Bayesian estimation of variability in adipose tissue blood flow in man by physiologically based pharmacokinetic modeling of inhalation exposure to toluene.

Due to the lipophilicity of many xenobiotics, the perfusion of fat tissue is of special interest in physiologically based pharmacokinetic (PBPK) modeling. In order to estimate inter- and intra-individual variability in fat tissue blood flow with exercise, a population PBPK model for toluene was fitted to experimental data from subjects exposed to toluene vapors (Carlsson, A., 1982. Exposure to toluene: uptake, distribution and elimination in man. Scand. J. Work Environ. Health 8, 43-55). Six male volunteers were exposed to 80 ppm toluene for two hours during rest and moderate to heavy exercise (50-150 W). Extensive data collection was made, including sampling of arterial blood, exhaled breath and subcutaneous fat tissue. The model was simultaneously fitted to the time courses of toluene in arterial blood, exhaled breath, and subcutaneous fat in the six individuals by Markov chain Monte Carlo (MCMC) simulation. In order to describe the experimental observations in subcutaneous fat accurately, the fat compartment was split in two. According to the analysis, the increased perfusion of perirenal fat associated with physical workload was best described if it was set to the same, elevated, level during all exercise levels, rather than scaled directly to the increase in oxygen uptake. No increase in subcutaneous fat perfusion could be detected at these exposure conditions.