessment of Testing Needs 1 Feedback to Data Base

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Information on the magnitude of production of the chemical from the TSCA Inventory US. Environmental Protection Agency, 1979, 1980), the International Trade Commission's synthetic organic chemicals data set, the Toxicity Data Bank (TDB), or any other accessible automated data banks. In our example, bisphenol A is found in the TDB, where it is shown as being produced at more than 1011 g/yr, or more than 2 x 108 lb/yr. Intended-use class in the Committee on Sampling Strategies data base for the select universe, or an equivalent use code from another data base. Bisphenol A is classified as a cosmetic ingredient in the committee's data base, although we shall see that it could well have been listed in another category. Chemical structure, if it has a defined structure and is in an accessible data base, such as the CAS connection tables or the Chemical Information System data base. Bisphenol A proves to have two phenol rings joined by a propyl group at the central carbon, as shown in the "microdossier" in Figure 3. Registry of Toxic Effects of Chemical Substances (RTECS) data on observed toxic effects. RTECS includes several listings for bisphenol A in the categories of mutagenic effects (MUT), equivocal tumorigenic effects (ETA), and teratogenic effects (TER) and has several entries for acute toxicity. Chemical fragments found in the structure by the Structure and Nomenclature Search System (SANSS) and the corresponding suspected effects from Table 5. Our current table would show bisphenol A only in the "phenol (substituted)" category and would show some suspicion of neurotoxicity, skin sensitization, and pulmonary irritation. When the data on a given chemical have been collected from the various automated data bases, the computer implements the decison rules derived from the optimization model as the "Stage 1 processor." These computer-generated rules (described in Appendix B) effectively compute a pair of probability distributions of exposure and toxicity, as indicated by the two small bar charts in Figure 3. Because the production of bisphenol A is greater than 108 lb/yr and it is used in cosmetics, the processor decides that exposure to it is more likely to be high than is exposure to a random chemical, but still shows that the most probable exposure is low. Similarly, the occurrence of so many RTECS entries and the suspicion of even more toxic effects from the structure-activity- relations (SAR) class suggest with more than usual confidence that the toxicity is likely to be at least moderate, so moderate toxicity is shown as having highest probability. On the basis of these distributions, the computer decides not only that bisphenol A should be passed to Stage 2, but that it deserves the 231

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higher level of investigation for both exposure and toxicity, as indicated on Figure 4 by "+, +," meaning that a moderate amount may be spent on gathering and assessing data both on exposure and on toxicity. In practice, the computer need not generate the explicit probability distributions in making the decision, because the rules used to select chemicals for further consideration in Stage 2 are always the same, given the same initial data ranges. However, the distributions can be useful inputs to Stage 2 and can be included in the microdossier that is the output of Stage 1. Figure 6 shows the selection rules when carcinogenicity is the only toxic effect considered. There would be other rules for suspicion of teratogenicity, neurotoxicity, and so on. The possibility of all such effects would be mentioned in the microdossier for consideration in Stage 2. STAGE 2 The microdossier (if available) is received by NTP staff and examined by two persons, one expert in toxicity assessment and one in exposure assessment. The exposure assessor may or may not deal with the toxicity part of the microdossier, and the toxicity assessor may or may not deal with the exposure part. Knowledge of the suspected toxic effects can help guide the exposure search, but can also bias it. me first task is to check the status of the chemical in the testing program to ensure that the effects of concern are not currently under examination and not yet reported in RTECS. Let us assume that no tests of bisphenol A are in progress. Each expert scans the microdossier and develops a strategy for searching the appropriate data bases, compilations, and reviews, noting what sorts of information are probably most important to retrieve. In the case of bisphenol A, the exposure assessor calls for a routine printout from the Toxicity Data Bank and checks the Cosmetic Ingredient Dictionary (Estrin et al., 1982), the Merck Index (Windholz et al., 1976), and the Directory of Chemical Producers for further information on production, uses, and physical and chemical properties. This strategy is carried out by the literature staff of NTP. In our example, they find that at least 90% of the bisphenol A produced is used as an intermediate in the production of other chemicals, especially resins. In cosmetics, it turns out to be a component of nail polish, but there are other dispersive uses, e.g., as a fungicide. The melting point implies that bisphenol A is ordinarily a solid; and it is relatively insoluble in water, but soluble in many other solvents. The exposure assessor integrates this information subjectively and decides that the best guess is still moderate exposure; but confidence in that guess is still low, because the amounts used in nail polish and fungicides are so uncertain. Meanwhile, the toxicity assessor requests a full printout of the RTECS listings and examines the TDB printout. The literature staff 232

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STAGE 1: EXPOSURE DATA ELEMENT . Intended Use and Production Food chemical, unclassified or pesticide with unknown production STAGE 1: TOXICITY DATA ELEMENTS Part 4 STAGES 2-4 Branch 2 Go to Stage 1 Toxicity Data Elements Part - 4 Go To Stages 2-4 via Branch Member of a chemical group associated with cancer with "low suspicion . not in in RTECS, no mention of MUT or CAR 2 in RTECS, mention of MUT, but not CAR 6 in RTECS, mention of ~ Stage 2: Perform search for exposure data and limited search for toxicity data Assessments Based on Data Gathered in Stage 2 Stage 3: Exposure Toxicity Data Gathering Assessments Based on Data Gathered in Stage 3 Stage 4: Recommended Testinga Medium Medium or high Dossier aST = Short-term test; LT = Long-term test High toxicity and high exposure Otherwise FIGURE 6 Decision rules used in processing example chemical bisphenol A. 233 LT ST

