| Title: | Extrapolating the acute behavioral effects of toluene from 1- to 24-h exposures in rats: roles of dose metric and metabolic and behavioral tolerance |
| Author(s): | Oshiro WM; Kenyon EM; Gordon CJ; Bishop B; Krantz QT; Ford J; Bushnell PJ; |
| Address: | "Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA" |
| ISSN/ISBN: | 1096-0929 (Electronic) 1096-0929 (Linking) |
| Abstract: | "Recent research on the acute effects of volatile organic compounds suggests that extrapolation from short ( approximately 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. 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 x 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 x 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" |
| Keywords: | "Animals Behavior, Animal/*drug effects Brain/drug effects/metabolism Databases, Protein Dose-Response Relationship, Drug Inhalation Exposure Learning/drug effects Male Models, Biological Rats Rats, Long-Evans Reaction Time/drug effects Signal Detection, P;" |
| Notes: | "MedlineOshiro, W M Kenyon, E M Gordon, C J Bishop, B Krantz, Q T Ford, J Bushnell, P J eng Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. 2011/06/28 Toxicol Sci. 2011 Sep; 123(1):180-92. doi: 10.1093/toxsci/kfr162. Epub 2011 Jun 24" |
