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A DOSIMETRIC ANALYSIS OF THE ACUTE BEHAVIORAL EFFECTS OF INHALED TOLUENE IN RATS
Citation:
BUSHNELL, P. J., W. M. OSHIRO, T. E. SAMSAM, V. A. BENIGNUS, AND E. M. KENYON. A DOSIMETRIC ANALYSIS OF THE ACUTE BEHAVIORAL EFFECTS OF INHALED TOLUENE IN RATS. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 99(1):181-189, (2007).
Impact/Purpose:
This manuscript provides new information regarding the acute behavioral effects of toluene, a hazardous air pollutant with acute neurotoxic activity. Toluene is a prototype chemical of the class of volatile organic compounds (VOCs), which have similar kinetic behavior and CNS activity. It is being used to develop an exposure-dose-response (EDR) model for VOCs. When complete, the EDR model will enable quantitative predictions of the effect of VOCs on the nervous system. Utility of the model requires knowledge of the dose metric associated with its toxicity: that is, the measure of dose that is most closely associated with the effect of concern. Using rats and physiologically-based toxicokinetic modeling, this paper demonstrates that the detrimental effects of inhaled toluene on signal detection behavior (a test of sustained attention in humans and in animals) are quantitatively predicted by the concentration of toluene in the brain of the rat at the time that the behavior is measured. Other metrics, including inhaled concentration, duration of exposure, cumulative inhaled exposure, and cumulative dose to the brain, do not predict its effects unambiguously. This critical piece of information, which also applies to neurophysiological measures of visual function, now enables further development of the EDR model, using brain concentration as the dose metric.
Description:
Knowledge of the appropriate metric of dose for a toxic chemical facilitates quantitative extrapolation of toxicity observed in the laboratory to the risk of adverse effects in the human population. Here we utilize a physiologically-based toxicokinetic (PBTK) model for toluene, a common volatile organic compound (VOC), to illustrate that its acute behavioral effects in rats can be quantitatively predicted on the basis of its concentration in the brain. Rats previously trained to perform a visual signal detection task for food reward performed the task while inhaling toluene (0, 1200, 1600, 2000, and 2400 ppm in different test sessions). Accuracy and speed of responding were both decreased by toluene; the magnitude of these effects increased with increasing concentration of the vapor and with increasing duration of exposure. Converting the exposure conditions to brain concentration of toluene using the PBTK model yielded a family of overlapping curves for each endpoint, illustrating that the effects of toluene can be described quantitatively by its internal dose at the time of behavioral assessment. No other dose metric, including inhaled concentration, duration of exposure, the area under the curve of either exposure (ppm-hr) or brain concentration (mg-hr/kg), provided unambiguous predictions of effect. Thus acute effects of toluene (and of other VOCs with a similar mode of action) can be predicted for complex exposure scenarios by simulations that convert the exposure scenario into brain concentration.
