Alteration of hexachlorobenzene disposition by PCB126 coexposure and application of PBPK modeling in a medium-term live FOCI bioassay.
Lu-Y; Lohitnavy-M; Lohitnavy-O; Perrigo-E; Yang-R
Toxicologist 2005 Mar; 84(Suppl 1):173
Hexachlorobenzene (HCB) is a probable human carcinogen which still exists in the environment despite the curtailment of its production and use. Human exposure to HCB is often accompanied by PCB126, a dioxin-like compound and the most potent congener of polychlorinated biphenyls. Earlier, we observed that PCB126 altered the kinetics of coexposed lipophilic chemicals. Here, we report our studies on HCB pharmacokinetics, with or without coexposure to PCB126. Our experiments included two separate kinetic studies (HCB alone and HCB+PCB126) integrated into a time-course medium-term liver foci bioassay. In both studies, fat had the highest concentrations of HCB, followed by the other tissues. The kinetics of tissue distribution of HCB are dramatically different between HCB alone group and the HCB+PCB126 combination group, suggesting complex interaction mechanisms. Using PBPK modeling as a hypothesis-testing tool, we carried out computer simulations based on the assumptions that PCB126 induced disruption at the levels of absorption, exsorption (i.e., the diffusion from blood to the lumen of GI tract), and fat metabolism. We utilized a previously constructed PBPK model for HCB to describe these altered disposition patterns. The model was composed of fat, liver, erythrocytes, blood plasma, GI lumen, and rapidly and slowly perfused tissues and incorporated the physiological changes related to partial hepatectomy in the time-course medium term liver foci bioassay protocol. The model adequately described the pharmacokinetics of HCB singly and in combination with PCB126. From our modeling exercises, we propose that the kinetic alterations were the results of a combination of the modification of HCB absorption and exsorption and the disruption of fat metabolism by PCB126.
Models; Bioassays; Carcinogens; Environmental-exposure; Exposure-levels; Polychlorinated-biphenyls; Tissue-distribution; Fat-metabolism; Liver; Liver-tissue; Physiological-factors; Dioxins
Research Tools and Approaches: Risk Assessment Methods
The Toxicologist. Society of Toxicology 44th Annual Meeting and ToxExpo, March 6-10, 2005, New Orleans, Louisiana
Colorado State University - Fort Collins