Development of a PBPK model for hexachlorobenzene in the context of ITO's medium-term liver foci bioassay.
Lu-Y; Reddy-M; Lohitnavy-M; Lohitnavy-O; Ashley-A; Yang-RS
Toxicologist 2004 Mar; 78(S-1):244-245
Hexachlorobenzene (HCB) is an important environmental contaminant. Due to its high lipophilicity and persistence in the environment, human exposure to HCB has continued despite the curtailment of its usage. HCB is carcinogenic to laboratory animals with the liver as one of the primary target organs. We have incorporated the study of the relationship between pharmacokinetics and pharmacodynamics into the Ito's medium-term liver foci bioassay. Thus, we describe here the development of a PBPK model for HCB in the context of Ito's bioassay protocol. The model was built based on two data sets: one from a single intravenous dosing study (Scheufler et al. 1984) and the other from a single oral gavage study (Yamaguchi et al. 1986). It was then modified to simulate the exposure conditions in the Ito's bioassay and verified with data from our laboratory. The PBPK model includes five compartments: blood, liver, fat and rapidly and slowly perfused tissues. As HCB can bind to red blood cells, the blood compartment was divided into red blood cells and plasma. The fat compartment was divided into two subcompartments, one with a higher perfusion rate and lower partitioning and the other with a lower perfusion rate and higher partitioning. Uptake of HCB was diffusion-limited in the fat compartments and flow-limited in the others. HCB was eliminated by metabolism in the liver and by passive transfer from plasma to the intestinal lumen. Reabsorption of HCB from the intestine was incorporated in the model. The resultant model adequately described the available data sets. This model may be linked with a clonal growth model to quantitatively describe the relationship between an external expo-sure to HCB and the consequent preneoplastic liver foci development.
Models; Benzenes; Bioassays; Environmental-contamination; Exposure-levels; Laboratory-animals; Animals; Animal-studies; Pharmacodynamics; Red-blood-cells; Quantitative-analysis; Carcinogens
The Toxicologist. Society of Toxicology 43nd Annual Meeting and ToxExpo, March 21-25, 2004, Baltimore, Maryland
Colorado State University - Fort Collins