Extrapolating the Acute Behavioral Effects of Toluene from 1- to 24-h Exposures in Rats: Roles of Dose Metric and Metabolic and Behavioral Tolerance

Abstract

Recent research on the acute effects of volatile organic compounds 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 × 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. 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 h and 1660 ppm for 21 h). Tests occurred at times yielding equivalent C × t products but different estimates of Br[Tol], and also at 1 and 6 h afterexposure. Effects of toluene were better predicted by Br[Tol] than by C × t. However, even using Br[Tol] as the dose metric (after accounting for metabolic induction), acute dose-effect functions during 24-h exposures were shifted to the right relative to 1-h exposures, indicating that a dynamic behavioral tolerance also developed during prolonged exposure to toluene.

Use of novel inhalation kinetic studies to refine physiologically-based pharmacokinetic models for ethanol in non-pregnant and pregnant rats

“…Exposures were performed using custom made, stainless steel W-B exposure chambers (39.2 L) described previously (Kenyon et al, 2008;Oshiro et al, 2011). Methodological details for EtOH vapor generation were similar to those described in Experiment 1.…”

“…Eyes were not immediately minced and could not be homogenized due to the small mass. Brain samples were immediately treated with ice-cold phosphate buffer solution and homogenized thoroughly using a stand homogenizer with metal blades (Polytron, Kinematica, Inc., Bohemia, NY) prior to storage, as per established methods for chemicals such as toluene (Oshiro et al, 2011). Blood and brain samples were treated with the inhibition cocktail upon removal from the freezer, prior to analysis.…”