Quantitative and Qualitative Extrapolation of Carcinogenesis Between Species,
Abstract
As currently conducted, standard rodent bioassays do not provide sufficient information to assess carcinogenic risk to humans at doses thousands of times below the maximum tolerated dose. Recent analysis indicate that measures of carcinogenic potency from these tests are restricted to a narrow range about maximum tolerated dose and that information on shape of the dose-response is limited in experiments with only two doses and a control. Extrapolation from high to low doses should be based on an understanding of the mechanisms of carcinogenesis. We have postulated the administration of the maximum tolerated dose can increase mitogenisis which, in turn, increase rates of mutagenisis and, thus, carcinogenisis. The animal data are consistent with this mechanism, because about half of all chemicals tested are indeed rodent carcinogens, and about 40% of the positives are not detectably mutagenic. Thus, at low doses where cell killing does not occur, the hazards to humans of rodent carcinogens may be much lower than commonly assumed. In contrast, for high-dose exposures in the workplace, assessment of hazard requires comparatively little extrapolation. Nevertheless, permitted workplace exposures are sometimes close to the tumorigenic dose-rate in animal tests
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 1993
- Accession Number
- ADP008710
Entities
People
- Bruce N. Ames
- Lois S. Gold
- Neela B. Manley
Organizations
- University of California, Berkeley