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DOI10.1093/toxsci/kfw022
Estimating Margin of Exposure to Thyroid Peroxidase Inhibitors Using High-Throughput in vitro Data, High-Throughput Exposure Modeling, and Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling
Leonard, Jeremy A.1,2; Tan, Yu-Mei2; Gilbert, Mary3; Isaacs, Kristin2; El-Masri, Hisham3
发表日期2016-05-01
ISSN1096-6080
卷号151期号:1页码:57-70
英文摘要

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 (T-4) and triiodothyronine (T-3) hormone levels measured in rats and humans. After evaluation, the model was used to estimate human equivalent intake doses resulting in reduction of T-4 and T-3 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.


英文关键词thyroid peroxidase;adverse outcome pathway;margin of exposure;PBPK;PD model;high-throughput in vitro assay
语种英语
WOS记录号WOS:000376662800006
来源期刊TOXICOLOGICAL SCIENCES
来源机构美国环保署
文献类型期刊论文
条目标识符http://gcip.llas.ac.cn/handle/2XKMVOVA/58432
作者单位1.Oak Ridge Inst Sci & Educ, Oak Ridge, TN 37831 USA;
2.US EPA, Natl Exposure Res Lab, Res Triangle Pk, NC 27709 USA;
3.US EPA, Natl Hlth & Environm Effects Res Lab, 109 TW Alexander Dr Mail Code B105-03, Res Triangle Pk, NC 27709 USA
推荐引用方式
GB/T 7714
Leonard, Jeremy A.,Tan, Yu-Mei,Gilbert, Mary,et al. Estimating Margin of Exposure to Thyroid Peroxidase Inhibitors Using High-Throughput in vitro Data, High-Throughput Exposure Modeling, and Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling[J]. 美国环保署,2016,151(1):57-70.
APA Leonard, Jeremy A.,Tan, Yu-Mei,Gilbert, Mary,Isaacs, Kristin,&El-Masri, Hisham.(2016).Estimating Margin of Exposure to Thyroid Peroxidase Inhibitors Using High-Throughput in vitro Data, High-Throughput Exposure Modeling, and Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling.TOXICOLOGICAL SCIENCES,151(1),57-70.
MLA Leonard, Jeremy A.,et al."Estimating Margin of Exposure to Thyroid Peroxidase Inhibitors Using High-Throughput in vitro Data, High-Throughput Exposure Modeling, and Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling".TOXICOLOGICAL SCIENCES 151.1(2016):57-70.
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