Use of a physiologically based model to predict systemic uptake and respiratory elimination of perchloroethylene.
The pharmacokinetics of inhaled perchloroethylene (PCE) were studied in male Sprague-Dawley rats to characterize the pulmonary absorption and elimination of the volatile organic chemical (VOC). The direct measurements of the time course of PCE in the blood and breath were used to evaluate the ability of a physiologically based pharmacokinetic (PBPK) model to predict systemic uptake and elimination of PCE. Fifty or 500 ppm PCE was inhaled for 2 hr through a miniaturized one-way breathing valve by unanesthetized male Sprague-Dawley rats of 325-375 g. Serial samples of the inhaled and exhaled breath streams, as well as arterial blood, were collected during and following PCE inhalation and analyzed by headspace gas chromatography. PCE-exhaled breath concentrations increased rapidly to near steady state (i.e., within 20 min) and were directly proportional to the inhaled concentration. Uptake of PCE into the blood was also rapid, but blood levels continued to increase progressively over the course of the 2-hr exposure at both exposure levels. Cumulative uptake, or total absorbed dose, was not proportional to the exposure level. A PBPK model was developed from in vivo parameters determined from tissue concentration-time data in a companion ia study (Dallas et al., 1994, Toxicol. Appl. Pharmacol. 128, 50-59). PCE concentrations in the blood and exhaled breath during and following PCE inhalation were well predicted by the PBPK model. Despite species differences in blood:air and lung:air partition coefficients, the model was used to account for similar levels of PCE and other VOCs in the expired air of rats and humans. The model also accurately simulated percentage uptake and cumulative uptake of PCE over time. The model's ability to predict systemically absorbed doses of PCE under a variety of exposure scenarios should be useful in assessment of risks in occupational and environmental settings.
Dallas
C E
CE
Department of Pharmacology and Toxicology, College of Pharmacy, University of Georgia, Athens 30602-2356.
Muralidhara
S
S
Chen
X M
XM
Ramanathan
R
R
Varkonyi
P
P
Gallo
J M
JM
Bruckner
J V
JV
D000042:Absorption; D000280:Administration, Inhalation; D000393:Air Pollutants / Q000032:analysis; D000818:Animals; D001273:Atmosphere Exposure Chambers; D001944:Breath Tests; D002849:Chromatography, Gas; D008168:Lung / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D011659:Pulmonary Gas Exchange; D051381:Rats; D017207:Rats, Sprague-Dawley; D013750:Tetrachloroethylene / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D000393:Air Pollutants; D013750:Tetrachloroethylene