Toxicity Testing Strategies to Determine Needs and Priorities (1984) / Chapter Skim
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4. DETAILED DESCRIPTION OF THE OPERATION OF AN ILLUSTRATIVE SYSTEM
4. DETAILED DESCRIPTION OF THE OPERATION OF AN ILLUSTRATIVE SYSTEM
Pages 237-284
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From page 237... ...
UNIVERSE The universe of chemicals to be considered is defined to include all chemicals to which there is potential human exposure. The universe defined by the Committee on Sampling Strategies has five categories of intended use: food chemicals, drug ingredients, pesticide chemicals, cosmetic ingredients, and general industrial chemicals (TSCA Inventory)
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From page 238... ...
STRUCTURE A multistage structure was chosen, so that the system could handle many thousands of chemicals and fit the current institutional structure of the NTP selection system. A multistage structure provides for using small amounts of data to assess large numbers of chemicals in the early stages and examining fewer chemicals in depth in later stages.
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From page 239... ...
Stage 1 is limited to data in machine-readable data bases, so that human intervention is minimized. The Committee on Priority Mechanisms chose to use the data bases and searching capability of the Chemical Information System (CIS)
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From page 240... ...
This quantity can be estimated by summing the products of the per capita annual intakes and the number of persons for all exposed groups with different intakes. Two surrogates of exposure -- class of intended use and production volume -- are used to define the possible classifications of a Stage 1 exposure data element (Table 3~; each classification consists of a pair of subelement classes -- use and production volume.
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From page 241... ...
TABLE 3 Illustrative Stage 1 Estimates of Probability of Exposure in Relation to Use and Production Probability That Exposure Is: UseaProduction, lb/yr Low Medium High F,D>104 0.40 0.40 0.20 P,C>105 0.40 0.40 0.20 G,O> 108 0.40 0.40 0.20 U> 106 0.40 0.40 0~20 G,O1o6_1o8 0.50 0.35 0.15 P,C104-105 0.50 0.35 0.15 U1o4_1o6 0.68 0.20 0.12 F,DU 0.68 0.20 0.12 F,D,U<104 0.73 0.18 0.09 P,C,G,O,UU 0.73 0.18 0.09 P,C< 104 0.75 0.17 0.08 G,O104-106 0.75 0.17 0.08 G,O<104 0.76 0.17 0.07 a F = food chemical. D = drug.
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From page 242... ...
b Estimated distribution of production volumes listed in CIS. c Estimated distribution of production volumes if all were known.
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From page 243... ...
They range from simple classifications of key types of substances to sophisticated statistical treatments that involve weighting of subgroups and from detailed treatments of specific health effects to general considerations of toxicity. These approaches have merit as research efforts, but none has evolved enough to provide a practical or accurate method for identifying potentially toxic chemicals.
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From page 244... ...
NTP POS * Many RTECS codes refer to NCI-positive or -negative results, rather than to quantitative results of tests conducted according to NTP-approved protocols.
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From page 245... ...
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From page 254... ...
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From page 255... ...
Depending on the results of this test, the chemical class, and the exposure data elements, a substance in question is either removed from current consideration or passed to Stage 2 with a recommendation for a specific minidossier on toxicity and exposure. The rules for the choice are summarized below.
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From page 256... ...
TABLE 6 Significance of Ranking of RTECS Codes for Carcinogenic Potential Code or Category NTP POS CAR MUT (MTDS) NEO ETA In RTECS, with no cancer code Not in RTECS NTP NEG 256 Meaning High probability positive Moderately high probability positive Moderate probability positive Moderate probability positive Moderately low probability positive Slight probability negative Moderate probability negative High probability negative
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From page 257... ...
or NEO 48. 040.3 11.7 CAR or NTP POS 55.033.0 12.0 TABLE 8 Estimated Proportions of Chemicals with RTECS Codes Related to Cancer Code or Category Not in RTECS In RTECS, with no cancer code MUT (MTDS I, not CAR CAR Proportion of Chemicals in Universe, 96 77 18 257
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From page 258... ...
EXPOSURE DATA ELEMENTS The data gathered in Stage 1 consist of: Annual production volume, if known. Use class.
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From page 259... ...
The types of toxic effects of concern with regard to a chemical will have some influence on the development of the exposure dossier. If the effect is likely to have a very low threshold or no threshold, as might be assumed for carcinogens, then both low exposures of large numbers of people and high exposures of smaller numbers of people may be of interest.
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From page 260... ...
1982. Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food.
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1981. Pesticide, metal, and other chemical residues in adult total diet samples {XII)
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From page 262... ...
1974. National Occupational Hazard Survey, Vol.
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From page 263... ...
. Computer data base available from National Library of Medicine, Specialized Information Services, Toxicology Information Program, Bethesda, Md.
