ArticleToxicological sciences : an official journal of the Society of Toxicology2016
Estimating Margin of Exposure to Thyroid Peroxidase Inhibitors Using High-Throughput in vitro Data, High-Throughput Exposure Modeling, and Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 32 citations in OpenAlex.
- Active Stacking-Deep Learning with Strategic Sampling for Small and Imbalanced Chemical Toxicity Prediction.ACS omega · 2025Article
- A proposal of criteria to support the EU classification on endocrine disruption for the thyroid modality and their application to four data-rich case studies.Archives of toxicology · 2025Article
- Advancing Toxicity Predictions: A Review onEnvironment & health (Washington, D.C.) · 2024Review
- A minimal human physiologically based kinetic model of thyroid hormones and chemical disruption of plasma thyroid hormone binding proteins.Frontiers in endocrinology · 2023Article
- Advances in computational methods along the exposure to toxicological response paradigm.Toxicology and applied pharmacology · 2022Article
- IVIVE: Facilitating the Use ofToxics · 2022Review
- Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion.Frontiers in endocrinology · 2022Review
- Mechanistic Computational Model for Extrapolating In Vitro Thyroid Peroxidase (TPO) Inhibition Data to Predict Serum Thyroid Hormone Levels in Rats.Toxicological sciences : an official journal of the Society of Toxicology · 2021Article
- Regulation of Thyroid-disrupting Chemicals to Protect the Developing Brain.Endocrinology · 2020Review
- The GOLIATH Project: Towards an Internationally Harmonised Approach for Testing Metabolism Disrupting Compounds.International journal of molecular sciences · 2020Article
- Mechanism of Action and Interactions between Thyroid Peroxidase and Lipoxygenase Inhibitors Derived from Plant Sources.Biomolecules · 2019Article
- A Quantitative Source-to-Outcome Case Study To Demonstrate the Integration of Human Health and Ecological End Points Using the Aggregate Exposure Pathway and Adverse Outcome Pathway Frameworks.Environmental science & technology · 2019Article
- Thyroid Peroxidase Activity is Inhibited by Phenolic Compounds-Impact of Interaction.Molecules (Basel, Switzerland) · 2019Article
- Aggregate Exposure Pathways in Support of Risk Assessment.Current opinion in toxicology · 2018Article
- Challenges Associated With Applying Physiologically Based Pharmacokinetic Modeling for Public Health Decision-Making.Toxicological sciences : an official journal of the Society of Toxicology · 2018Review
- Bridging the Data Gap FromFrontiers in public health · 2018Review
- Neurodevelopment and Thyroid Hormone Synthesis Inhibition in the Rat: Quantitative Understanding Within the Adverse Outcome Pathway Framework.Toxicological sciences : an official journal of the Society of Toxicology · 2017Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.