Carcinogen Induced Deletions in the MouseEPA Grant Number: R825359
Title: Carcinogen Induced Deletions in the Mouse
Investigators: Schiestl, Robert H.
Institution: Harvard T.H. Chan School of Public Health
Current Institution: Harvard University
EPA Project Officer: Reese, David H.
Project Period: December 2, 1996 through December 1, 1999 (Extended to December 1, 2000)
Project Amount: $583,191
RFA: Exploratory Research - Human Health (1996) RFA Text | Recipients Lists
Research Category: Health Effects , Human Health , Health
Description:Many environmental hazards result from concurrent exposures to mixtures of compounds that may operate by similar or dissimilar mechanisms. Yet more often than not, toxicologic data will only be available on mixture components, with little or no quantitative information on the potential for toxicological interactions (such as additivity, synergism, and antagonism) among components. In such data poor situations, the U.S. Environmental Protection Agency (USEPA) assumes independence of action by the individual components, and thus additivity in the estimation of hazard indices and carcinogenic risk. The assumption of additivity can lead to substantial errors in estimates of hazard indices or cancer risk if synergistic or antagonistic interactions occur. Thus, there is clearly a need for information about potential toxicological interactions among components of environmental mixtures.
An additional regulatory problem exists for the risk assessment of carcinogenic compounds that are "not mutagenic." It is generally impractical in long term carcinogenesis studies to generate dose responses down to low doses. Such dose responses might be obtained with short-term tests but not for "nonmutagenic" compounds. However, such dose responses are necessary for risk assessment since people are exposed to very low doses in comparison to the maximum tolerated doses used in carcinogenesis studies.
Finally, it is important to determine the risk to environmental carcinogen exposure of individuals that are more sensitive than the general population.
A short-term in vivo mouse assay is being used that readily detects both mutagenic and "nonmutagenic" carcinogens to determine dose responses and interactions among carcinogens. Furthermore, carcinogen induced effects will be determined in mice heterozygous for the p53 gene, an animal model for Li-Fraumeni disease that is associated with an increased cancer risk. The assay detects DNA deletion events in melanocyte precursor cells during embryonal development of the mouse that gives rise to a coat color change in the offspring which can be easily counted. The frequencies of deletions are determined by counting the number of spots on the coat. This mouse assay is useful in developing dose-response relationships, and in testing the effects of various combinations of carcinogenic agents. The assay may take only several weeks to perform and thus may require only modest funding in comparison to current long term assays. It may be possible to quantify deletions at low doses of exposure. Assays scoring for the same genetic endpoint are available in cell culture to allow in vivo - in vitro comparisons and can readily distinguish between mutagenic and "nonmutagenic" carcinogens by different dose responses. If this mouse assay can distinguish between these two classes on the basis of their dose response, this would have important implications for risk assessment.
More widespread use of this mouse assay may provide better information for risk assessment and may lead to a more widespread use of the cell culture assays with the same genetic endpoint which in turn may result in a reduction in the number of animals used in toxicity testing.