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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: F6D40991Title: 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: Willett, Stephanie H.
Project Period: September 1, 2006 through September 1, 2007
Project Amount: $106,720
RFA: STAR Graduate Fellowships (2006)
Research Category: Academic Fellowships , Biology/Life Sciences , Health Effects , Fellowship - Toxicology , Fellowship - Biological Modeling
Description:
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,
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Scientific Discipline, Health, RFA, Endocrine Disruptors - Environmental Exposure & Risk, Toxicology, Health Risk Assessment, endocrine disruptors, Biochemistry, Endocrine Disruptors - Human Health, animal models, endocrine disrupting chemicals, toxicity, EDCs, PCBs, pharmacokinetics, HPT axis, pharmacodynamic modeling, thyroid toxicants