Toxicity Testing Strategies to Determine Needs and Priorities (1984) / Chapter Skim
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APPENDIXES
APPENDIXES
Pages 301-382
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From page 301... ...
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)
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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)
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From page 303... ...
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)
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From page 304... ...
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.
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From page 305... ...
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)
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From page 306... ...
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.
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From page 307... ...
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.
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From page 308... ...
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.
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From page 309... ...
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.
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From page 310... ...
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.
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From page 311... ...
· 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.
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From page 312... ...
of TSCA. The scheme consists of several screening processes grouped into five components: biologic toxicity I, biologic toxicity II, environmental fate, production and release, and human exposure.
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From page 313... ...
This scoring process is strictly qualitative and does not deal with the potency of a carcinogen. It appears that absence of data is considered to imply low priority; "no data but suspect" is given a score of 3; "no data but not considered suspect" is given a score equal to that for "no data available, no estimate made." The mutagenicity scoring procedure considers the potential for genetic impairment at both the somatic cell and germinal cell levels.
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From page 314... ...
SELECTING PRIORITIES FROM LARGE SETS OF ALTERNATIVES: THE CASE OF TOXIC SUBSTANCES REGULATION (WILHELM, 1981) Although it is not explicitly stated, this scheme seems designed to rank the TSCA Inventory list of chemicals for further toxicity testing.
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From page 315... ...
Scoring by the number of lines in the RTECS file ignores both the nature and the quality of the published data. In defense of this approach, it is hard to imagine schemes capable of processing the 55,000 TSCA Inventory chemicals without severe simplifications.
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From page 316... ...
1979. Ranking chemicals for testing: A prioritysetting exercise under the Toxic Substances Control Act, pp.
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1981. Selecting Priorities from Large Sets of Alternatives: me Case of Toxic Substances Regulation.
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, there would be nine categories in all (low exposure, low toxicity; low exposure, medium toxicity; and so on)
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From page 320... ...
The collection of possible paths is denoted ~ = Eni~ / r1 ~ ~r4 Jo \ \ 1rj FIGURE B-1 Decision tree with example path hi, consisting of tlrl, t2r2, t3r3' and t4r4 The performance of a test tk may be described by the conditional probabilities P(rki|sj) , where i = 1, .
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From page 321... ...
The magnitude of the misclassification cost depends on how much the assigned category differs from the actual category. For example, if a highly toxic chemical with high exposure is erroneously classified as having low exposure and low toxicity, the associated misclassification cost is greater than it would have been if the chemical had been classified as having low exposure and medium toxicity.
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From page 322... ...
Rather than a single testing cost, the priority-setting scheme has a vector of expected costs, E:, where j = 1, .
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The foregoing shows how a priority-setting process acting on an initial collection of chemicals described by a probability distribution P(sj) incurs a misclassification cost ACME and a testing cost TCT~.
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From page 324... ...
, in that both embody the value-of-information concept and the minimization of expected costs. Four principal differences between Weinstein's approach and the approach used by the Committee on Priority Mechanisms should be pointed out.
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From page 325... ...
Three data elements are used in Stage 1 -- one for exposure and two for toxicity. The exposure data element is based on intended use and production.
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Chemical groups associated with cancer are divided into groups of low, medium, and high suspicion. The second toxicity data element used in Stage 1 is listing in RTECS.
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From page 327... ...
Note that Branch 2 calls for the larger search for exposure data and the smaller search for toxicity data in Stage 2. Branch 2 provides for dossiers, except when the results of the search for toxicity data suggest low toxicity and the results of the search for exposure data suggest low or medium exposure.
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From page 328... ...
That entry leads us to Stage 1 toxicity data element Part 4, where we seek a member of a chemical group with a low suspicion of cancer (the fourth entry)
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From page 329... ...
