Dose-response analysis of hypothalamic-pituitary-thyroid (HPT) axis perturbations in the adult rat using statistical methods for the binary mixture of PCB126 and perchlorate and computational modeling for iodide deficiency and perchlorate
McLanahan, Eva Daneke
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Some environmental chemicals affect endocrine function and may alter hormone systems at low doses. The hypothalamic-pituitary-thyroid (HPT) axis controls many physiologic functions, including metabolism, growth, development, and reproduction. Two studies were -conducted to evaluate the low dose effects of ammonium perchlorate (ClO4) on the HPT axis of adult male rats pretreated with 3,3’,4,4’5,-pentachlorobiphenyl (PCB126). Both compounds are widespread environmental contaminants and have well characterized primary modes of action for disruption of the HPT axis. Results indicated that for rats pretreated with PCB126 and then -placed on drinking water containing ClO4 the effects on the HPT axis endpoints examined were -less than additive, and PCB126 appeared to mask the effects of ClO4. The TSH stimulated -thyroid created a condition where the effect of ClO4 on inhibition of thyroidal iodide uptake was diminished. In addition, no synergistic or greater than additive responses were observed when animals were dosed at concentrations at or near the no-observed-effect-level (NOEL). A biologically based dose-response (BBDR) model of the adult male rat HPT axis was also constructed. The model for the adult male rat includes sub-models for dietary iodide, thyroid stimulating hormone (TSH), as well as thyroid hormones, thyroxine (T4) and 3,5,3’-triiodothyronine (T3). First, the individual sub-models were developed independently of one another using radiolabeled tracer studies to estimate various model parameters. Then, the models were combined to form one endogenous model that includes (1)feedback of T4 on TSH production, (2)stimulation of T4/T3 production and thyroidal iodide uptake by TSH, and (3)the use of thyroidal iodide in hormone production. Model application included prediction of perturbations in the thyroid axis that result in iodide deficient conditions, as well as linking the -BBDR-HPT axis model with a physiologically based pharmacokinetic (PBPK) model for ClO4 by the primary mode of action, competitive competition of thyroidal iodide uptake. Model -exercises revealed the distinct possibility of an additional mode of action for ClO4 perturbation of the system. These models demonstrate the ability of the BBDR-HPT axis model to be integrated with other PBPK models for thyroid toxic compounds to predict changes based on the mode of action of the compound.