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.

A review of perchloroethylene and rat mononuclear cell leukemia.

Mononuclear cell leukemia (MNCL) is an extremely common spontaneous disease of ageing F344 rats accompanied by splenomegaly, anemia, thrombocytopenia, and leukemic infiltration (initially of the spleen, liver, and lung). Rare in other rat strains, incidence in F344 rats is variable, has been increasing, and can exceed 70% in controls. MNCL cells possess natural killer (NK) cell characteristics and apparently, the neoplastic cells derive from large granular lymphocytes (LGL), hence the alternative name of LGL leukemia. LGL leukemia is uncommon in man and occurs in two forms: T-LGL leukemia which has a chronic course, and the much rarer NK-LGL leukemia. In addition to cell type, the latter resembles F344 LGL leukemia being acute in course and involving more pronounced splenomegaly and thrombocytopenia. Chemically related increases in MNCL in F344 rats have not been associated with induction of human LGL leukemia. Carcinogenicity studies of perchloroethylene (PERC) in several rat strains have shown moderate, not clearly dose-related, increases in MNCL only in F344 rats (two studies). There was no consistent decrease in latency and the incidence in the PERC treated groups is within the overall control range. As a response in a rat strain highly predisposed to developing MNCL, these results are not considered predictive for human cancer risk.