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Issues in Risk Assessment (1993)


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Suggested Citation:"8. ACKNOWLEDGEMENTS." National Research Council. 1993. Issues in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2078.

species concordance depends on carcinogenic potency, and that for weak carcinogens, the maximum possible species concordance may be only about 80%. Lave et al. (1988) suggested that concordance between rats and mice may represent an upper bound on concordance between rodents and humans. Quantitative interspecies extrapolation of carcinogenic potency is therefore done under the presumption that the agent in question will be effective in both species involved.

If progress in carcinogenic risk assessment based on bioassay data is to be made, it seems that additional information beyond that contained in traditional experiments is required. In particular, studies of the mechanisms of chemical carcinogenesis may provide new insights on the estimation of low dose risk (Moolgavkar & Luebeck, 1990). The relative importance of mutation and cell proliferation in carcinogenesis particularly requires further discussion. Cohen & Ellwein (1990) show that proliferation of urinary bladder tissue is essential for the induction of bladder tumors with 2-acetylaminofluorene. Cunningham et al. (1991) recently demonstrated that 2,4-diaminotoluene (2,4-DAT) and 2,6-diaminotoluene (2,6-DAT) are equally mutagenic in Salmonella , yet only 2,4-DAT produces a sufficient increase in cell turnover in rat liver to lead to hepatocarcinogenesis. Ames & Gold (1990) conclude that "without studies of the mechanism of carcinogenesis, the fact that a chemical is a carcinogen at the MTD in rodents provides no information about low dose risk to humans". Physiologically based pharmacokinetic models may afford an opportunity to increase the accuracy of risk estimates through improved tissue dosimetry (Krewski et al., 1991b); measurement of metabolic parameters in different species may also lead to improved interspecies extrapolation (Andersen et al., 1987). More sensitive indicators of effects at very low doses, such as markers of DNA damage suspected to play a role in neoplastic conversion (cf. Lutz, 1990), may also serve to provide improved estimates of risk in the future. All of these considerations suggest a more biologically based approach to cancer risk assessment is needed (Clayson, 1987).

8. Acknowledgements

We are grateful to Drs. David Clayson, Kenny Crump, Lois Gold, Lester Lave, Mary Paxton, and Marvin Schneiderman for helpful com-

Suggested Citation:"8. ACKNOWLEDGEMENTS." National Research Council. 1993. Issues in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2078.
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The scientific basis, inference assumptions, regulatory uses, and research needs in risk assessment are considered in this two-part volume.

The first part, Use of Maximum Tolerated Dose in Animal Bioassays for Carcinogenicity, focuses on whether the maximum tolerated dose should continue to be used in carcinogenesis bioassays. The committee considers several options for modifying current bioassay procedures.

The second part, Two-Stage Models of Carcinogenesis, stems from efforts to identify improved means of cancer risk assessment that have resulted in the development of a mathematical dose-response model based on a paradigm for the biologic phenomena thought to be associated with carcinogenesis.

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