Study on the cytochrome P-450- and glutathione-dependent biotransformation of trichloroethylene in humans
Bloemen, L J × Monster, A C Kezic, S Commandeur, J N Veulemans, Hendrik Vermeulen, N P Wilmer, J W #
International Archives of Occupational and Environmental Health vol:74 issue:2 pages:102-8
OBJECTIVES: To investigate in humans the contribution of the cytochrome P-450- and glutathione-dependent biotransformation of trichloroethylene (TRI) under controlled repeated exposure in volunteers, and under occupational conditions. METHODS: Volunteers were exposed to TRI, using repeated 15 min exposures at 50 and 100 ppm. This exposure schedule resulted in internal doses of 1.30 and 2.40 mmol of TRI respectively. Urine samples were collected for a minimum of 45 h. Urine samples were also collected from occupationally exposed workers. The samples were analysed for the known human metabolites of TRI, trichloroethanol (TCE), trichloroacetic acid (TCA) and both regio-isomeric forms of the mercapturic acid N-acetyl-S-(dichlorovinyl)-L-cysteine (DCV-NAC), and for (dichlorovinyl)-L-cysteine (DCVC). In order to further elucidate the 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-cysteine after deamination: the S-conjugates of 3-mercaptolactic acid, 3-mercaptopyruvic acid and 2-mercaptoacetic acid. RESULTS: None of the glutathione metabolites was found in urine of volunteers. In workers occupationally exposed to TRI at levels between 0.4 and 21 ppm [8-h time-weighted average (TWA)], levels of DCV-NAC in urine samples collected at the end of the 4th working day and also next morning were below detection limit (0.04 mumol/l). This confirms the findings of Bernauer et al. (1996) that these metabolites are excreted at very low levels in humans. Urinary levels of DCVC and six postulated metabolites of dichlorovinyl-S-cysteine conjugates via deamination were also below 0.04 mumol/l, indicating that at most 0.05% of the dose is excreted in the form of these metabolites. These data further strengthen 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 importance in humans exposed to TRI. In spite of indications to the contrary, significant metabolism of the cysteine conjugate via beta-lyase, which could result in a toxic metabolite, cannot be ruled out completely.