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ROUTE-DEPENDENT EFFECTS OF TOLUENE ON SIGNAL DETECTION BEHAVIOR IN RATS.
Citation:
Bushnell, P J., T E. Samsam, W M. Oshiro, C R. Eklund, AND M V. Evans. ROUTE-DEPENDENT EFFECTS OF TOLUENE ON SIGNAL DETECTION BEHAVIOR IN RATS. Presented at Society of Toxicology, New Orleans, LA, March 06 - 10, 2005.
Description:
The acute effects of toluene and other solvents on behavior are thought to depend upon their concentration in the brain. We have shown previously that inhaled toluene and trichloroethylene disrupt sustained attention in rats as assessed with a visual signal detection task (SDT). To test the hypothesis that acute toxicity of solvents is mediated exclusively by their internal dose, and to develop a dosing regimen not requiring inhalation equipment, we explored the efficacy of toluene given by the oral route on this task. Toluene was dissolved in corn oil and administered to 25 adult male Long-Evans rats by gavage at doses of 0, 400, 800, 1200, and 1600 mg/kg in two separate studies. Two rats in each study failed to work at the highest dose; toluene did not significantly affect performance of the other rats at any dose. Internal doses of toluene (concentrations in blood and brain) at the times of behavioral assessment were estimated for both exposure routes. Concentrations of toluene in the blood after oral dosing were estimated from published data in the literature, and concentrations in blood and brain during inhalation were estimated using a physiologically-based toxicokinetic (PBTK) model developed in our laboratory. Whereas the effects of inhaled toluene on the SDT (accuracy of signal detection and response time) were monotonically related to the concentration of toluene in blood and in brain, SDT performance was not affected by oral toluene, despite nearly-complete overlap in the range of internal doses produced by the two routes of administration (10 to 50 ug/mL in blood). These observations indicate that the momentary concentration of toluene in the brain is an insufficient dose metric for explaining its effects on signal detection behavior, and complicate route extrapolations based on this dose metric. Hypotheses regarding these route-dependent effects are explored in an accompanying poster (Samsam et al.) [This abstract of a proposed presentation does not reflect EPA policy.]