You are here:
A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL FOR TRICHLOROETHYLENE WITH SPECIFICITY FOR THE LONG EVANS RAT
Citation:
Simmons, J E., W K. Boyes, P J. Bushnell, J. H. Raymer, T. Limsakun, A McDonald, Y M. Sey, AND M V. Evans. A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL FOR TRICHLOROETHYLENE WITH SPECIFICITY FOR THE LONG EVANS RAT. Presented at Society of Toxicology, San Francisco, CA, March 25 - 29, 2001.
Description:
A PBPK model for TCE with specificity for the male LE rat that accurately predicts TCE tissue time-course data has not been developed, although other PBPK models for TCE exist. Development of such a model was the present aim. The PBPK model consisted of 5 compartments: fat; slowly perfused tissue; rapidly perfused viscera; brain; and liver. Optimization for Vmaxc and all tissue data simulations were conducted with Simusolv?. Partition coefficients (blood, fat, muscle, brain, liver) for LE rats were determined by vial equilibration techniques. The volumes of the brain, liver and fat compartments were estimated, for each rat, with tissue-specific regression equations that were developed from measurements made in LE rats of 3 ages (72, 102 and 149 days). Gas uptake data from LE rats (initial concentrations of 100, 500, 1000 and 3000 ppm TCE) were used for estimation of Vmaxc (Km set to 0.25 mg/1). As blood flow values for LE rats were not available, values from both Sprague-Dawley (SD) (Delp et al., 1991) and F-344 (Delp et al., 1998) rats were used. Use of SD flows resulted in a Vmaxc of 5.77 mg/hr/kg. Use of F-344 flows resulted in a Vmaxc of 6.34 mg/hr/kg and a slight improvement of the model fit to the 100 ppm uptake data. Tissue (blood, liver, brain, fat) TCE concentrations were measured during (5, 20, 60 min) and after (60 min of TCE followed by 60 min of air) flow-through inhalation exposures of LE rats to 200, 2000 or 4000 ppm TCE. Better fits to the tissue data were obtained with F-344 blood flow values and the Vmaxc derived using F-344 flows than with SD flows and the Vmaxc derived using SD flows. In conclusion, a PBPK model was developed for the LE rat. Until LE blood flow data are available, use of F-344 blood flows are recommended. The present model is being used to examine the relationship between TCE tissue concentration and functional effects on the nervous system. (This abstract may not reflect EPA policy.)