, other, or unclassified with production less than 104 lb/yr Cosmetic with production less than 104 lb/yr; or general commerce, other, or unclassified with production between 104 and 106 lb/yr Go to Stage 1 Toxicity Data Elements Part 1 2 Drug, food chemical, pesticide or unknown with production less than 104 lb/yr; or cosmetic, general commerce, other, or unclassified with unknown production 3 Food chemical, drug, or pesticide with unknown production General commerce, other, or unclassified with production between 106 and 108 lb/yr; or cosmetic with production between 104 and 105 lb/yr Drug, food chemical, or pesticide with production equal to or greater than 104 lb/yr; cosmetic with production greater than 105 lb/yr; or general commerce or other with production greater than 108 lb/yr 329 4 5 6
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STAGE 1: TOXTCTTY DATA ELEMENTS Part 1 Go to Stages 2-4 via Branch Not a member of a chemical group (Table 5) not in RTECS e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e 1 1 in RTECS, no mention of MUT in RTECS, mention of MUT, but not CARe e ~ ~ ~ ~ ~ e in RTECS.
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Part 2 Go to Stages 2-4 via Branch Not a member of a chemical group (Table 5)
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From page 332... ...
Part 3 Go to Stages 2-4 via Branch Not a member of a chemical group (Table 5)
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Part 4 Go to Stages 2-4 via Branch Not a member of a chemica' group (Table 5)
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Part 5 Go to Stages 2-4 via Branch Not a member of a chemical group (Table 5)
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Part 6 Go to Stages 2-4 via Branch Not a member of a chemical group (Table 5)
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From page 336... ...
Branch 2 Do not consider Stage 2: Perform search for exposure data and limited search for toxicity data. Assessments Based on Data Gathered in Stare 2 Exposure Toxicity Assessments Based Stage 4: Stage 3: on Data Gathered Recommended Data Gathering in Stage 3 Testinga Low Low No dossier None ST Low Medium Dossier None ST Low High Dossier High toxicity LT Otherwise ST Medium Low No dossier None ST Medium Medium Dossier High toxicity LT or high and high exposure Otherwise ST High Low, Dossier High exposure LT medium, or high a ST = short-term test; LT = long-term test.
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From page 337... ...
Low Low Low Low No dossier Medium Dossier High Medium Low Doss ier Dossier Medium Medium Dossier Medium High Assessments Based on Data Gathered in Stage 3 High toxicity and high exposure Otherwise High toxicity Otherwise Stage 4: Recommended Testinga LT ST LT ST . High toxicity; or LT high exposure and medium toxicity Otherwise ST High toxicity; or LT high exposure and medium toxicity Otherwise ST High exposure or LT high toxicity Otherwise .
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338 ST Low exposure and low toxicity Anything but low exposure and low toxicity ST LT
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From page 339... ...
Branch 4 Stage 2: Perform search for exposure data and limited search for toxicity data. Assessments Based on Data Gathered in Assessments Based Stage 4: Stage 2 Stage 3: on Data Gathered Recommended Exposure Toxicity Data Gathering in Stage 3 Testinqa Low Low Dossier High toxicity and LT low or medium exposure Medium exposure and low or medium toxicity ST Low exposure and None low or medium toxicity Low Medium Dossier High toxicity LT Medium toxicity; ST or low toxicity and medium exposure Low toxicity None and low exposu re Low High Dossier High toxicity LT Otherwise ST Medium Low Glossier Medium Medium Dossier or high High toxicity Medium toxicity Low toxicity and low exposure LT ST None High toxicity or LT high exposure Otherwise ST High Low, Dossier High toxicity LT medium, or high exposure or high Otherwise ST aST = short-term test; LT = long-term test.
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From page 340... ...
Branch 5 Stage 2: Perform search for exposure data and limited search for toxicity data Assessments Based on Data Gathered in Stage 2 Exposure Toxicity Low Low Low Low Medium Dossier High Medium Low Stage 3: Data Gathering Dossier Dossier Dossier Medium Medium Dossier Medium High Assessments Based on Data Gathered in Stage 3 High toxicity and low or medium exposure Stage 4: Recommended Testinga LT Medium toxicity ST and low or medium exposure Low exposure and None low toxicity High toxicity and LT low or medium exposure Otherwise High toxicity; or medium toxicity and medium or high exposure Otherwise ST LT ST High toxicity and LT low or high exposure Otherwise High toxicity and low or high exposure Otherwise Dossier ST LT ST High exposure or LT high toxicity; or medium exposure and medium toxicity Otherwise 340 ST
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From page 341... ...
Branch 5 (continued) High Low Dossier High or medium LT exposure or high toxicity Otherwise ST High Medium Dossier High exposure or LT high toxicity; or medium toxicity and low or medium exposure Otherwise ST High High Dossier High or medium LT toxicity Otherwise ST a ST = short-term test; LT = long-term test.
