Age-related changes in benzene disposition in male C57BL/6N mice described by a physiologically based pharmacokinetic...

A physiologically based pharmacokinetic (PBPK) model was developed to describe the disposition of benzene in 3- and 18-month C57BL/6N mice and to examine the relevant physiologic and/or biochemical parameters governing previously observed age-related changes in the disposition of benzene. The model developed was based on that of Medinsky et al. (Toxicol. Appl. Pharmacol. 99 (1989) 193-206), with the inclusion of an additional rate constant for urinary elimination of benzene metabolites. Experimentally determined tissue partition coefficients for benzene in 3- and 18-month mice, as well as actual body weights and fat compartment volumes, were included as part of the model. Model simulations were conducted for oral exposure of 3-month mice to 10 and 200 mg benzene/kg and for oral exposure of 18-month mice to 10 and 150 mg benzene/kg. Total amount of benzene metabolized, as well as metabolism of benzene to specific metabolites and their elimination, was simulated. Modeling results for total amount of benzene metabolites eliminated in urine over a 24-h period at 10 mg/kg showed that a greater total amount of benzene metabolites would be excreted by 18-month versus 3-month old mice. At saturating doses of 150 and 200 mg/kg, total amount of benzene metabolites excreted 24 h post-dose was predicted to be equivalent in 18-month mice and 3-month old mice, but the rate of elimination over time was shown to be decreased in 18-month vs. 3-month mice. Decreased urinary elimination of total benzene metabolites was simulated by a smaller renal elimination rate constant in 18-month vs. 3-month mice, which is consistent with decreased renal blood flow noted in aging rodents. These model predictions were consistent with observed in vitro and in vivo experimental data. Model simulations for production of specific metabolites from benzene and elimination in urine agreed well with experimental data in showing no significant age-related changes in formation of benzene metabolites, with the exception of hydroquinone conjugates. Model simulations and experimental data showed decreased total urinary elimination of hydroquinone conjugates in 18-month vs. 3-month mice. The change in hydroquinone conjugate elimination with age was simulated in modeling experiments as an age-related increase in Km for production of hydroquinone conjugates from benzene. The results of this study indicate that age-related changes in physiology are primarily responsible for altered disposition of benzene in aged mice and suggest that concentrations for toxicity of benzene and/or metabolites may differ in target tissues of aged mice.