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Predicting the acute behavioral effects in rats inhaling toluene for up to 24 hrs: Inhaled vs, internal dose metrics and tolerance.
Citation:
OSHIRO, W. M., Q. T. KRANTZ, C. J. GORDON, E. M. KENYON, AND P. J. BUSHNELL. Predicting the acute behavioral effects in rats inhaling toluene for up to 24 hrs: Inhaled vs, internal dose metrics and tolerance. Presented at Neurobehavorial Teratology Society Annual meeting, Louisville, KY, June 25, 2010.
Impact/Purpose:
abstract for meeting
Description:
The acute toxicity of toluene, a model volatile organic compound (VOC), depends on the concentration (C) and duration (t) of exposure, and guidelines for acute exposures have traditionally used extrelationships to extrapolate protective and/or effective concentrations across durations of exposure. Recent research suggests an alternative approach for duration adjustment, which uses PBPK model-derived estimates of internal dose as the basis for duration extrapolation. For example, acute behavioral effects observed in rats performing a visual signal detection task (SDT) while being exposed to common VOCs (including toluene) for up to 1 hour are better predicted by the momentary concentration of the VOC in the brain at the time ofthe observed effect than by the extproduct. The current study was designed to compare the ability ofthe two approaches to predict acute effects incurred during exposures to toluene lasting up to 24 h. Thus, 16 male, Long-Evans rats were trained to perform the SDT, and then were exposed to toluene at concentrations of 0, 1125 and 1450 ppm for 24 h and to 1660 ppm for 21 h. During each exposure the animals were tested at times predetermined to yield comparable extproducts (2900, 8700,27,000 and 34,800 ppm-h) but differing estimates of brain toluene concentrations (estimated by a PBPK model to range from 80 to 140 mg/L). Results showed that toluene reduced accuracy and increased response time, and these effects were better predicted by the brain toluene concentration than by either the inhaled C or C x t product of exposure. Nevertheless, effects of 24-hr exposures were far less severe than effects of l-hr exposures, even when gauged against the estimated concentration oftoluene in the brain. Thus, whereas use of an internal dose metric improved prediction of acute behavioral effects oftoluene, this metric did not improve the accuracy of extrapolating from short-to long-duration exposures, which was complicated by the development of both metabolic and behavioral tolerance to the acute effects oftoluene. (This abstract does not necessarily reflect EPA policy.)