Application of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model in studying the carcinogenic potential of hexacholorobenzene, PCB 126, and their mixture

We studied the carcinogenic potential of hexachlorobenzene (HCB), PCB 126, and their mixture based on experimental bioassay and physiologically based modeling. Experimentally, we collected pharmacokinetic and preneoplastic foci data of the individual chemicals and the mixture in the context of an established time-course medium-term liver foci bioassay. The bioassay involved a single injection of an initiating agent, a two-thirds partial hepatectomy, and daily oral gavage of a chemical solution in male Fischer 344 rats. All bioassays were conducted at two doses: HCB 8.55 and 28.5 mg/kg, PCB 126 3.3 and 9.8 mug/kg, and HCB+PCB 126 8.55 mg/kg + 3.3 mug/kg and 28.5 mg/kg + 9.8 mug/kg.; HCB was mainly distributed in the fat, followed by the liver and other tissues, in accordance with its lipophilicity. Coexposure of PCB 126 changed accumulation of HCB in the body and partitioning of HCB into the fat, liver, and muscle. HCB, PCB 126, and their mixture displayed their carcinogenic potential in the bioassays by increasing the foci number and/or foci size. The foci data suggested that there appeared to be a greater-than-additivity interaction at the low doses and a less-than-additivity interaction at the high doses between HCB and PCB 126.; Modeling wise, a PBPK model was developed for HCB. It included two special features: division of the blood compartment into plasma and erythrocytes and incorporation of the exsorption process (i.e., the plasma-to-gut lumen passive diffusion---a reversal of the absorption process). A clonal growth model was developed to analyze the foci data. The concept of negative selection and two-cell (types A and B; the latter with growth advantage) hypothesis were incorporated in the clonal growth model. Furthermore, we explored the size-dependent growth kinetics of the initiated cells. The model was parameterized with the information from the literature as well as from our own study. The clonal growth model analysis suggested that a greater-than-additivity interaction occurred in promoting mini- (2-11 cells) and medium-foci (12-399 cells) at the low doses, and that a less-than-additivity interaction took place in promoting large-foci (>399 cells) at the high doses between the two chemicals.