Pharmacokinetic (PK)/pharmacodynamic (PD) relationship of PCB126 under the conditions of modified ITO medium-term liver bioassay.
Lohitnavy-M; Chubb-L; Lohitnavy-OS; Yang-CC; Homburg-J; Campain-JA; Yang-RS
Toxicologist 2004 Mar; 78(S-1):271
PCB126 is the most toxic congener of PCBs with carcinogenic potential. By using the modified Ito medium-term bioassay protocol, male F344 rats were given a single ip dose of 200 mg/kg of diethylnitrosamine (DEN) as an initiator. Daily oral PCB126 administration (3.3 and 9.8 g/kg/day) was started at week 2 after DEN injection. One week after PCB126 dosing, a 2/3rd partial hepatectomy was con-ducted. Rats were sacrificed at 20, 24, 28, 47 and 56 days post-DEN injection. Tissue concentrations in the liver, fat, whole blood, kidney and muscle were measured by using GC/ECD following liquid extraction and clean up. Morphometric analysis of glutathione-S-transferase (GST)- P foci formation in the liver slices was performed as a PD endpoint to determine numbers and sizes of preneoplastic foci. Concentration-time courses of PCB126 in the liver, fat, kidney, muscle and whole blood were obtained. Despite high lipophilicity of PCB126, liver concentrations were the highest with the ratio between liver and fat concentrations of about 110-400 to 1. Assuming this is protein binding in the liver, our results revealed that PCB126 binds to liver about 11 to 40 times more strongly than TCDD. Proteomic analyses will shed further light on this interesting binding phenomenon. Dose- and time-dependence of GST-P foci formation were studied. Correlation analyses between area under the curve of PCB126 in the liver (AUC Liver ) as an internal dose and PD endpoints (foci numbers, area, and relative foci area) demonstrate linear relationship at low AUCs and nonlinear response at higher AUCs . The linkage of PBPK and clonal growth models will enable us to predict target tissue dosimetry as well as preneoplastic foci formation in F344 rats upon exposure to PCB126 in an Ito medium-term bioassay.
Pharmacodynamics; Bioassays; Carcinogens; Carcinogenicity; Laboratory-animals; Animals; Animal-studies; Liver-tissue; Blood-samples; Blood-analysis; Muscle-tissue; Dosimetry; Models; Polychlorinated-biphenyls
The Toxicologist. Society of Toxicology 43nd Annual Meeting and ToxExpo, March 21-25, 2004, Baltimore, Maryland
Colorado State University - Fort Collins