Contribution of trichloroacetic acid to liver tumors observed in perchloroethylene (perc)-exposed mice

Perchloroethylene (perc), a solvent used in dry cleaning operations and industrial applications, has been found to produce increases in hepatocellular carcinomas and/or adenomas in mice in chronic inhalation bioassays. Perc is metabolized primarily to trichloroacetic acid (TCA), which is also a mouse hepatocarcinogen. The fractional conversion of perchloroethylene to TCA by mice was determined from physiologically based pharmacokinetic (PBPK) modeling of TCA in mouse blood at the conclusion of inhalation exposure of male and female B6C3F1 mice to 10, 50, 100, or 200 ppm perc for 6 h/day for 5 days. The dose-dependent bioavailability of TCA in B6C3F1 mice exposed to TCA in drinking water was estimated by optimizing the fit of time course blood, plasma, and liver TCA concentrations for TCA doses ranging from 12 to 800 mg/(kg day) to predictions of a previously published TCA PBPK model. Using the PBPK models, the area under the liver TCA concentration vs. time curve (liver TCA AUC) was calculated for TCA and perc bioassays. Benchmark dose analyses were conducted to determine the dose–response relationship between liver TCA AUC and the additional risk of hepatocellular adenomas or carcinomas (combined) in mice ingesting TCA. Using the dose–response relationships derived for the TCA-exposed mice, the contribution of TCA produced by metabolism to the additional risk of liver adenomas and carcinomas in mice exposed to perchloroethylene by inhalation was computed. The analysis indicated that the levels of TCA observed in perchloroethylene-exposed mice are sufficient to explain the incidence of liver adenomas and carcinomas.