CHARACTERIZATION OF PRESYSTEMIC ELIMINATION OF TRICHLOROETHYLENE AND ITS NONLINEAR KINETICS IN RATS

1,1,2-Trichloroethylcne (TCE) is a volatile organic chemical which con taminates drinking water and food supplies and is primarily of concern because of the risk of cancer it may pose. The objectives of the pres ent study were to evaluate the efficiency and dose dependency of presy stemic elimination of TCE in rats. Cannulas were surgically implanted into male Sprague-Dawley rats (330-380 g) 24 hr before TCE dosing. TCE (0.17, 0.33, 0.71, 2, 8, 16, and 64 mg/kg) in a 5% aqueous Aikamuls e mulsion was administered over 30 sec into the carotid artery, jugular vein (JV), hepatic portal vein, or the stomach. Serial arterial blood samples of 1-500 mu l were collected for up to 12 hr from the unanesth etized animals and analyzed for TCE content by headspace gas chromatog raphy. Pharmacokinetic analyses indicated that TCE was eliminated thro ugh dose-dependent, nonlinear processes. A three-compartment model wit h Michaelis-Menten and first-order elimination was derived to fit simu ltaneously the TCE blood data following JV administration. Total presy stemic elimination of TCE was inversely related to dose, ranging from approximately 60 to <1%. A dose-dependent decrease in hepatic extracti on was primarily responsible for the reduction in total first-pass eli mination at high doses, whereas pulmonary extraction (i.e., 5-8%) was relatively constant over the dosage range. When metabolic saturation w as minimal or absent, hepatic presystemic elimination of TCE accounted for approximately 45-55% of the administered dose, These findings ind icate that a substantial proportion of trace amounts of VOCs ingested in environmental media may not enter the systemic circulation nor reac h extrahepatic target organs. (C) 1996 Academic Press, Inc.