Physiologically Based Modeling of the Accumulation in Plasma and Tissue Lipids of a Mixture of PCB Congeners in Female Sprague-Dawley Rats

Abstract

This study aimed to develop a physiologically based model for simulating the concentrations of polychlorinated biphenyls (PCBs) in tissue and plasma lipids of rats exposed to PCB mixtures. The model was based on the assumption that the neutral lipid fraction is the only critical determinant of the tissue distribution of PCBs, and that the solubility/retention in other tissue components is negligible. The volumes of the model compartments reflected the volumes of neutral lipids, whereas the flow rates corresponded to those of the neutral lipids in blood. Since the equilibrium ratio of PCB concentrations in neutral lipids of tissues and plasma equals 1, the present modeling approach does not require the use of tissue:blood partition coefficients. Metabolism rates were derived from the best visual fit of the model to the PCB concentrations in hepatic lipids determined on d 41 and 90 in rats exposed to a mixture containing 5, 50, or 500 μg PCBs (118, 138, 153, 170, 180 and 187) per kilogram body weight according to various protocols: (a) every-day dosing, (b) once-a-week dosing, (c) consecutive dosing for 13 d with no further treatment, and (d) 13 irregularly spaced doses. The resulting model consistently simulated the concentrations of PCBs in adipose tissue and plasma lipids of rats exposed according to the four described protocols. The physiologically based pharmacokinetic (PBPK) model developed in this study should be useful as a basis for interpretating blood or plasma lipid concentration data on PCBs collected during biomonitoring studies.