CHLOROETHYLENE MIXTURES - PHARMACOKINETIC MODELING AND IN-VITRO METABOLISM OF VINYL-CHLORIDE, TRICHLOROETHYLENE, AND TRANS-1,2-DICHLOROETHYLENE IN RAT

Environmental and occupational exposures are typically to mixtures of chemicals, although mast toxicity information is for individual compou nds. Interactions between chemicals may involve pharmacokinetic and/or pharmacodynamic effects resulting in modulation of toxicity. Therefor e, physiologically based pharmacokinetic modeling has been used to ana lyze data describing the metabolism of vinyl chloride (VC) and trichlo roethylene (TCE) mixtures in rats. A single saturable pathway was mode led, representing cytochrome P450 2E1. This was partially validated us ing preexposure to trans-1,2-dichloroethylene (tDCE) which virtually e liminated in vivo metabolism of both VC and TCE at low concentrations. Microsomes from tDCE-exposed animals showed inhibition of metabolism of P450 2E1 substrates (chlorzoxazone, p-nitrophenol, and TCE) and no effect on 7-ethoxycoumarin deethylation. Studies with liver microsomes from VC-exposed animals found that neither suicide inhibition nor ind uction occurred during 6-hr exposures to high concentrations. Therefor e, these effects were not modeled. Modeling of mixtures of VC and TCE was successful only using competitive inhibition, as might be predicte d for cytochrome P450 2E1 substrates, and not uncompetitive or noncomp etitive inhibition. These results were further confirmed by determinin g the depletion of glutathione due to VC metabolism. The validation of a detailed model for the inhibition kinetics of metabolism of these t wo compounds permits better understanding of the implications of coexp osures for toxicity. It is notable that competitive inhibition only be comes significant at relatively high concentrations (tens of ppm), whi le at typical low environmental concentrations (ppb), absorption is pe rfusion limited and enzyme is in excess so that the chemicals will be metabolized independently. (C) 1995 Academic Press, Inc.