National Academies Press: OpenBook

Issues in Risk Assessment (1993)

Chapter: OPTION 2

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Suggested Citation:"OPTION 2." National Research Council. 1993. Issues in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2078.
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This option has the advantage that the MTD bioassay is the only currently standardized method in the United States for identifying carcinogens. Continuing the bioassay as it is currently used allows comparisons with the results of similar studies conducted in the past. The test is designed to achieve high sensitivity. Compounds found to be negative in a standard set (two species and both sexes) of bioassays conducted at the MTD can be designated as noncarcinogens with a relatively high degree of confidence.

The negative aspects of the test are that its results indicate only whether a chemical is a rodent carcinogen under the conditions of the assay. The current screening system is oriented toward identifying potential carcinogens. Without additional studies, the bioassay does not indicate how predictive the results of the rodent bioassay are for humans, and it provides little information with which to estimate responses at low doses—which might be of particular concern to humans. For materials for which the evidence of carcinogenicity is weak (i.e., related to only one sex-species group or to the highest dose) and that are economically important, further studies to elucidate the metabolism or mechanisms of action, particularly regarding effects on cell proliferation, are in order.

OPTION 2

Redesign the bioassay so that the highest dose is some small fraction of the EMTD.

When human exposures were reasonably anticipated to be within a factor of 10 or 100 of the animal MTD or when the test substance was judged to have a high potential for direct interaction with DNA (as judged by results of short-term tests for genotoxicity), the MTD would continue to be used as the highest dose.

For materials that did not meet those criteria, however, the MTD would not be routinely used as the highest dose in chronic bioassays. Instead, a fraction of the EMTD (e.g., MTD/3) would serve as the highest dose for bioassays. Additional doses would be spaced geometrically below the high (MTD/3) dose at half-log intervals (i.e., the second dose would be MTD/10, the third dose would be MTD/33, etc.).

Suggested Citation:"OPTION 2." 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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