The objectives of this project are: (1) to evaluate age- and dosing-related changes in pharmacokinetics, biochemical markers, liver cell proliferation, and histopathology in male Fischer 344 chronically (up to 2 yrs) exposed to low levels of a chemical mixture of 7 organic and inorganic groundwater pollutants (arsenic, benzene, chloroform, chromium, lead, phenol, trichloroethylene); (2) to explore pharmacokinetic modeling of chemical mixtures; (3) to incorporate time-course information on biochemical markers, cell proliferation and histopathology into pharmacokinetic and pharmacodynamic modeling. In all of the studies proposed, pharmacokinetics refer to physiologically based pharmacokinetic modeling, using a simple and noninvasive method (gas uptake technique) to assess the kinetics of trichloroethylene, a model chemical and a top groundwater pollutant, with or without the modulation of drinking water exposure of the chemical mixture. Blood and liver levels of lead and chromium, two components of the mixture, will be analyzed and the results will be utilized for possible pharmacokinetic modeling. Biochemical markers to be measured include glutathione (GSH) content, cytochrome P450 content and activity, glutathione S-transferase activity and cysteine beta-lyase activity in liver and kidney. Liver cell proliferation rate will be investigated at various time points in parallel with the 2-year study. Clinical and histopathology will be conducted such that comparative evaluations may be made among rats (this project) and rabbits (Project 3). Because of logistic restrictions, the experiments in this project will be divided into two phases. Phase I studies which will be conducted in the first 6 mos involve the time-course (1 and 4 days, 1 and 2 wks) investigation of pharmacokinetics, biochemical markers, and cell proliferation (liver). It is during these short-term studies the exploration for the endpoint(s) for future studies on teasing out the possible additivity or synergism or antagonism by component chemicals responsible for the toxic responses will be effected. Phase II which will be initiated after the completion of Phase I studies, similarly, will be time-course I1, 3, 6, 12, 18, 24 mos) investigation of pharmacokinetics, biochemical markers, cell proliferation (liver) plus clinical and histopathology.
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