MOLECULAR TOXICOLOGY OF ENVIRONMENTAL CARCINOGENS

The aim of this Program Project is to increase understanding of the mechanisms of chemical carcinogenesis in human. Mechanisms will be studied directly in human who have exposures to known environmental carcinogens: cigarette smoke (whose constituents include ethylene oxide, styrene, 4- aminobiphenyl, polycyclic aromatic hydrocarbons or PAHs) and foundry air (which contains high levels of PAHS). All of the laboratories within he Program will evaluate biologic samples from the same individuals, using biologic markers to assess the association between potential markers of genetic susceptibility (P1-450 induction, AHH activity and glutathione-S- transferase activity) on induction of procarcinogenic effects (carcinogen- DNA and -protein adducts, gene mutations at the hprt locus and activation of c-ras, c-myc and c-fes proto-oncogenes). In contrast to these mechanisms of genetic toxicity, associated with cancer initiation and possibly other stages in the carcinogenic process, little is known about the mechanisms involved in tumor promotion. Because these are important determinants of individual cancer risk, novel methods will be developed to measure effects of certain non-genotoxic agents and tumor promotors on the activity of our model populations, who also experiences high exposure to known tumor promotors, will be studied. Thus, the combined resources of the Program will provide comprehensive data on a broad spectrum of events and processes in human carcinogenesis. They will also help to clarify the nature and significance of interindividual variability in response to carcinogens. These studies are an essential prerequisite to incorporating biologic markers into quantitative risk assessment and epidemiologic studies of cancer causation. Our goal, at the end of 5 years, is to carry our a longitudinal epidemiologic study, in order to determine the ability of biologic markers to predict individual risk of cancer.