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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-



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APPENDIX F 149 original typesetting files. Page breaks are true to the original; line lengths, word breaks, heading styles, and other typesetting-specific formatting, however, cannot be About this PDF file: This new digital representation of the original work has been recomposed from XML files created from the original paper book, not from the retained, and some typographic errors may have been accidentally inserted. Please use the print version of this publication as the authoritative version for attribution. 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