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From page 342... ...
Branch 6 Stage 2: Perform search for exposure data and limited search for toxicity Data. Assessments Based on Data Gathered in Assessments Based Stage 4: Stage 2 Stage 3: on Data Gathered Recommended Exposure Toxicity Data Gathering in Stage 3 Testinga Low Low, Dossier High toxicity LT medium, or high Otherwise ST Medium Low, Dossier High exposure; or LT medium, high toxicity and or high low exposure Otherwise ST High Low Dossier High toxicity and LT medium or high exposure; or low toxicity and high exposure Otherwise ST High Medium Dossier High toxicity; or LT high exposure and low toxicity Otherwise ST High High Dossier High toxicity and LT medium or high exposure; or medium toxicity and medium exposure Otherwise a ST = short-term test; LT = long-term test.
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From page 343... ...
Dossler Dossier Medium Medium Dossier Medium High High Dossier High, medium, or low Dossier a ST = short-term test; LT = long-term test. 343 Assessments Based on Data Gathered in Stage 3 High toxicity Otherwise Stage 4: Recommended Testinga LT ST High toxicity or LT high exposure Otherwise ST High toxicity or LT high exposure Otherwise ST High exposure; or LT high toxicity and low exposure Otherwise ST High toxicity or LT high exposure Otherwise ST Low or high exposure LT and high toxicity; or medium exposure and medium or high toxicity Medium exposure and low toxicity ST Low or high exposure LT and high toxicity; or medium exposure and medium or high toxicity Medium exposure and ST low toxicity
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From page 344... ...
Branch 8 Stage 2: Perform search for exposure data and limited search for toxicity Oata. Assessments Based on Data Gathered in Assessments Based Stage 4: Stare 2 Stage 3: on Data Gathered Recommended Exposure Toxicity Data Gathering in Stage 3 Testinga Low Low Dossier High exposure; or LT high toxicity and low exposure Otherwise Low or Medium Dossier medium ST High exposure or LT high toxicity Otherwise ST Low High Dossier High toxicity; or LT high exposure; or medium toxicity and medium exposure Otherwise Medium Low ST Dossier High exposure; or medium exposure and high toxicity Otherwise LT ST Medium High Dossier Medium or high LT toxicity or high exposure Otherwise ST High Low Dossier Medium or high LT toxicity or high exposure Otherwise ST High Medium Dossier Medium or high LT toxicity; or low toxicity and medium or high exposure Low toxicity and low exposure High High Dossier All assessments LT a ST = short-term test; LT = long-term test.
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From page 345... ...
Branch 9 Stage 2: Perform search for exposure data and limited search for toxicity data. Assessments Based on Data Gathered in Assessments Based Stage 4: Stage 2 Stage 3: on Data Gathered Recommended Exposure Toxicity Data Gathering in Stage 3 Testinga Low Low Dossier High exposure; or LT high toxicity and medium exposure Otherwise ST Low Medium Dossier High toxicity or LT high exposure; or medium toxicity and medium exposure Otherwise ST Low High Dossier High or medium LT toxicity; or high exposure Low toxicity and ST medium or low exposure Medium Low Dossier High toxicity or LT high exposure Otherwise ST Medium Medium Dossier High or medium LT exposure or high toxicity Otherwise ST Medium High Dossier Low toxicity and ST low exposure Otherwise 345 LT
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From page 346... ...
1979. Decision making for toxic substances control: Cost-effective information for the control of environmental carcinogens.
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From page 347... ...
In its first report, the Committee on Priority Mechanisms recommended that the priority-setting process to be developed for NTP be explicit about the use of uncertainty and judgment, provide a rationale and means for taking them into account, and address their use in a deliberate manner that is documented and articulated, but also preserve a record for later review and evaluation (National Research Council, 19811. PROBABILITY JUDGMENTS Existing priority-setting systems fail to offer a persuasive treatment of the uncertainty with which the health hazards of chemicals are evaluated (National Research Council, 1981~.
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From page 348... ...
Although the identification of chemicals and tests depends on probability judgments, as well as cost estimates, the values used are open to public scrutiny, and objective analysis of the process is facilitated. The use of a mathematical model enables investigators to analyze the sensitivity of the data elements used and of the values attached to them.
