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 i s of special interest in physiologically based pharmacokinetic (PBPK) model ing. In order to estimate inter- and intra-individual variability in fat ti ssue blood flow with exercise, a population PBPK model for toluene was fitt ed 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 arte rial blood, exhaled breath and subcutaneous fat tissue. The model was simul taneously fitted to the time courses of toluene in arterial blood, exhaled breath, and subcutaneous fat in the six individuals by Markov chain Monte C arlo (MCMC) simulation. In order to describe the experimental observations in subcutaneous fat accurately, the fat compartment was split in two. Accor ding to the analysis, the increased perfusion of perirenal fat associated w ith physical workload was best described if it was set to the same, elevate d, level during all exercise levels, rather than scaled directly to the inc rease in oxygen uptake. No increase in subcutaneous fat perfusion could be detected at these exposure conditions. (C) 2000 Elsevier Science Ireland Lt d. All rights reserved.