A Dosimetric Analysis of Behavioral Effects of Acute Toluene Exposure in Rats and Humans

Abstract

The literature on behavioral effects of exposure to toluene is difficult to assess due, in part, to a wide variety of exposure conditions employed and outcomes measured. This study investigated whether previous experiments would be more consistent with each other if toluene exposure parameters were expressed not as concentration and duration, but as estimated amount of toluene in tissues. A physiologically based pharmacokinetk (PBPK) model was used to estimate concentration of toluene in arterial blood (⁠C¯aTOL) from published studies in rats and humans exposed acutely to toluene vapor. Data for rats were selected from studies of avoidance behavior using both rate of responding and measures of successful responding. Data for humans were from studies of choice reaction time (CRT). Behavioral measures were converted to proportion of baseline to place them on a common scale across experiments. A meta-analysis was done to fit dose-effect curves using C¯aTOL and the rescaled effects. Results demonstrated that effects were an orderly function of C¯aTOL and were not influenced by concentration or duration of exposure, except as exposure influenced C¯aTOL. In rats, response rates first increased, reached a peak, and then declined as C¯aTOL increased. Successful avoidance in rats and CRT in humans always declined as C¯aTOL increased. In rats, response rates were increased by 10% at C¯aTOL ˜ 13 ml/L. In humans, reaction times increased by 10% at C¯aTOL ˜ 3 ml/L. Cross-species comparisons were made with the following caveats: PBPK uncertainties, few human data, and poor task comparability.