title: 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.
authors: *Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee, 37831; National Exposure Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina, 27709;
authors: Jeremy A
authors: JA
authors: Leonard
authors: National Exposure Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina, 27709;
authors: Yu-Mei
authors: YM
authors: Tan
authors: National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina, 27709.
authors: Mary
authors: M
authors: Gilbert
authors: National Exposure Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina, 27709;
authors: Kristin
authors: K
authors: Isaacs
authors: National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina, 27709 el-masri.hisham@epa.gov.
authors: Hisham
authors: H
authors: El-Masri
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D004791:Enzyme Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics*; D057166:High-Throughput Screening Assays; D006801:Humans; D007453:Iodide Peroxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008954:Models, Biological; D011485:Protein Binding; D051381:Rats; D018570:Risk Assessment; D013961:Thyroid Gland / Q000187:drug effects* / Q000201:enzymology; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D014284:Triiodothyronine; D007453:Iodide Peroxidase; D013974:Thyroxine
keywords: PBPK/PD model; adverse outcome pathway; high-throughput in vitro assay.; margin of exposure; thyroid peroxidase