Epidemiological studies on the etiologies of human cancers are exceedingly difficult due to the multiplicity of carcinogens to which humans are exposed, and due to the long latency periods between exposure and the expression of the disease state. The multiplicity of exposures also complicates efforts to predict human cancer risks based on bioassays in which animals are exposed to a single agent. In order to make better predictions for human cancer risks, it is exceedingly important to understand the mechanisms by which low levels of environmental carcinogenic agents interact to promote this disease. We have selected a group of known or suspected carcinogenic agents and propose to measure patterns of interaction for endpoints which are highly correlated with the carcinogenic pathway. Specific agents were chosen based on i) our knowledge of the mechanism by which they produce DNA damage and the type of lesions which result, and ii) either because some of these agents are cancer chemotherapeutic drugs, permitting comparison with human responses, or because the agents are ubiquitous in our environment, and exposures are unavoidable. We propose to examine several endpoints in vitro which include: cytotoxicity, specific locus mutation, sister chromatid exchange, chromosomal aberrations, and inhibition of cell replication kinetics. These last three endpoints will also be studied in vivo and in utero to confirm the validity of in vitro observations. The time interval between exposures is an important parameter in evaluating potential interaction. Our protocols will evaluate both simultaneous and sequential exposure to carcinogenic agents. Simultaneous exposure to interactive agents will determine if acute effects are mitigating, additive or synergistic. Exposures separated by both long (hours) and short (days or greater) intervals will measure how risk factors are affected by histories or previous exposures. These types of data may prove important in predicting human risks involved in exposure to multiple carcinogenic agents.
