The goal of this proposal is to develop precision cut liver slice culture into a tool for the study of interactive hepatotoxicology. Our studies will concentrate on specific pairs chosen from a group of metal(oids) [As, Cd, Hg, Pb, Se] and a group of halogenated hydrocarbons [carbon tetrachloride, chloroform, trichloroethylene, chlorobenzene, dichlorobenzenes] known to be present at chemical waste sites and with past evidence of indications of interactive toxicity. Three exposure modes will be utilized: one in which both toxicans are administered in vivo, secondly a mode in which one of the toxicants is administered to the intact animal and consecutively the other to liver slices produced from the preexposed animal and finally a mode in which both toxicants are either simultaneously or consecutively added to cultured liver slices. This latter mode is also applied to human tissue with the hope to correlate in vitro with in vivo data in the rat and to predict from in vitro human data interactive hepatotoxicology in exposed human populations. Toxic endpoints are determined with general viability assays applicable to all three exposure modes. Mechanisms of interactive toxicity will be investigated by probing a number of cellular biochemical parameters indicative of: cellular energy status, covalent binding of reactive intermediates generated from the organic toxicant, cell membrane integrity, cellular macromolecule synthesis membrane transport phenomena, deleterious effects of active oxygen species, biotransformation pathways, cellular glutathione status and abnormal cellular architecture.
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