Aromatic Amines An Assessment of the Biological and Environmental Effects (1981) / Chapter Skim
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Carcinogenic Potency and Risk Estimation
Carcinogenic Potency and Risk Estimation
Pages 86-101
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From page 86... ...
, but in such cases, animal data are usually deficient. CARC INOGENI C POTENCY Ire potency of a carcinogen depends on three factors: the dose of carcinogen required to induce tumors, the time to tumor induction, and the percentage of tumor response.
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From page 87... ...
The negative of the logarithm is used because potency is inversely related to the dose required to induce tumors, and the number 7 is used to bring all values to a readily comprehensible positive form. As calculated according to the above criteria, typical potencies of a number of carcinogens that induce liver or bladder tumors in rat or mouse are shown in Table 4-1.
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From page 88... ...
Table 4-1 The Potency of a Range of Carcinogens to Rat or Mouse Liver Following Continuous Feeding Chemica 1 Spec ies logic dESO Potency (mg/kg/week ) Aflatoxin B1 Rat 0.67 9.18 Michler's ketone Rat 4.88 4.62 Dimethylnitrosamine Rat 4 .90 4 .00 Carbon tetrachlor ide Ra t 5.27 3 .87 2-Aminoanthraqu ine Rat 6 .72 4 .44 Tr ichloroethylene Mouse 7.03 2.
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From page 89... ...
2 5 3 0 0 Food (g/day) 4 6 12 15 300-500 Drinking water (ml/day)
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From page 90... ...
Whatever tumor incidence-dose model is used, the potency values discussed here have a considerable advantage in that only they may be der ived without excessive data extrapolation. In many cases, where two or more doses of a carcinogen have been used, interpolation rather than extrapolation may be required.
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From page 91... ...
Table 4-3 Potency of 2-Naphthylamine in Different Spec ies Following Ore1 Administration Species loglo dE50 Potency tm9/kg/week )
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From page 92... ...
Table 4-4 to Different Species Route of Species Administration Tissue Potency Dog Oral Bladder 6.22 Mouse Gavage Liver 4.52 Rat Subcutaneous Intestine 4.37 92
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From page 93... ...
Lung 5.08 4 . 35 Breast 5.48 3.95 Zymbal ' s gland 5.18 4.25 a Each value of dEs0 is calculated as life correction x tumor yield correction x dose x 105 ~g/kg/week.
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From page 94... ...
, ensures that the highest feasible dose level is used, but that this level may lead to abnormal results due to the intervention of the agent's toxic properties in the carcinogenic process. However, substances with ~ very low level of toxicity may, if the maximum tolerated dose is used, be administered at levels that interfere physiologically with the host, for example, by inducing nutr itional imbalance, and similarly lead to difficulty in interpreting results.
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From page 95... ...
HIGH- TO LOW-DOSE EXTRAPOLATION It is now generally regarded as prudent to assume, when extrapolating data from high carcinogenic dose rates in animals to low~ose exposure in humans, that the mathematically simple linear one-hit model is appropriate even if the limited experimental evidence does not necessarily support this conclusion. The relevance of this model, which implies that a single carcinogenic itical receptor interaction is involved, has not been seriously questioned, although it may prove unsuitable in many cases.
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From page 96... ...
Species Route Site of Tumor Potency Dog Diet Liver, bladder ~ . 5 Rabbit Gavage Bladder, ureter 4.46 Hamster Diet Gall bladder 4.29 Rat Slonaker (M+F)
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From page 97... ...
The validity of these suggestions is suggested by the large scale [EDoi ~ exper iment conducted by the National Center for Toxicological Research (Staf fa and Mehlman, 1979) , in which low levels of N,2-fluorenylacetamide were fed to BALB/c mice.
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From page 98... ...
These data are for BALB/c mice, (Staf fa and Hehlman, 1979 ~ .
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From page 99... ...
Emus, one explanation of the dose-response relationships exhibited is that the carcinogen must act as both initiator and promoter in bladder carcinogenicity to give a tumor incidence-dose curve that is very dif ferently shaped than that for the liver, where only promotion occurs. These observations could mean that, although a linear dose-response curve may be appropr late in specif ic cases (possibly with pure initiators or with pure promoters acting on an appreciable spontaneous tumor yield)
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From page 100... ...
1979. Interspecies comparison of care inogen ic potency.
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From page 101... ...
1980. Risk Assessment (EDo~ Study ~ Inno~ra t ions in Cancer : Proceedings of a Symposium Sponsored by the National Center for Toxicological Research, U
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