Extrapolating the acute behavioral effects of toluene from 1- to 24-h exposures in rats: roles of dose metric and metabolic and behavioral tolerance

• Published in: Toxicological sciences 2011-09, Vol.123 (1), p.180-192
• Main Authors: Oshiro, W M, Kenyon, E M, Gordon, C J, Bishop, B, Krantz, Q T, Ford, J, Bushnell, P J
• Format: Article
• Language: English
• Subjects: Animals; Behavior, Animal - drug effects; Brain - drug effects; Brain - 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, Psychological - drug effects; Solvents - pharmacokinetics; Solvents - toxicity; Time Factors; Toluene - pharmacokinetics; Toluene - toxicity; Toxicity Tests, Acute
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfr162

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.