Linking Transthyretin-Binding Chemicals and Free Thyroid Hormones: In Vitro to In Vivo Extrapolation Based on a Competitive Binding Model

Large numbers of pollutants competitively inhibit thebinding betweenthyroid hormones and transthyretin (TTR) in vitro. However, the impactof this unintended binding on free thyroid hormones in vivo has notyet been characterized. Herein, we established a quantitative in vitroto in vivo extrapolation (QIVIVE) method based on a competitive bindingmodel to quantify the effect of TTR-binding chemicals on free thyroidhormones in human blood. Twenty-five TTR-binding chemicals including6 hydroxyl polybromodiphenyl ethers (OH-PDBEs), 6 hydroxyl polychlorobiphenyls(OH-PCBs), 4 halogenphenols, 5 per- and polyfluorinated substances(PFASs), and 4 phenols were selected for investigation. Incorporatingthe in vitro binding parameters and human exposure data, the QIVIVEmodel could well predict the in vivo effect on free thyroid hormones.Co-exposure to twenty-five typical TTR-binding chemicals resultedin median increases of 0.080 and 0.060% in circulating levels of freethyroxine (FT4) and free triiodothyronine (FT3) in the general population. Individuals with occupational exposureto TTR-binding chemicals suffered 1.88-32.2% increases in freethyroid hormone levels. This study provides a quantitative tool toevaluate the thyroid-disrupting risks of TTR-binding chemicals andproposes a new framework for assessing the in vivo effects of chemicalexposures on endogenous molecules. Thisstudy quantitatively reveals the relationship betweentransthyretin-binding chemicals and free thyroid hormones in vivoand provides a new framework for risk assessment of endocrine-disruptingchemicals.

Automated summary

This study establishes a quantitative in vitro to in vivo extrapolation method to quantify the effect of transthyretin (TTR)-binding chemicals on free thyroid hormones in human blood. The results show that exposure to TTR-binding chemicals can increase the levels of free thyroid hormones in the body, providing a new framework for risk assessment of endocrine-disrupting chemicals.