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From page 349... ...
probability assessment procedures to these experts simply, effectively, and unintrusively. USE OF PROBABILITIES IN DECISION-MAKING The studies of Ramsay, van Neumann and Morgenstern, Wald, and others have provoked rapid development in the theory of decision-making over the last 30 years (see reviews by Howard, 1975; Mishan, 1976~.
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From page 350... ...
For example, when expressing incomplete knowledge about a continuous quantity, one may assess a cumulative probability distribution (e.g., there is a 0.05 chance that the rate is less than 0.003, a 0.10 chance that it is less than 0.005, etc.) or use the fractile method described by Raiffa (1968)
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From page 351... ...
responding with their true beliefs (Murphy, 1973~. Evidence suggests that the procedures for organizing one's knowledge in a manner that will produce the best appraisal of what is known are the same procedures that produce the best probability assessment (i.e., a careful review of all that Is known with an emphasis on evidence that seems to contradict the dominant opinion)
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From page 352... ...
In setting priorities for testing chemicals for health effects, the utility of estimating explicit probabilities is likely to be substantial. They will lead to better testing decisions, and they will facilitate evaluation of the scheme's efficacy.
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From page 353... ...
REFERENCES Christensen-Szalanski, J., P Diehr, and R
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From page 354... ...
12:595-600. National Research Council, Steering Committee on Identification of Toxic and Potentially Toxic Chemicals for Consideration by the National Toxicology Program.
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From page 355... ...
~a: A, I: _ of_._ _ ~ ~ _ , _ ~ ~ _ _ =~'v" ~'v~vy'~ ~. This would make it possible to predict a specific kind of toxicity simply from a chemical structure of a substance and a few physical properties.
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From page 356... ...
are based on Equations 1 and 2, which assume additivity -- the biologic activity of a 356
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From page 357... ...
The relationship between log B (biologic activity) and log P is roughly parabolic, if a wide enough range of log P is considered.
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From page 358... ...
The only change in recent times is to view them as being more flexible. me problems encountered when using chemical structures to predict biologic activity are similar to those found when translating a language by computer.
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From page 359... ...
Hodes indicated that this is better than chance, but not by much. CHEMICAL CLASSES RELATED TO HEALTH EFFECTS IN HUES Given the paucity of toxicity data on most chemicals in commerce, it is impossible to formulate general correlation equations that relate chemical structure to biologic activity.
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From page 360... ...
Safe Handling of Chemical Carcinogens, Mutagens, Teratogens and Highly Toxic Substances.
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From page 361... ...
A method for correlation of biological activity and chemical structure.
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From page 363... ...
The net social benefit (excluding health costs) is defined as the area between the supply and demand curves up to the point of production.
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From page 364... ...
By By 11 o LL Am o o qr PRODUCTION (q) qm FIGURE E-1 Variation in supply and demand caused by changes in production, q.
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From page 365... ...
o An z b(q ) / PRODUCTION qm FIGURE E-2 Variation in net social benefit, b(q)
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From page 366... ...
UP w X - b(q) z qr PRODUCTION qm FIGURE E-3 Health costs , c (q)
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From page 367... ...
If society acts on this erroneous information, it does not regulate the chemical. Production then is set by the market at qm, with a net benefit (excluding health costs)
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From page 368... ...
. First, consider the case of a chemical classified as of medium potency when it is actually nontoxic (tl)
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From page 369... ...
b(qm) am qm FIGURE E-4 Health costs c(q)
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From page 370... ...
Testing costs could run to about $1 million, which is not far from the 1 unit already assigned to the cost of regulatory error if toxicity of a chemical is estimated as strong when it is actually a low-potency carcinogen or a noncarcinogen. It is estimated that the comprehensive testing cost for a chemical classified as strong is not much different from bm.
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From page 371... ...
- c2(qr) 0 TABLE E-2 Cost of Regulatory Error in Terms of Social Benefit per Average Chemical under Market Conditions, balm)
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From page 372... ...
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.
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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)
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From page 374... ...
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.
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From page 375... ...
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.
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From page 376... ...
. 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)
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From page 377... ...
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)
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From page 378... ...
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.
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From page 379... ...
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.
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From page 381... ...
· 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.
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From page 382... ...
· 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.
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