Tags

Type your tag names separated by a space and hit enter

Extrapolating the acute behavioral effects of toluene from 1- to 24-h exposures in rats: roles of dose metric and metabolic and behavioral tolerance.
Toxicol Sci. 2011 Sep; 123(1):180-92.TS

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+Show Affiliations

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.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

21705712

Citation

Oshiro, W M., et al. "Extrapolating the Acute Behavioral Effects of Toluene From 1- to 24-h Exposures in Rats: Roles of Dose Metric and Metabolic and Behavioral Tolerance." Toxicological Sciences : an Official Journal of the Society of Toxicology, vol. 123, no. 1, 2011, pp. 180-92.
Oshiro WM, Kenyon EM, Gordon CJ, et al. Extrapolating the acute behavioral effects of toluene from 1- to 24-h exposures in rats: roles of dose metric and metabolic and behavioral tolerance. Toxicol Sci. 2011;123(1):180-92.
Oshiro, W. M., Kenyon, E. M., Gordon, C. J., Bishop, B., Krantz, Q. T., Ford, J., & Bushnell, P. J. (2011). Extrapolating the acute behavioral effects of toluene from 1- to 24-h exposures in rats: roles of dose metric and metabolic and behavioral tolerance. Toxicological Sciences : an Official Journal of the Society of Toxicology, 123(1), 180-92. https://doi.org/10.1093/toxsci/kfr162
Oshiro WM, et al. Extrapolating the Acute Behavioral Effects of Toluene From 1- to 24-h Exposures in Rats: Roles of Dose Metric and Metabolic and Behavioral Tolerance. Toxicol Sci. 2011;123(1):180-92. PubMed PMID: 21705712.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Extrapolating the acute behavioral effects of toluene from 1- to 24-h exposures in rats: roles of dose metric and metabolic and behavioral tolerance. AU - Oshiro,W M, AU - Kenyon,E M, AU - Gordon,C J, AU - Bishop,B, AU - Krantz,Q T, AU - Ford,J, AU - Bushnell,P J, Y1 - 2011/06/24/ PY - 2011/6/28/entrez PY - 2011/6/28/pubmed PY - 2011/12/21/medline SP - 180 EP - 92 JF - Toxicological sciences : an official journal of the Society of Toxicology JO - Toxicol Sci VL - 123 IS - 1 N2 - 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. SN - 1096-0929 UR - https://www.unboundmedicine.com/medline/citation/21705712/Extrapolating_the_acute_behavioral_effects_of_toluene_from_1__to_24_h_exposures_in_rats:_roles_of_dose_metric_and_metabolic_and_behavioral_tolerance_ L2 - https://academic.oup.com/toxsci/article-lookup/doi/10.1093/toxsci/kfr162 DB - PRIME DP - Unbound Medicine ER -