Most chemical exposures to humans are to mixtures, particularly through drinking water, yet little information is available on the carcinogenicity of chemical mixtures and we know little about carcinogenic promoters in the environment. In previous studies in our laboratory, a model groundwater mixture containing seven chemicals among the most common found at hazardous waste sites (arsenic, benzene, chloroform, chromium, lead, trichloroethylene, and phenol) was administered to rats in their drinking water. One of the significant findings was increased hepatocellular proliferation, although the level of most of the individual chemicals was below that expected to have such an effect. Since cell proliferation is recognized as a critical factor in both initiation and promotion of carcinogenesis, we hypothesize that this seven-chemical mixture may serve as a promoter in the carcinogenic process. Chloroform, trichloroethylene, and lead are known to induce hepatic cell proliferation, through by different mechanisms. The former two are also hepatotoxins and hepatocarcinogens. We further hypothesize that the promoting effects of this chemcial mixture will be related to hepatocellular proliferation and manifested through an interactive effect of these three agents. Finally, we hypothesize that gene expression in protooncogenes and/or suppressor genes which affect the cell cycle will reflect the differences in promoting activity seen between treatment with mixtures, and individual chemicals. We will test these hypotheses using a medium-term, 8-week bioassay for modifiers of hepatocarcinogenesis in the rat. This assay uses placental glutathione-S-transferase positive preneoplastic foci as the endpoint for predicting promoting activity. Rats will be exposed, via drinking water, to various submixtures of the full seven-chemical mixture, as well as to individual chemicals, to determine the promoting effects. We will use histomorphometry to quantify preneoplastic focus formation and cell proliferation, and PCR and RT-PCR to evaluate oncogene and/or suppressor gene expression or mutation, and how these may be affected by individual chemicals and mixtures of these.
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