My laboratory utilizes Drosophila as an experimental organism, exploiting the well-characterized genetic, molecular and practical advantages of this model higher eukaryote. We have identified Drosophila melanogaster geographic variants that display genetic variability in their response to the toxic effects of a range of environmentally distributed heavy metals, e.g. arsenic, lead. Our premise is that the molecular and functional characterization of genetic alleles that confer relative tolerance or susceptibility to such metals will substantially enhance our understanding of their interactions with biological tissues. Given individual variation in susceptibility to several of these metals in human studies, the identification of allelic variability in homologous human genes could provide a valuable diagnostic tool for risk assessment of individuals living in contaminated environments. Recent studies have led us to identify variability in the glutathione synthetic pathway as a key component of such natural susceptibility to arsenic. We are also pursuing genomic analyses with recombinant inbred and congenic strains to identify additional pathways involved in both acute and chronic, long-term susceptibilities. Chronic exposure to arsenic can lead to several different forms of cancer, although arsenic is typically characterized as a non-genotoxic agent. Methylation is one means by which arsenic is metabolized in tissues, and it is thought such metabolites could be instrumental in this carcinogenic activity. We are developing a transgenic model for such activities in Drosophila, allowing us to overtly test the carcinogenic activity of methylated metabolites, and to explore the cellular pathways with which they interact to exert their effects.