The long-term objective of the proposed research is to elucidate the mechanisms and role of genetic toxicity in chemical carcinogenesis. In multidisciplinary integrated studies, various complementary markers of genetic toxicity will be investigated: carcinogen-DNA and protein adducts using immunological methods, sister chromatid exchange (SCE) and micronuclei in lymphocytes (MNL), and products of activated oncogenes. The overall approach will be to validate these markers in parallel experimental animal and molecular epidemiological studies by assaying biological samples following in vivo exposure to a number of carcinogens. In the first phase, quantifiable and well-characterized model compounds (chemotherapy agents, ethylene oxide) will be studied. In the second phase, following development of antibodies to the specific DNA and protein adducts of interest, the same battery of immunological and cytogenetic assays will be applied to two environmentally relevant chemicals (vinyl chloride and styrene). The feasibility of extending this approach to benzene and butadiene will also be evaluated. This approach will provide greater understanding of the relationship between DNA binding and measurable chromosomal damage and will permit assessment of the relative usefulness of each as a marker of biologically effective dose of carcinogen in future biomonitoring and molecular epidemiology studies. The proposed research will be carried out by developing new antibodies to carcinogen-DNA and protein adducts, modifying existing immunological methods to increase their sensitivity, implementing the MNL assay, and applying innovative methods (cytofluorography, fluorescence line narrowing, and image intensification microscopy) to quantification of DNA adducts.
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