You are here:
Modeling the toxicokinetics of 24-hour toluene exposure in rats, impact of activity patterns and enzyme induction
Citation:
KENYON, E. M., W. M. OSHIRO, C. R. EKLUND, C. Gordon, Q. T. KRANTZ, AND P. J. BUSHNELL. Modeling the toxicokinetics of 24-hour toluene exposure in rats, impact of activity patterns and enzyme induction. Presented at Society of Toxicology 49th Annual Meeting, Salt Lake City, UT, March 07 - 11, 2010.
Impact/Purpose:
This work supports development of extrapolation factors and principles to predict the concentration of solvents following differing durations of inhalation exposure
Description:
Toluene, a solvent used in numerous consumer and industrial applications, exerts its critical effects on the brain and nervous system following inhalation exposure. Our previously published PBPK model successfully predicted toluene concentrations in blood and brain over a range of conditions, but in recent experimental studies it over-predicted (by -2-fold) concentrations in blood and brain after 24 hrs of continuous exposure to 775 or 1125 ppm toluene. The goal of this current modeling effort was to determine if changes in physical activity patterns (as measured by telemetry) and/or enzyme induction could explain toluene pharmacokinetics following 24 hrs of continuous exposure to toluene. Compartments in the model are lung, slowly and rapidly-perfused tissue groups, fat, liver, GI tract and brain; tissue transport is blood-flow limited and metabolism occurs in the liver. Chemical-specific parameters and initial organ volumes and blood flow rates were obtained from the literature. Observed changes in motor activity and heart rate during the period of exposure were implemented in the model by increasing cardiac output and alveolar ventilation up to 10%, but this was insufficient to account for the observed pharamacokinetic behavior. Alternatively, incorporation of cytochrome P450mediated enzyme induction (increasing VmaxC up to 5-fold) allowed successful prediction of the experimental data. The degree of enzyme induction tested was biologically plausible based on literature data for shorter term toluene exposure which report up to 8.3-fold induction. Our results suggest the need to consider the potential impact of enzyme induction when simulating chronic toxicity studies for purposes of risk analysis, i.e. when using a PBPK model to obtain estimates of internal dose for application to dose.-response analysis. (This abstract does not necessarily reflect EPA policy.)