Physiological pharmacokinetic modeling of inhaled trichloroethylene in rats

Abstract

The pharmacokinetics of trichloroethylene (TCE) was characterized during and following inhalation exposures of male Sprague-Dawley rats. The blood and exhaled breath TCE time-course data were used to formulate and assess the accuracy of predictions of a physiologically based pharmacokinetic (PB-PK) model for TCE inhalation. Fifty or 500 ppm of TCE was inhaled by unanesthetized rats of 325-375 g for 2 hr through a miniaturized one-way breathing valve. Repetitive samples of the inhaled and exhaled breath streams, as well as arterial blood, were collected concurrently during and for 3 hr following the exposures and analyzed for TCE by headspace gas chromatography. Respiratory rates and volumes were continuously monitored and used in conjunction with the pharmacokinetic data to delineate uptake and elimination profiles. Levels of TCE in the exhaled breath attained near steady-state soon after the beginning of exposures, and were then directly proportional to the inhaled concentration. Exhaled breath levels of TCE in rats were similar in magnitude to values previously published for TCE inhalation exposures of humans. Levels of TCE in the blood of the 50 ppm-exposed animals also rapidly approached near steady-state, but blood levels in the 500 ppm-exposed animals rose progressively, reaching concentrations 25- to 30-fold higher than in the 50 ppm group during the second hour of exposure. The 10-fold increase in inhaled concentration resulted in an 8.7-fold increase in cumulative uptake, or total absorbed dose. These findings of nonlinearity indicate that metabolic saturation ensued during the 500 ppm exposure. The PB-PK model was characterized as blood flow-limited with TCE eliminated unchanged in the exhaled breath and by saturable liver metabolism. The uptake and elimination profiles were accurately simulated by the PB-PK model for both the 50 and 500 ppm TCE exposure levels. Such a model may be quite useful in risk assessments in predicting internal (i.e., systemically absorbed) doses of TCE and other volatile organics under a variety of exposure scenarios.