Study on the cytochrome P-450-and glutathione-dependent biotransformation of trichloroethylene in humans

To investigate in humans the contribution of the cytochrome P-450- and glut athione-dependent biotransformation of trichloroethylene (TRI) under contro lled repeated exposure in volunteers, and under occupational conditions. Me thods: Volunteers were exposed to TRI, using repeated 15 min exposures at 5 0 and 100 ppm. This exposure schedule resulted in internal doses of 1.30 an d 2.40 mmol of TRI respectively. Urine samples were collected for a minimum of 45 h. Urine samples were also collected from occupationally exposed wor kers. The samples were analysed for the known human metabolites of TRI, tri chloroethanol (TCE), trichloroacetic acid (TCA) and both regio-isomeric for ms of the mercapturic acid N-acetyl-S-(dichlorovinyl)-L-cysteine (DCV-NAC), and for (dichlorovinyl)-L-cysteine (DCVC). In order to further elucidate t he metabolism of TRI in humans, we analysed samples for dichloroacetic acid and for the proposed break-down products of 1,2 and 2,2-dichlorovinyl-L-cy steine after deamination: the S-conjugates of 3-mercaptolactic acid, 3-merc aptopyruvic acid and 2-mercaptoacetic acid. Results: None of the glutathion e metabolites was found in urine of volunteers. In workers occupationally e xposed to TRI at levels between 0.4 and 21 ppm [8-h time-weighted average ( TWA)I, levels of DCV-NAC in urine samples collected at the end of the 4th w orking day and also next morning were below detection limit (0.04 mu mol/l) . This confirms the findings of Bernauer et al, (1996) that these metabolit es are excreted at very low levels in humans, Urinary levels of DCVC and si x postulated metabolites of dichlorovinyl-S-cysteine conjugates via deamina tion were also below 0.04 mu mol/l, indicating that at most 0.05% of the do se is excreted in the form of these metabolites. These data further strengt hen the argument for a very low activity of glutathione-mediated metabolism for chronically exposed workers. Conclusions: This study gives additional data which indicate that glutathione-mediated metabolism is of minor import ance in humans exposed to TRI, In spite of indications to the contrary, sig nificant metabolism of the cysteine conjugate via D-lyase, which could resu lt in a toxic metabolite, cannot be ruled out completely.