Estimating Margin of Exposure to Thyroid Peroxidase Inhibitors Using High-Throughputin vitroData, High-Throughput Exposure Modeling, and Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling
| Autor: | Jeremy A. Leonard, Kristin Isaacs, Yu-Mei Tan, Mary E. Gilbert, Hisham A. El-Masri |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Physiologically based pharmacokinetic modelling Thyroid Gland 010501 environmental sciences Pharmacology Toxicology Iodide Peroxidase Models Biological Risk Assessment 01 natural sciences 03 medical and health sciences Thyroid peroxidase Internal medicine medicine Animals Humans Enzyme Inhibitors 0105 earth and related environmental sciences Triiodothyronine biology Chemistry Thyroid In vitro toxicology Estimation of Margin of Exposure for Thyroid Peroxidase Inhibitors Environmental exposure High-Throughput Screening Assays Rats Thyroxine 030104 developmental biology Endocrinology medicine.anatomical_structure biology.protein Propylthiouracil Biomarkers Protein Binding Hormone medicine.drug |
| Zdroj: | Toxicological Sciences. 151:57-70 |
| ISSN: | 1096-0929 1096-6080 |
| DOI: | 10.1093/toxsci/kfw022 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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