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ToxSci Advance Access published online on June 4, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm146
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Published by Oxford University Press 2007.

A Dosimetric Analysis of the Acute Behavioral Effects of Inhaled Toluene in Rats

Philip J. Bushnell1, Wendy M. Oshiro1, Tracey E. Samsam1, Vernon A. Benignus2, Q. Todd Krantz3 and Elaina M. Kenyon3

1 Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 2 Human Studies Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 3 Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina

Correspondence concerning this article should be addressed to: Philip J. Bushnell, Ph.D. , Neurotoxicology Division, B105-04, US Environmental Protection Agency , Research Triangle Park, NC 27711, Tel: 919/541-7747, FAX: 919/541-4849, Email: bushnell.philip{at}epa.gov

Received February 16, 2007; revision received May 16, 2007; accepted May 25, 2007


  Abstract

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 toluene concentration 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 toluene concentration, duration of exposure, the area under the curve of either exposure (ppm-hr) or modeled brain toluene concentration (mg-hr/kg), provided unambiguous predictions of effect. Thus the acute behavioral effects of toluene (and of other VOCs with a similar mode of action) can be predicted for complex exposure scenarios by simulations that estimate the concentration of the VOC in the brain from the exposure scenario.

Key Words: Attention; Dose metric; Signal detection behavior; Toxicokinetics; Volatile organic compounds.


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