Regular Article
Development of a Physiologically-Based Pharmacokinetic Model for Perchloroethylene Using Tissue Concentration-Time Data

https://doi.org/10.1006/taap.1994.1179Get rights and content

Abstract

The tissue disposition of perchloroethylene (PCE) was characterized experimentally in rats in order to (1) obtain input parameters from in vivo data for the development of a physiologically based pharmacokinetic (PBPK) model, and (2) use the PBPK model to predict the deposition of PCE in a variety of tissues following inhalation exposure. For the derivation of model input parameters, male Sprague-Dawley rats received a single bolus of 10 mg PCE/kg body wt in polyethylene glycol 400 by ia injection through an indwelling carotid arterial cannula. Other male Sprague-Dawley rats inhaled 500 ppm PCE for 2 hr in dynamic exposure inhalation chambers. Serial samples of brain, liver, kidney, lung, heart, skeletal muscle, perirenal fat, and blood were taken for up to 72 hr following ia injection, during the 2-hr inhalation exposure, and for up to 72 hr postexposure. Blood and tissue PCE concentrations were analyzed using a gas chromatography headspace technique. Following ia administration, the tissues exhibited similar terminal elimination half-lives (t12). As comparable tissue t12s are consistent with a blood-flow-limited model, tissue:blood partition coefficients were calculated for noneliminating compartments by division of the area under the tissue concentration-time curve (AUC) by the blood AUC. Liver PCE concentration versus time data were employed in the calculation of in vivo metabolic rate constants. A PBPK model was developed using these parameters derived from the ia data set and used to predict tissue PCE concentrations during and following PCE inhalation. Predicted tissue levels were in close agreement with the levels measured over time in the seven tissues and in blood. Tissue concentration-time data can thus provide valuable input for parameter estimation and for validation of PBPK model simulations, as long as independent in vivo data sets are used for each step.

References (0)

Cited by (27)

  • Development and evaluation of a harmonized physiologically based pharmacokinetic (PBPK) model for perchloroethylene toxicokinetics in mice, rats, and humans

    2011, Toxicology and Applied Pharmacology
    Citation Excerpt :

    As expected, the optimized parameters had increased oxidation and decreased conjugation, resulting in a clear improvement in model fit across all the data (see Fig. 6B, and Table 8 calibration data residuals). For rat calibration data, the poorest fits are to the fraction of retained perc metabolized and rate of perc exhalation (both from Reitz et al., 1996) and perc in various tissues (from Dallas et al., 1994a, 1994c; and Warren et al., 1996), with residual errors of 2- to 3-fold. As with mice, it is unclear how to completely reconcile the extremely well-fit closed chamber data with the more poorly fit C-14 data from Reitz et al. (1996), but inter-study variation cannot be ruled out.

View all citing articles on Scopus
View full text