Several lines of evidence support the concept that induced environmental carcinogenesis in humans is a time-dependent multi-genic process. Evidence is also continuing to develop to indicate the importance of the inheritance of specific genetic susceptibility as a critical determinant of the disease process. These data have been principally related to the familial inheritance of mutated genes. The primary assays for the identification of carcinogens is the two year rodent bioassay, where inbred mice and rats are used as surrogates for humans. Inbred rodents, however, are enriched for specific alleles of polymorphic genes that often have the capacity to influence susceptibility to carcinogens. This is manifested in strain specific susceptibility to chemical effects and the inheritance of susceptibility to spontaneous tumors. Thus, the rodents thus may show a chemical sensitivity that may be manifested in only a small portion of the random breeding human population, or not represented at all. The use of the p53+/- and TG.AC transgenic mouse lines to identify human carcinogens is predicated on the preferential identification of trans-species carcinogens. In the past two years efforts were directed to the testing of over twenty selected chemicals in the two lines. Current efforts involve collaboration with staff of the ETP to select other chemicals for testing the design of protocols for effective chemical evaluation and further characterization of the phenotypes of the transgenic lines. It is anticipated that within the next year it should be possible to evaluate up to ten additional chemicals, the results of which should go a long way toward validating the strategy for using the transgenic lines to supplement and supplant 2 year bioassays. Many critical questions must be addressed in order to promote a scientific consensus on the use of these transgenic lines. Foremost is understanding the mechanisms by which carcinogens act in these mice. We are currently attempting to study the fate of the functional p53 allelein tumors induced in p53+/- and to understand the process by which transgene expression is induced in the TG.AC line.
