Estimating Margin of Exposure to Thyroid Peroxidase Inhibitors Using High-Throughput in vitro Data, High-Throughput Exposure Modeling, and Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling

Abstract

Some pharmaceuticals and environmental chemicals bind the thyroid peroxidase (TPO) enzyme and disrupt thyroid hormone production. The potential for TPO inhibition is a function of both the binding affinity and concentration of the chemical within the thyroid gland. The former can be determined through in vitro assays, and the latter is influenced by pharmacokinetic properties, along with environmental exposure levels. In this study, a physiologically based pharmacokinetic (PBPK) model was integrated with a pharmacodynamic (PD) model to establish internal doses capable of inhibiting TPO in relation to external exposure levels predicted through exposure modeling. The PBPK/PD model was evaluated using published serum or thyroid gland chemical concentrations or circulating thyroxine (T4) and triiodothyronine (T3) hormone levels measured in rats and humans. After evaluation, the model was used to estimate human equivalent intake doses resulting in reduction of T4 and T3 levels by 10% (ED10) for 6 chemicals of varying TPO-inhibiting potencies. These chemicals were methimazole, 6-propylthiouracil, resorcinol, benzophenone-2, 2-mercaptobenzothiazole, and triclosan. Margin of exposure values were estimated for these chemicals using the ED10 and predicted population exposure levels for females of child-bearing age. The modeling approach presented here revealed that examining hazard or exposure alone when prioritizing chemicals for risk assessment may be insufficient, and that consideration of pharmacokinetic properties is warranted. This approach also provides a mechanism for integrating in vitro data, pharmacokinetic properties, and exposure levels predicted through high-throughput means when interpreting adverse outcome pathways based on biological responses.

Keywords: PBPK/PD model; adverse outcome pathway; high-throughput in vitro assay.; margin of exposure; thyroid peroxidase.

FIG. 1.

Workflow of the integrated modeling approach and its individual HT components. Squares represent processes, diamonds represent intermediates used as inputs into the next component, and ovals represent final outputs for decision making. The dashed line represents extrapolation of human equivalent dose from the combined PBPK and PD model.

FIG. 2.

Results of the sensitivity analysis of physiological parameters influencing changes in T₃ (A) and T₄ (B) during evaluation of the PD model and chemical concentration in the thyroid gland compartment during evaluation of the PBPK model (C). Abbreviations are as follows: PTh, thyroid lumen-to-plasma PC; PLiv, liver-to-plasma PC; Ka, absorption rate; KT₄, elimination rate of T₄, KTSH, elimination rate of TSH, KT₃, elimination rate of T₃; fr, fraction of T₄ peripherally converted to T₃; NF1-NF3, slope factor constants 1–3 used in the PD model. Unlabeled lines in (C) represent influence of partition coefficients of remaining tissues.

FIG. 3.

Time-course measured and predicted concentrations of 6-PTU in the thyroid gland tissue (A) and blood (B) of rats provided 0.05% PTU in drinking water for 7 days and PTU-induced changes in predicted and measured rat T₃ (C) and T₄ (D) serum concentrations. Measured data taken from Cooper et al. (1983).

FIG. 4.

Time-course measured and predicted concentrations of MMI in the thyroid gland tissue (A) and blood (B) of rats provided 0.05% MMI in drinking water for 7 days. Measured data taken from Cooper et al. (1984b).

FIG. 5.

Time-course measured and predicted concentrations of TCS in the blood of rats provided a single oral dose of 5 mg/kg in 1 ml corn oil. Measured data taken from Wu et al. (2009).

FIG. 6.

Measured and predicted changes in T₄ (A) and T₃ (B) levels in the serum of male Wistrar rats after 31 days of dosing, and percent change from the control for T₄ (C) and T₃ (D) in the serum of female Long-Evans rats after 4 days of dosing. Measured data taken from Zorrilla et al. (2009) and Paul et al. (2010). Error bars of measured data represent SE.

FIG. 7.

Time-course measured and predicted concentrations of MMI in the blood of humans provided a single oral dose of 30 mg (A) or 60 mg (B). Measured data taken from Cooper et al. (1984a).