Assessment of the carcinogenic or mutagenic effects of two or more environmental agents combined has become an important health issue. The risk from joint exposure may be substantially higher than the sum of the risks of the individual agents. Quantitative mutagenesis assay systems allow an assessment of health risks for exposure to radiation and other environmental contaminants. Because of the exquisite sensitivity of the AL human-hamster hybrid cell system, possible in large, self-contained experiments, damage caused by low doses of radiation and/or chemicals can be studied that are quite impractical to detect in human epidemiological surveys, or indeed in most experimental animal systems. The effects of radiation doses of the order of cGy of neutrons or tens of cGy of gamma rays can be detected and measured. The carcinogenicity of asbestos fibers and cigarette smoke have been well established, and a synergism between the two agents has been established epidemiologically in producing lung cancer in asbestos workers. Similarly, a synergism in carcinogenicity has been established among uranium miners who also smoke. The underlying cellular and molecular mechanism for these synergistic effects are not known. In the present project, it is proposed to examine the mutagenic effects of low doses of gamma rays at the a1, a2, and the HGPRT loci within the same cell system. Emphasis will be placed on the interaction between gamma irradiation with other known carcinogens, such as asbestos fibers and cigarette-smoke condensate. Based on the quantitative mutagenic data, the mode of interaction between the various agents in mutant induction -- additive, synergistic, or antagonistic -- over a range of doses can be assessed. The human-hamster hybrid AL cell line in an antibody-complement-mediated cell lysate system will be used to score mutagenesis. With the use of appropriate antibodies, mutations can be scored in the human chromosome (no. 11) with great specificity and quantification. By using specific DNA probes of other genes that have been mapped to various sites on human chromosome 11, the molecular mechanism(s) of mutation in the AL cells can also be examined. Since the AL cells also contain the HGPRT gene, the extent of genetic damage expressed by the mutants at an essential chromosome (X-) vs. a non- essential chromosome (human chromosome 11) in the AL cells will provide useful information on the types and sizes of molecular changes induced by the various treatments.
