National Academies Press: OpenBook

Issues in Risk Assessment (1993)

Chapter: 4.1 Predictions Based on the MDT

« Previous: 3.5 Genotoxic vs. Nongenotoxic Carcinogens
Suggested Citation:"4.1 Predictions Based on the MDT." National Research Council. 1993. Issues in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2078.

about the fitted regression line

was somewhat greater for genotoxic carcinogens than for nongenotoxic carcinogens, implying that this relationship is weaker for genotoxic carcinogens as compared to nongenotoxic carcinogens. The authors suggested that this is consistent with the hypothesis that carcinogenic effects observed at the MTD are mediated to a certain extent by toxicity, and that the larger variability exhibited by genotoxic carcinogens is because of their ability to induce carcinogenic effects by direct damage to genetic material. This does not imply that toxicity does not play a role in the induction of tumors by mutagenic chemicals; rather it is the inability of nongenotoxic agents to interact directly with DNA that leads to this difference.

Goodman & Wilson (1992) also examined a second set of 245 compounds which had tested positive in various Salmonella strains (cf. Zeiger et al., 1988). Since no significant differences in the variablity of fitted regressions lines were noted within three categories of mutagenic potency, it did not appear possible to further characterize the variability in the potency of genotoxic carcinogens relative to the MTD on the basis of genotoxic potency.

4. Prediction of the TD50
4.1 Predictions Based on the MDT

The high correlation between the TD50 and the MTD demonstrated in section 3 suggests that the TD50 may be predicted from the MTD. To explore this possibility, we fit the linear regression model

to data on the 191 chemical carcinogens considered previously in section 2.3. Here, e represents a random error term which is assumed to be normally distributed with mean zero and variance s2, and a and b are parameters that can be estimated using ordinary least squares. Separate

Suggested Citation:"4.1 Predictions Based on the MDT." National Research Council. 1993. Issues in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2078.
Page 131
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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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