Grantee Research Project Results

Biologically-Based Pharmacodynamic Modeling of the Mixture Effects of Two Widespread Environmental Contaminants, PCB 126 and Perchlorate, on the Male Rat Hypothalamic-Pituitary-Thyroid Axis

EPA Grant Number: F6D40991
Title: Biologically-Based Pharmacodynamic Modeling of the Mixture Effects of Two Widespread Environmental Contaminants, PCB 126 and Perchlorate, on the Male Rat Hypothalamic-Pituitary-Thyroid Axis
Investigators: McLanahan, Eva Daneke
Institution: University of Georgia
EPA Project Officer: Hahn, Intaek
Project Period: September 1, 2006 through September 1, 2007
Project Amount: $106,720
RFA: STAR Graduate Fellowships (2006) RFA Text |  Recipients Lists
Research Category: Academic Fellowships , Biology/Life Sciences , Fellowship - Biological Modeling , Fellowship - Toxicology , Human Health

Objective:

The overall goal of the project is to quantitatively examine the anti-thyroid effects of co-exposure to 3,3’,4,4’,5-pentachlorobiphenyl (PCB 126) and perchlorate (ClO₄-) in adult rats. A biologically based pharmacodynamic (BBPD) model for the adult male rat hypothalamic-pituitary-thyroid (HPT) axis and physiologically based pharmacokinetic (PBPK) models for PCB 126 and ClO₄- will be developed to assist in predicting the perturbations in the thyroid axis.

Approach:

To develop PBPK models for PCB 126 and ClO₄- and a BBPD model for the thyroid axis in the adult rat, several laboratory experiments, data mining, and simulation exercises will be undertaken. PBPK models for ClO₄- and PCB 126 will be developed based on published literature and data collected in our laboratory. Specifically, the ClO₄- model will describe the kinetics of ClO₄- and dietary iodide, as well as the interaction between dietary iodide and ClO₄- in tissues containing the Na⁺/I- symporter (NIS). Kinetics of PCB 126 will be described by a separate PBPK model that will include the induction of hepatic UDP-glucuronyl transferases (UDPGTs) induced by PCB 126 binding to the Ah-receptor. The BBPD model for the HPT axis will contain sub-models for thyroid stimulating hormone (TSH), thyroxine (T4), 3,5,3’-triiodothyronine (T3), as well as total iodide. The sub-models will be linked mathematically to one another and the feedback control mechanisms of the HPT axis will be described. Finally, the rat PBPK models for PCB 126 and ClO₄- will be linked to the HPT axis model, based on the chemical mode of action, in order to predict HPT axis perturbations resulting from exposure to these chemicals.

Expected Results:

The successful completion of this research will result in the development of a computational description of the HPT axis in the rat with associated PBPK models to predict disturbances in the HPT axis. This first generation modeling effort will set the stage for future work in this field and provide tools to evaluate dose-response data in rodents administered a single thyroid toxic chemical or mixtures of thyroid toxic chemicals. These biological based models will also assist in understanding unexpected laboratory results and advance the scientific understanding the of HPT axis.

Supplemental Keywords:

thyroid, PCB 126, 3,3’,4,4’,5-pentachlorobiphenyl, perchlorate, PBPK model, BBPD model, hypothalamic-pituitary-thyroid axis, HPT axis, mode of action, environmental contaminants, biologically based pharmacodynamic model, physiologically based pharmacokinetic model, rat, animal model, endocrine disruptors, NIS, TSH, T4, T3, iodide,, RFA, Health, Scientific Discipline, Toxicology, Health Risk Assessment, Endocrine Disruptors - Environmental Exposure & Risk, endocrine disruptors, Biochemistry, Endocrine Disruptors - Human Health, HPT axis, EDCs, endocrine disrupting chemicals, PCBs, pharmacokinetics, thyroid toxicants, animal models, toxicity, thyroid function

Progress and Final Reports:

Final