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From page 264... ...
vet en o a o in v .5 .~ u, H in o Pi o ·~ W o o o U2 .~ U] o V Production volume Production locations Fraction used as intermediate Detailed uses Volume by use Measured concentrations Molecular weight Structural diagram Solubility in water Partition coefficient Melting point Boiling point Vapor presure Reactivity National Occupational Hazard Survey Regulatory status 2 1 2 2 2 2 2 2 2 l 2 3 2 2 3 3 2 2 2 1 1 2 1 1 1 1 1 1 1 1 1 1 1 3 1 1 2 2 2 2 3 2 3 2 2 2 1 1 2 1 1 2 2 2 2 3 2 2 2 3 2 2 2 2 2 2 2 3 3 2 2 3 3 2 2 2 2 1 1 1 2 3 2 2 _ 2 3 3 a 3 = highly desirable; 2 = desirable; 1 = useful; -- = irrelevant.
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From page 265... ...
that the true exposure is low, 17 the probability that it is medium, and 8 the probability that it is high; and so on. TABLE 11 Hypothetical Estimates of Probability Distributions of Degree of Exposure Generated in Stage 2 in Relation to Estimated Degrees of Concern and Confidence Estimated Degree of Exposurea Low Medium High aSee text for explanation.
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From page 266... ...
Degree of Confidence (Circle one) L - Evidence spotty and uncertain; poor understanding of exposure process M - Evidence moderately available, but still often missing, uncertain, or difficult to interpres H - Evidence missing only for a few of the less important kinds of information; implications of information generally clear; quantitative exposure estimates may be possible Explanation: explain reason for medium or high confidence Probability Distribution Indicate on the histogram below (for comparison with the "standard" distribution)
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From page 267... ...
TOXICITY DATA ELEMENTS Toxicity data elements are analogous to exposure data elements, except for the content of the information. The Stage 1 information is reviewed for relevance to Stage 2 data-gathering decisions.
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From page 268... ...
17. (Continues IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man, v.
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From page 269... ...
National Institute for Occupational Safety and Health. (More recent updates available as microfiche from NIOSH or as computer data base from National Library of Medicine, Bethesda, Md., or from Chemical Information Systems, Inc., Baltimore, Md.)
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From page 270... ...
For each health effect, the appropriate table of estimated probability distributions should be consulted. The hypothetical distributions for carcinogenicity shown in Table 14 are consistent with the assumption that 90% of the chemicals considered in Stage 2 are noncarcinogens, 7% are weak carcinogens, and 3% are strong carcinogens.
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From page 271... ...
TABLE 14 Hypothetical Estimates of Probability Distributions of Carcinogenic Potency as Generated in Stage 2, in Relation to Assigned Degree of Concern about Carcinogenicity and Degree of Confidence in Assignment Degree of Concern about Carcinogenicity Degree of Confidence in Estimate (Estimated Probability Distribution of True Potency) , ~ Low Medium High Low 95- 3- 2 96-3- 1 97-2- 1 Medium 80-15- 5 65-30- 5 50-45- 5 High 50-35-15 40-40-20 30-40-30 For illustrative purposes, the Committee on Priority Mechanisms has assumed that the standard budget for preparation and review of Stage 3 dossiers would be $1,000 for exposure and $1,000 for toxicity.
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From page 272... ...
TABLE 15 Hypothetical Estimates of Probability Distributions of Degree of Exposure Generated in Stage 3, in Relation to Assigned Degree of Confidence in Assignment Degree of Exposure Low Medium High Degree of Confidence in Estimate (Estimated Probability Distribution of True Exposure) , % Low Medium High 80-15-5 45-40-15 20-40-35 85-12-3 40-50-10 15-40-45 90-9-1 35-60-5 10-35-55 *
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From page 273... ...
As with exposure, the Stage 3 toxicity dossier strategy should be designed to yield the information of most use to the expert committee that will be reviewing the dossiers. Information on obscure details of biochemistry and on effects whose clinical significance has not been interpreted probably is not useful.
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From page 274... ...
High Low Med. High Stage 3 toxicity dossier 60 30 10 60 25 15 These distributions are consistent with an assumpton that 81% of the chemicals moving from Stage 2 to Stage 3 are noncarcinogens, 15% are weak carcinogens, and 4% are strong carcinogens.
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From page 275... ...
. This choice was made both because methods for carcinogenicity testing are better than methods for most other toxicity testing and because carcinogenicity testing consumes a larger fraction of NTP resources than does testing for any other toxic effect.
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From page 276... ...