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supplies copies of the data found in such handbooks as Dangerous Properties of Industrial Materials by Sax (1979) and the Merck Index, which shed little additional light on the toxicity picture. However, it becomes evident that bisphenol A is not very acutely toxic (LD50, around 4,000 mg/kg) and that it has shown some teratogenicity (also at high doses) and has been judged indefinite in a cancer bioassay. The cancer hazard is still judged as moderate, but with only moderate confidence, and the reproductive hazards are considered high, also with only moderate confidence. No support arises for any of the SAR suspicions, and they are eliminated as concerns. Both assessors have filled out the matrix of concern, as shown in Figure 4 immediately under the minidossier. Using the decision rules (summarized in Figure 6 for the carcinogenicity datal, they find that a dossier covering both exposure and toxicity searching is justified in Stage 3. Hey can also generate the exposure and toxicity probability distributions (Figure 4, "Stage 2 Processor") either automatically from the matrix assignment or on the basis of their own judgment. These estimated probability distributions are passed to Stage 3 with the augmented minidossier containing all information gathered to date. STAGE 3 Exposure and toxicity experts (not necessarily the same ones) now examine the minidossier and determine the Stage 3 search strategy (Figure 5~. Clearly, it is desirable to acquire more information about consumer exposures to bisphenol A in both cosmetics and fungicides and about occupational exposures to bisphenol A in its large use as an intermediate. Searches of the Chemical Economics Handbook (SRI International), the NIOSH National Occupational Hazard Survey (U.S. Department of Health, Education, and Welfare, 1974, 1977, 1978), EPA contractor reports, and so on are ordered. The literature staff finds additional uses of bisphenol A as an indirect food additive (because of residue in plastic food containers), as a fire retardant, as an anticorrosive in coatings, in dental fillings, and in various other minor applications. The fungicidal application turns out to be for use on wheat and oats. In the manufacture of bisphenol A and its derivatives, over 200,000 workers may be exposed. Considerable effort goes into computer-assisted literature searches of the secondary and primary literature for citations on the toxicity of bisphenol A. The teratology experiments are found to be rated as inadequate, but there has been a finding of sperm abnormalities in rats after intraperitoneal injection. The "indefinite" cancer bioassay is now assessed as showing "no convincing evidence of carcinogenicity." Once the toxicity and exposure parts of the dossier are compiled, they are submitted to expert committees on toxicity and exposure, respectively. Again, there are pro's and con's as to whether the committees should see both dossiers or only the parts pertinent to their 234

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own expertise. The dossiers are studied by the committee members both individually and collectively, but the full toxicity committee is asked to evaluate the evidence and reach a consensus on the toxicity for each human effect, and the full exposure committee likewise for exposure. Each committee is also asked to state its members' confidence in the rating. If there is much disagreement over the rating, there is good reason to lower the stated degree of confidence. The ratings are reported on a matrix as in Stage 2, or the committee may prefer to generate a probability distribution directly, instead of using the standard one generated by the Stage 3 processor. The important difference from current procedure, however, is that the committees are not asked to make testing recommendations, but only to assess the available data in their field of expertise. Whether the committees generate their own probability distributions or simply use matrix rankings, the Stage 3 processor uses the previously developed decison rules to decide what tests should be recommended to NTP. In the case of bisphenol A, the committee on exposure has rated the exposure as still only moderate, but now with high confidence. The toxicity committee now believes that there is comparatively little evidence of carcinogenicity, but is highly confident of moderate teratogenicity. It now believes that other reproductive effects may be of high concern, but has only moderate confidence in that judgment. The carcinogenicity rule, reproduced in Figure 6, suggests that no repeat of the bioassay is advisable now, but that an expansion of the battery of short-term tests for mutagenic potential may be worth while. We assume that the rule for reproductive effects would call for a test, as shown in the box on the final version of the dossier in Figure 5. Before this recommendation is accepted, however, the dossier and recommendations are reviewed by the NTP panels for scientific merit--especially to see whether the recommendation is unrealistic for some reason not perceived in the formal process--and for such policy considerations as public concerns, costs and feasibility of controls, or regulatory responsibility. Recommendations may be overridden on the basis of results of either type of review. Assuming that the NTP panels accept the processor's recommendations, the dossier and test directions are sent on to the testing program in Stage 4. STAGE 4 Finally, the substance goes into the specific type of reproductive study warranted by the particular combination of concerns about exposure and toxicity and the degree of confidence in each. In the case of bisphenol A, fertility assessment by continuous breeding of rodents is the preferred test. When the test is complete, its results are evaluated with respect to public policy and their relevance to further refinement of the selection process (Figure 5, "Feedback to Data Based. The test 235

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results can also be fed back into the specific data base on bisphenol A to determine whether further tests are justified. Although it is not shown in Figure 5, the argument for a new bioassay would be much more compelling if the short-term mutagenicity assays had proved consistently positive. 236