A dosimetric analysis of behavioral effects of acute toluene exposure in rats and humans

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 pharmacokinetic (PBPK) model was used to estimate concentration of toluene in arterial blood ((C) over tilde a(TOL)) 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) over tilde a(TOL) and the rescaled effects. Results demonstrated that effects were an orderly function of (C) over tilde a(TOL) and were not influenced by concentration or duration of exposure, except as exposure influenced (C) over tilde a(TOL). In rats, response rates first increased, reached a peak, and then declined as (C) over tilde a(TOL) increased. Successful avoidance in rats and CRT in humans always declined as (C) over tilde a(TOL) increased. In rats, response rates were increased by 10% at (C) over tilde a(TOL) approximate to 13 ml/L. In humans, reaction times increased by 10% at (C) over tilde a(TOL) approximate to 3 ml/L. Cross-species comparisons were made with the following caveats: PBPK uncertainties, few human data, and poor task comparability.