$ Responses _ 1-4,6-13 Salmonella his-1,200 10 19 Escherichia cold WP2400 2 21 Bacillus subtilis rec-800 1 22-24 Escherichia cold rec-1,500 1 29 Degranulation 2,500 1 37 Yeast cell: Saccharomyces D7 · ~ cereals 1ae Mammalian cell: 1,400 1 40-42 Unscheduled DNA synthesis -- 5,200 3 human fibroblasts, HeLa ceils 43,45 Sister-chromatid exchange -- 3,000 1 CHO cells 44 Chromosomal aberrations -- 7,500 3 CHO cells, rat liver cells c Transformation -- CHO cells 1,400 1 c Transformation -- C3H-lOT 1/2 5,400 4 48 TK +/- L5178Y mouse 4,900 1 lymphoblasts 50,51 HGPRT-CHO cells, 6,500 4 V79 cells Whole Animal: 56-58 Sex-linked recessive lethal -- 10,000 1 Drosophila melanoqaster (injection) 59 Sister-chromatid exchange -- mouse 3,000 1 60-62 Micronucleus -- mouse 3,400 2 63 Sperm morphology -- mouse 11,400 1 Whole-animal two-species rodent bioassay a Modified from Lave et al., 1982.
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From page 277... ...
Table 18 shows the degree of agreement found by the International Collaborative Program, which had 12 laboratories apply the test to a series of 19 carcinogens and noncarcinogens (de Serres and Ashby, 1981~. The discrepancies are attributable at least in part to the use of differing procedures.
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From page 278... ...
TABLE 18 Correlation among Results of Salmonella/microsome Tests Performed by 12 Investigatorsa Investi- 1 2 3 4 6 7 8 9 10 11 12 13 1 1.00 0.81 0.53 0.47 0.47 0.34 1.00 0.62 0.81 0.47 0.34 0.22 1.00 0.65 0.62 0.62 0.53 0.81 0.81 1.00 0.65 0.53 0.15 1.00 0.65 0.65 0.34 0.53 0.53 0.65 0.42 0.34 0.19 4 1.00 0.33 0.53 0.47 0.47 0.62 0.65 0.26 0.15 6 1.00 0.53 0.47 0.47 0.62 0.35 0.26 0.03 7 1.00 0.34 0.34 0.53 0.46 0.30 0.05 8 1.00 0.62 0.81 0.47 0.34 0.22 9 1.00 0.81 0.47 0.34 0.07 10 11 12 13 a From Lave et al., 1982. 1.00 0.65 0.53 0.15 1.00 0.46 0.02 1.00 0.21 1.00 Entries are squared correlation coefficients computed from test results on 19 chemicals reported to International Collaborative Program by 12 investigators.
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From page 279... ...
cold WP/2/plate 34 0.65 20 E cold 343 18 0.72 Bacterial Repair, Phage Tnduction, Degranulation, and Nuclear Enlargement Assays 21 B
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From page 280... ...
cerevisiae JD1 32 0.72 39 S cerevisiae red 32 0.72 In Vitro Mammalian Test Systems 40 Unscheduled DNA synthesis, 18 0.39 human fibroblasts 41 Unscheduled DNA synthesis, 21 0.62 human fibroblasts 42 Unscheduled DNA synthesis, 38 0.68 human fibroblasts 43 Sister chromatic exchange, 19 0.53 CHO cells 44 Sister chromatic exchange, 18 0.67 CHO cells 45 Sister chromatic exchange, 33 O.S2 CHO cells 46 Cytogenetic analysis, 21 0.57 micronucleus test 47 Cytogenet~c analysis, 18 0.72 micronucleus test 48 Forward-mutation assay, 19 0.53 mouse lymphoma cells L518Y 280
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From page 281... ...
Data subset includes all 42 chemicals listed in Table 21 except presumptive noncarcinogens 2, 16, 20, 22, and 27, which had high frequencies of positive results in international study (de Serres and Ashby, 19817. Diphenylnitrosamine (22)
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From page 282... ...
Unscheduled DNA synthesis, HeLa cells {42) Cell transformation, BHK-21 cells (54)
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From page 283... ...
4-Dimethylaminoazobenzene-4-sulfonic acid, Na salt Benzo~alpyrene Pyrene _ , _ ,, ~ , ~, _, Methylazoxymethanol acetate Azoxybenzene DL-Ethionine Methionine Hydrazine sulfate Hexamethylphosphoramide (HMPA) Ethylenethiourea Diethylstilbestrol Safrole Cyclophosphamide Epichlorhydrin 3-Aminotriazole 4,4'-Methylenebis(2-chloroaniline)
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From page 284... ...
To set testing priorities among different types of toxic effects, two tasks must be accomplished: a catalog of human health effects must be established, and the various effects must be ranked according to relative severity. The relative importance of different types of health effects depends on their consequences to the affected persons and to society.
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