Compounds of arsenic, nickel, calcium, chromium and beryllium are considered human carcinogens. Other metal compounds, while not proven human carcinogens, can cause tumors in experimental animals. The genetic effects of metal compounds are poorly understood. Bacterial short-term bioassays have been poor at predicting the carcinogenicity of metal compounds. In the previous funding period, it was found that genotoxic effects of metal compounds could be demonstrated in bacterial systems provided one used a narrow dose range of the compounds in a sub-toxic range, long-term exposure to growing cells, and a genetic endpoint of broad specificity. Using a newly developed microtitre system which simultaneously screens for toxicity, Lambda prophage induction, and mutagenicity, genotoxic effects were detected for compounds of chromium, nickel, lead, manganese, molybdenum and tungston. This system also allows detection of organic carcinogens at extremely low concentrations, including some which are negative in standard Ames strains. Compounds of copper, arsenite, manganese and molybdenum were detected in a comutagenesis assay. The present proposal has two parts. First, the microtitre system will be improved by incorporating a forward mutation assay capable of detecting base-pair substitutions, frameshifts and deletions. If feasible, an enzymatic assay for prophage induction (an indication of DNA damage) will replace the Lambda plaque assay. Second, the studies will be extended to eukaryotic cells, using the Chinese hamster V79 line. Gene mutations at the GHPRT locus, chromosome aberrations, sister chromatid exchanges and comutagenesis will be the genetic endpoints. The emphasis will be on a comparison between insoluble metal compounds (of particle size les than 5 Mum) and soluble compounds of the same metals. Insoluble particles cannot be assayed in bacterial systems. The use of eukaryotic cells will allow the study of compounds which do not enter bacteria, as well as providing a prokaryotic/eukaryotic comparison of the genetic toxicity of metal compounds.
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