DETERMINATION OF PARAMETERS RESPONSIBLE FOR PHARMACOKINETIC BEHAVIOR OF TCDD IN FEMALE SPRAGUE-DAWLEY RATS

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic member of a class of planar and halogenated chemicals. Improvements in exposure assessment of TCDD require scientific information on the distribution of TCDD in target tissues and cellular responses induced by TCDD. Sin ce 1980, several physiologically based pharmacokinetic (PBPK) models f or TCDD and related compounds have been reported. Some of these models incorporated the induction of a hepatic binding protein in response t o interactions of TCDD, the Ah receptor, and DNA binding sites and des cribed the TCDD disposition in a biological system for certain data se ts. Due to the limitations of the available experimental data, differe nt values for the same physical parameters of these models were obtain ed from the different studies. The inconsistencies of the parameter va lues limit the application of PBPK models to risk assessment. Therefor e, further refinement of previous models is necessary. This paper deve lops an improved PBPK model to describe TCDD disposition in eight targ et tissues. The interaction of TCDD with the Ah receptor and with hepa tic inducible CYP1A2 were also incorporated into the model. This model accurately described the time course distribution of TCDD following a single oral dose of 10 mu g/kg, as well as the TCDD concentration on Day 3 after six different doses, 0.01, 0.1, 0.3, 1, 10, and 30 mu g TC DD/kg, in target tissues. This study extends previous TCDD models by i llustrating the validity and the limitation of the model and providing further confirmation of the potential PBPK model for us in optimal ex perimental design and extrapolation across doses and routes of exposur e. In addition, this study demonstrated some critical issues in PBPK m odeling. (C) 1997 Academic Press.