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. Since 1980, several physiologically based pharmacokinetic (PBPK) models for TCDD and related compounds have been reported. Some of these models incorporated the induction of a hepatic binding protein in response to interactions of TCDD, the Ah receptor, and DNA binding sites and described the TCDD disposition in a biological system for certain data sets. Due to the limitations of the available experimental data, different values for the same physical parameters of these models were obtained from the different studies. The inconsistencies of the parameter values limit the application of PBPK models to risk assessment. Therefore, further refinement of previous models is necessary. This paper develops an improved PBPK model to describe TCDD disposition in eight target tissues. The interaction of TCDD with the Ah receptor and with hepatic 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 microg/kg, as well as the TCDD concentration on Day 3 after six different doses, 0.01, 0.1, 0.3, 1, 10, and 30 microg TCDD/kg, in target tissues. This study extends previous TCDD models by illustrating the validity and the limitation of the model and providing further confirmation of the potential PBPK model for us in optimal experimental design and extrapolation across doses and routes of exposure. In addition, this study demonstrated some critical issues in PBPK modeling.
Wang
X
X
Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina 27599-7270, USA. xwang@mga.com
Santostefano
M J
MJ
Evans
M V
MV
Richardson
V M
VM
Diliberto
J J
JJ
Birnbaum
L S
LS
D000284:Administration, Oral; D000818:Animals; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008954:Models, Biological; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D018570:Risk Assessment; D014018:Tissue Distribution
D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D019388:Cytochrome P-450 CYP1A2