Xf. Wang et al., DETERMINATION OF PARAMETERS RESPONSIBLE FOR PHARMACOKINETIC BEHAVIOR OF TCDD IN FEMALE SPRAGUE-DAWLEY RATS, Toxicology and applied pharmacology, 147(1), 1997, pp. 151-168
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.