DOSE-DEPENDENT BINDING OF TRICHLOROETHYLENE TO HEPATIC DNA AND PROTEIN AT LOW-DOSES IN MICE

Trichloroethylene (TCE) is a widely used industrial chemical and a low level contaminant of surface and ground water in industrialized areas . It is weakly mutagenic in several test systems and carcinogenic in r odents. However, the mechanism for its carcinogenicity is not known. W e investigated the binding of [1,2-C-14]TCE ([C-14]TCE) to liver DNA a nd proteins in male B6C3F1 mice at doses more relevant to humans than used previously. The time course for the binding was studied in animal s dosed with 4.1 mu g [C-14]TCE/kg body weight (b.w.) and sacrificed b etween 0.5 and 120 h after i.p. injection. A dose response study was c arried out in mice given [C-14]TCE at doses between 2 mu g/kg and 200 mg/kg b.w. and sacrificed 2 h post-treatment. [C-14]TCE associated wit h the DNA and protein extracts was measured using accelerator mass spe ctrometry. The highest level of protein binding (2.4 ng/g protein) was observed 1 h after the treatment followed by a rapid decline, indicat ing pronounced instability of the adducts and/or rapid turnover of liv er proteins. DNA binding was biphasic with the first peak (75 pg/g DNA ) at 4 h. However, the highest binding (120 pg/g DNA) was found betwee n 24 and 72 h after the treatment. Dose response curves were linear fo r both protein and DNA binding. The binding of TCE metabolites to DNA was ca. 100-fold lower than to proteins when calculated per unit weigh t of macromolecules and when measured 2 h post-exposure. This study sh ows that TCE metabolites bind to DNA and proteins in a dose-dependent manner in liver, one of the target organs for its tumorigenicity. Thus , protein and DNA adduct formation should be considered as a factor in the tumorigenesis of TCE. (C) 1997 Elsevier Science Ireland Ltd.