Citation:

Hassan, I., H. El-Masri, J. Ford, S. Handa, AND M. Gilbert. Application of Physiologically-Based Pharmacokinetic/Pharmacodynamic Model for Interpretation of High-throughput Screening Assay for Thyroperoxidase Inhibition. Society of Toxicology Annual Meeting, San Antonio, TX, March 08 - 15, 2018.

Impact/Purpose:

Abstract for Society of Toxicology Annual Meeting in San Antonio, TX.

Description:

In vitro based assays are used to identify potential endocrine disrupting chemicals. Thyroperoxidase (TPO), an enzyme essential for thyroid hormone (TH) synthesis, is a target site for disruption of the thyroid axis for which a high-throughput screening (HTPS) assay has recently been developed. Physiologically based pharmacokinetic (PBPK) and pharmacodynamic (PBPD) models can aid in translating findings from in vitro assays to in vivo effects. This study used known TPO inhibitors, methimazole (MMI) and 6-propylthiouracil (PTU), to provide in vivo data for PBPD modeling. Adult male LE rats were exposed to 0, 1, 3, and 10 ppm PTU or 0, 3, 30 or 200 ppm MMI in drinking water for 4, 7, and 14 days. Serum and thyroid glands were collected to assess PTU, MMI, and TH levels. Serum and gland PTU and MMI levels increased in a dose-dependent manner. Chemical levels were comparable at each time-point, suggesting that PTU and MMI do not accumulate in the gland. Serum T3 and T4 were reduced by PTU in a dose- and time-dependent manner, with larger decrements seen at all time-points with exposure to 3 and 10 ppm. TSH was elevated after 7 days of exposure, larger increases observed with 14-day exposure to 10 ppm PTU, but the low dose group did not differ from controls, despite declines in serum T3 and T4. Serum T3 and T4 decreased with 4-day exposure to MMI. TSH increased with 7 and 14-day exposure to 30 and 200 ppm MMI. T3, T4, rT3, and mono- and di- iodotyrosines (MIT, DIT) were measured in the glands of rats exposed to PTU for 4 days. TH levels decreased in a dose-dependent manner with greatest decreases observed in DIT (53%, 73%) and T4 (40%, 80%) following exposure to 1 and 10 ppm PTU, respectively. Glandular TH and PTU measures permitted the estimation of in vivo TPO inhibition using a PBPD model. The in vitro based IC50 for PTU (1.24 μM) overestimated the degree of TPO inhibition observed in vivo study (IC50=1.55 μM). This revised estimate was applied to predict serum PTU concentrations that inhibit TPO, and predictions were evaluated against observed serum PTU and TH. Analyses of additional time-points are underway for gland concentrations of chemical and TH in addition to ex vivo measures of TPO inhibition in the glands of exposed animals. These data provide a framework to translate the degree of TH perturbation in vivo relative to the magnitude of TPO inhibition obtained from HTPS assay. Does not necessarily reflect US EPA policy.

Record Details: