Biotransformation of perchloroethene: dose-dependent excretion of trichloroacetic acid, dichloroacetic acid, and N-acetyl-S-(trichlorovinyl)-L-cysteine in rats and humans after inhalation.
Chronic exposure of rodents to perchloroethene (PER) increased the incidence of liver tumors in male mice and resulted in a small but significant increase in the incidence of renal tumors in male rats. The tumorigenicity of PER is mediated by metabolic activation reactions. PER is metabolized by cytochrome P450 and by conjugation with glutathione. Cytochrome P450 oxidation of PER results in trichloroacetyl chloride which reacts with water to trichloroacetic acid (TCA) which is excreted. The formation of S-(trichlorovinyl)glutathione (TCVG) from PER results in nephrotoxic metabolites. TCVG is cleaved to S-(trichlorovinyl)-L-cysteine (TCVC) and acetylated to N-acetyl-S-(trichlorovinyl)-L-cysteine (N-ac-TCVC), which is excreted with urine. TCVC is also cleaved in the kidney by cysteine conjugate beta-lyase to dichlorothioketene which may react with water to dichloroacetic acid (DCA) or with cellular macromolecules. The object of this study was to comparatively quantify the dose-dependent excretion of PER metabolites in urine of humans and rats after inhalation exposure. Three female and three male human volunteers and three female and three male rats were exposed to 10, 20, and 40 ppm PER for 6 h, and three female and three male rats to 400 ppm. A dose-dependent increase in the excretion of TCA and N-ac-TCVC after exposure to PER was found both in humans and in rats. A total of 20.4 +/- 7.77 mumol of TCA and 0.21 +/- 0.05 mumol of N-ac-TCVC were excreted in urine of human over 78 h after the start of exposure to 40 ppm PER; only traces of DCA were present. After identical exposure conditions, rats excreted 1.64 +/- 0.42 mumol of TCA, 0.006 +/- 0.002 mumol of N-ac-TCVC and 0.18 +/- 0.04 mumol of DCA. Excretion of N-ac-TCVC in male rats exposed to 400 ppm PER (103.7 nmol) was significantly higher, compared to female rats (31.5 nmol) exposed under identical conditions. N-ac-TCVC was rapidly eliminated with urine both in humans (t1/2 = 14.1 h) and in rats (t1/2 = 7.5 h). When comparing the urinary excretion of N-ac-TCVC, a potential marker for the formation of reactive intermediates in the kidney, humans received a significantly lower dose (3 nmol/kg at 40 ppm) compared to rats (23.0 nmol/kg) after identical exposure conditions. In addition, rats excreted large amounts of DCA which likely is a product of the beta-lyase-dependent metabolism of TCVC in the kidney. The obtained data suggest that glutathione conjugate formation and beta-lyase-dependent bioactivation of TCVC in PER metabolism is significantly higher in rats than in humans. Thus, using rat tumorigenicity data for human risk assessment of PER exposure may overestimate human tumor risks.
Völkel
W
W
Institut für Toxikologie, Universität Würzburg, Germany.
Friedewald
M
M
Lederer
E
E
Pähler
A
A
Parker
J
J
Dekant
W
W
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000652:urine; D000328:Adult; D000368:Aged; D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics*; D003999:Dichloroacetic Acid / Q000652:urine; D004785:Environmental Pollutants / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006801:Humans; D019570:Inhalation Exposure; D008297:Male; D008875:Middle Aged; D051381:Rats; D017208:Rats, Wistar; D012997:Solvents / Q000493:pharmacokinetics*; D013750:Tetrachloroethylene / Q000493:pharmacokinetics*; D014238:Trichloroacetic Acid / Q000652:urine
D002273:Carcinogens; D004785:Environmental Pollutants; D012997:Solvents; C053445:S-trichlorovinyl-N-acetylcysteine; D014238:Trichloroacetic Acid; D003999:Dichloroacetic Acid; D013750:Tetrachloroethylene; D000111:Acetylcysteine