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HERO ID
104657
Reference Type
Journal Article
Title
Determination of parameters responsible for pharmacokinetic behavior of TCDD in female Sprague-Dawley rats
Author(s)
Wang, X; Santostefano, MJ; Evans, MV; Richardson, VM; Diliberto, JJ; Birnbaum, LS
Year
1997
Is Peer Reviewed?
1
Journal
Toxicology and Applied Pharmacology
ISSN:
0041-008X
EISSN:
1096-0333
Volume
147
Issue
2
Page Numbers
151-168
Language
English
PMID
9356318
DOI
10.1006/taap.1997.8242
Web of Science Id
WOS:A1997YE97400018
Abstract
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.
Keywords
Administration, Oral; Animals; Cytochrome P-450 CYP1A2/biosynthesis; Dose-Response Relationship, Drug; Enzyme Induction/drug effects; Female; Liver/enzymology/metabolism; Models, Biological; Rats; Rats, Sprague-Dawley; Receptors, Aryl Hydrocarbon/metabolism; Risk Assessment; Tetrachlorodibenzodioxin/metabolism/pharmacokinetics/toxicity; Tissue Distribution; 0 (Receptors, Aryl Hydrocarbon); 1746-01-6 (Tetrachlorodibenzodioxin); EC 1.14.14.1 (Cytochrome P-450 CYP1A2)
Tags
IRIS
•
Dioxin (2012 Project Page for Final Report)
Other
•
Nanoscale Carbon
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