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 the
binding between
thyroid hormones and transthyretin (TTR) in vitro. However, the impact
of this unintended binding on free thyroid hormones in vivo has not
yet been characterized. Herein, we established a quantitative in vitro
to in vivo extrapolation (QIVIVE) method based on a competitive binding
model to quantify the effect of TTR-binding chemicals on free thyroid
hormones in human blood. Twenty-five TTR-binding chemicals including
6 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. Incorporating
the in vitro binding parameters and human exposure data, the QIVIVE
model could well predict the in vivo effect on free thyroid hormones.
Co-exposure to twenty-five typical TTR-binding chemicals resulted
in median increases of 0.080 and 0.060% in circulating levels of free
thyroxine (FT4) and free triiodothyronine (FT3) in the general population. Individuals with occupational exposure
to TTR-binding chemicals suffered 1.88–32.2% increases in free
thyroid hormone levels. This study provides a quantitative tool to
evaluate the thyroid-disrupting risks of TTR-binding chemicals and
proposes a new framework for assessing the in vivo effects of chemical
exposures on endogenous molecules.