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A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL FOR TOLUENE IN THE LONG EVANS RAT: BODY COMPOSITION AND PHYSICAL ACTIVITY.
Citation:
Samsam, T E., W M. Oshiro, T. L. Jackson, E M. Kenyon, W K. Boyes, AND P J. Bushnell. A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL FOR TOLUENE IN THE LONG EVANS RAT: BODY COMPOSITION AND PHYSICAL ACTIVITY. Presented at Society of Toxicology, Nashville, TN, 3/17/2002.
Description:
A physiologically-based pharmacokinetic (PBPK) model for inhaled toluene was developed for Long-Evans rats as a component of an exposure-dose-response (EDR) model for volatile organic compounds. The PBPK model was needed to link airborne toluene exposure to its concentration in blood and brain, the target organ for its neurotoxicity. The acute neurotoxicity of toluene was quantified in rats as impaired detection of visual signals and reduced visual evoked potentials (VEPs). The model required evaluation under test conditions for both of these endpoints, i.e., signal detection behavior is measured in weight-maintained, physically-active rats, whereas VEPs are measured in rats fed ad libitum and restrained during testing. Blood and brains were obtained from 64 sedentary rats, either weight-maintained (350 g) or fed ad libitum (400 ? 500 g), after inhaling toluene at either 200 or 2000 ppm for 5, 20, or 60 min, or 60 min after a 60-min exposure to toluene (n = 4/gp). Weight maintenance had little effect on either predicted or observed concentrations of toluene. Effects of toluene on signal detection were not readily predicted by parameters of exposure, but were accurately predicted by concentrations of toluene in brain and blood estimated by the model. In contrast to the lack of effect of weight status, higher values of cardiac output and alveolar ventilation, expected as a result of physical activity, greatly increased the tissue concentrations of toluene predicted by the model. We are currently evaluating heart rate, obtained by telemetry from rats performing the signal detection task, as an index of activity-induced elevations of cardiac output and ventilation rate in the PBPK model. Adjusting these parameters for physical activity will improve the accuracy of the estimated concentrations of toluene necessary to impair signal detection. (This abstract does not necessarily reflect EPA policy.)