Assessment of the carcinogenic and mutagenic effects of two or more environmental agents in than predicted from the sum of risks of the individual agents. Epidemiological studies have shown that uranium miners exposed to high levels of alpha particles form radon progeny show the largest number of radiation induced lung cancers found in any exposed population. Studies designed to identify a link between lung cancer and radon levels in homes have resulted in equivocal conclusions. With the availability of the microbeam facility at the Radiological Research Accelerator Facility, the first objective of this proposal is to examine both the quantitative mutagenic yield and the spectrum of mutations by either a single or a defined number of alpha particle traversals, where this low dose exposure is more consistent with domestic experience. While cigarette smoke remains the single most important modulator in lung cancer incidence among uranium and other miners, recent epidemiological studies have also identified the compounding effect of arsenite in the etiology of radon-induced lung cancer in miners. The second objective, then, is to examine the combined mutagenic effects of alpha particles from radon progeny with either tobacco smoke nitrosamines (NNK) or sodium arsenite. Specifically, the quantitative mutagenic data will be used tin assessing the mode of interaction between radon and these two environmental pollutants. The molecular spectrum will be used to ascertain qualitatively the presence or absence of specific signature changes at the gene level. Mutation will be scored at both the S1 and HGPRT loci using the human- hamster hybrid AL cells. To compare the mutagenic effects with in vivo target tissues, the frequencies and types of mutations induced by alpha particles either alone or in combination with NNK will also be examined using primary human bronchial epithelial cells. The AL cell line contains only one copy of human chromosome II and mutations on marker genes located on this chromosome can be readily scored using an antibody complement lysis technique. By using specific DNA probes of other genes that have been regionally mapped to various site on chromosome II, the molecular mechanisms of mutation in AL cells will also be examined. Because of the demonstrated sensitivity of the AL cell mutagenic system, it will be possible to examine the effects of low level exposure to radon progeny and/or chemicals that are quite impractical to detect in human epidemiological surveys, or indeed in most experimental animal systems.
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