Physiologically Based Pharmacokinetic Modeling of Metabolic Interactions between n‐Hexane and Toluene in Humans

Physiologically based Pharmacokinetic Modeling of Metabolic Interactions Between n‐Hexane and Toluene in Humans: Xiaozhong Y u , et al . Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine —Some animal experiments have shown that mutual metabolic inhibition takes place between n‐hexane and toluene, but we have found only one report dealing with their metabolic interaction at occupationally relevant exposure levels (Baelum et al . 1998). In order to evaluate the effect of dose‐dependent metabolic interaction between toluene and n‐hexane, especially in occupationally relevant exposure conditions such as relevant exposure levels, physical activities and exposure patterns, a physiologically based pharmacokinetic (PBPK) model for co‐exposure to n‐hexane and toluene was developed. The PBPK model for the binary co‐exposure was established by initially validating or refining the existing PBPK models for n‐hexane and toluene and then linking the individual solvent models via the hepatic metabolism terms. In reporting previous findings, noncompetitive inhibition was assumed and the inhibition constant of toluene on n‐hexane biotransformation and that of n‐hexane on toluene biotransformation used in simulation were 7.5, 30 μm, respectively, in previous data. According to the model, 8 h of constant exposure to 50 ppm n‐hexane and 25,50,100 and 500 ppm toluene will cause about 7%, 18%, 62% and 96% decreases in the urinary excretion of 2,5‐hexanedione (2,5‐HD) and 4%, 10%, 25% and 30% increases in the n‐hexane concentration in blood at the end of the fifth day of exposure simulated in a standard man at a 25 W work load. Simulations of co‐exposure to 50 ppm n‐hexane and 50 ppm toluene in a standard man who inhaled 50 ppm n‐hexane with 0 or 50 ppm toluene for 8 h at different work loads suggest that toluene causes a slight decrease in urinary 2,5‐HD in the resting condition, a 17% decrease at 25 W, and a 41% decrease at 50 W work load. The simulations of co‐exposure in different exposure patterns with the same time‐weighted concentration (TWA) of 50 ppm, i.e. 50 ppm for 8 h, 100 ppm of 4 times for 1 h and 200 ppm of twice for 1 h, showed reductions in urinary 2,5‐HD of 17%, 40% and 67%, respectively. These simulations suggest that co‐exposure to n‐hexane and toluene around 50 ppm (TWA) could affect urinary n‐hexane metabolites to various degrees depending on the fluctuations in exposure concentrations and variety of work activities in the workplace.