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Extrapolating the Acute Behavioral Effects of Toluene from 1-Hour to 24-Hour Exposures in Rats: Roles of Dose Metric, and Metabolic and Behavioral Tolerance.
Citation:
OSHIRO, W. M., E. M. KENYON, C. J. GORDON, B. Bishop, Q. T. KRANTZ, J. Ford, AND P. J. BUSHNELL. Extrapolating the Acute Behavioral Effects of Toluene from 1-Hour to 24-Hour Exposures in Rats: Roles of Dose Metric, and Metabolic and Behavioral Tolerance. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 123(1):180-92, (2011).
Impact/Purpose:
The current manuscript supports previous observations that the concentration of toluene in the brain more accurately predicts its acute neurological effects than does the cumulative inhaled dose (C x t). More importantly, it extends the duration for which this dose metric applies to exposures lasting up to 24 hr. However, these findings also demonstrate that the acute effects of 24-h exposure to toluene cannot be accurately predicted from the effects of a 1-h exposure by use of either dose metric due to both metabolic induction and behavioral tolerance induced by prolonged exposure. Consideration of both kinetic and dynamic processes should be applied when setting acute exposure guidelines (AEGLs) or provisional advisory levels (PALs) for compounds like toluene that induce tolerance (e.g. ethanol and many VQCs).
Description:
Recent research on the acute effects of volatile organic compounds (VQCs) suggests that extrapolation from short (~ 1 h) to long durations (up to 4 h) may be improved by using estimates of brain toluene concentration (Br[Tol]) instead of cumulative inhaled dose (C x t) as a metric of dose. This study compared predictions of these two dose metrics on the acute behavioral effects of inhaled toluene in rats during exposures up to 24 h in duration. 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 behavioral 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 were trained to perform a visual signal detection task and were then tested while inhaling toluene (0, 1125 and 1450 ppm for 24 hand 1660 ppm for 21 h). Tests occurred at times Yielding equivalent ext products but different estimates of Br[Tol], and also at 1 and 6 h post exposure. Effects of toluene were better predicted by Br[Tol] than by ext. 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 I-h exposures, indicating that behavioral tolerance developed during prolonged exposure to toluene, in addition to the induction of metabolism
