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.
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.
authors.affiliation: 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.
authors.forename: W M
authors.initials: WM
authors.lastname: Oshiro
authors.forename: E M
authors.initials: EM
authors.lastname: Kenyon
authors.forename: C J
authors.initials: CJ
authors.lastname: Gordon
authors.forename: B
authors.initials: B
authors.lastname: Bishop
authors.forename: Q T
authors.initials: QT
authors.lastname: Krantz
authors.forename: J
authors.initials: J
authors.lastname: Ford
authors.forename: P J
authors.initials: PJ
authors.lastname: Bushnell
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D030562:Databases, Protein; D004305:Dose-Response Relationship, Drug; D019570:Inhalation Exposure; D007858:Learning / Q000187:drug effects; D008297:Male; D008954:Models, Biological; D051381:Rats; D020318:Rats, Long-Evans; D011930:Reaction Time / Q000187:drug effects; D017603:Signal Detection, Psychological / Q000187:drug effects; D012997:Solvents / Q000493:pharmacokinetics / Q000633:toxicity*; D013997:Time Factors; D014050:Toluene / Q000493:pharmacokinetics / Q000633:toxicity*; D023382:Toxicity Tests, Acute
chemical_list: D012997:Solvents; D014050:Toluene