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PREDICTING THE ACUTE BEHAVIORAL EFFECTS OF TOLUENE INHALED FOR 24 HRS IN RATS: DOSE METRICS, METABOLISM AND BEHAVIORAL TOLERANCE
Citation:
BUSHNELL, P. J., W. M. OSHIRO, Q. T. KRANTZ, C. J. GORDON, E. M. KENYON, AND J. Ford. PREDICTING THE ACUTE BEHAVIORAL EFFECTS OF TOLUENE INHALED FOR 24 HRS IN RATS: DOSE METRICS, METABOLISM AND BEHAVIORAL TOLERANCE. Presented at International Neurotoxicology Association Meeting, X'ian, CHINA, June 05 - 10, 2011.
Impact/Purpose:
These results indicate that effects of short (I-h) exposure to toluene over-predict effects measured during a 24-h exposure, probably because behavioral tolerance developed during prolonged exposure to toluene in addition to the induction of metabolism
Description:
Purpose: Recent research on the acute effects of volatile organic compounds (VOCs) suggests that extrapolation from short (~ 1 h) to long durations (up to 4 h) is improved by using estimates of brain toluene concentration ( Br[ToI)] instead of cumulative inhaled dose (C x t) as a metric of dose. This study compared predictions by these two dose metrics of the acute behavioral effects of inhaled toluene in rats during exposures up to 24 h in duration. Methods: We first evaluated estimates of Br[Tol] with a physiologically-based toxicokinetic (PBTK) model for rats intermittently performing an operant task while inhaling toluene for up to 24 h. Exposure longer than 6 h induced P450-mediated metabolism of toluene, and operant testing increased heart rate by ~10%. Adjusting the corresponding parameters of the PBTK model improved agreement between estimated and observed values of Br[Tol] in the 24-h exposure scenario. Rats trained to perform a visual signal detection task then inhaled toluene (0, 1125 and 1450 ppm for 24 h and 1660 ppm for 21 h) while performing the test. Rats were tested at exposure times that yielded equivalent C x t products but different estimates of Br[Tol], and also at 1 and 6 h post exposure. Results: Effects of toluene on accuracy and response time were better predicted by Br[Tol] than by C x t. However, even using Br[Tol] as the dose metric (thus accounting for metabolic induction), acute dose-effect functions during 24-h exposures were shifted to the right relative to 1-h exposures. Conclusions: These results indicate that effects of short (I-h) exposure to toluene over-predict effects measured during a 24-h exposure, probably because behavioral tolerance developed during prolonged exposure to toluene in addition to the induction of metabolism. This abstract does not reflect EPA policy.