A Mechanistic Model of Effects of Dioxin on Thyroid Hormones in the Rat

A physiological dosimetric model of the disposition of TCDD in the rat

Michael C. Kohn; Charles H. Sewall; George W. Lucier; Christopher J. Portier

2002

Key concepts

Scholarcy highlights

  • A physiological dosimetric model of the disposition of TCDD in the rat
  • The extended model included distribution of blood among major vessels and tissue capillary beds and resorption of TCDD released into the gut lumen from the liver by cell lysis consequent to cytotoxicity
  • TCDD metabolism was represented by Hill kinetics
  • Parameter values were estimated by fitting time-course data for a single subcutaneous injection of TCDD and dose–response data for biweekly oral dosing
  • Secretion of thyroid hormones was modeled as regulated by thyrotropin, whose secretion was modeled as regulated by the hypothalamic factors thyrotropin releasing hormone and somatostatin
  • The model reproduced the responses observed for blood T3, T4, and TSH after 31 weeks of biweekly oral dosing of rats with TCDD
  • Increases in UGT activity may be useful as a biomarker for tumorigenic changes in hormone levels subsequent to TCDD exposure

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