PFPC Commentary:
NOTE: This study was conducted by Procter & Gamble, makers of Crest toothpaste. Crest was the first consumer fluoride toothpaste introduced in the United States in 1955, and Joseph C. Muhler was the central figure behind its development. It is therefore notable that the Procter & Gamble researchers make no mention of the extensive earlier work by Muhler, Shafer, Bixler, and colleagues on fluoride, thyroid activity, salivary gland function, and dental caries from the 1950s. That work had already shown that thyroid manipulation strongly altered experimental caries in rats, and fluoride effects were evaluated within this endocrine context. Muhler and Shafer reported evidence “suggestive of a supplementary activity between fluorides and the thyroid gland with respect to dental caries,” finding that desiccated thyroid reduced caries to about the same degree as fluoride in drinking water, while combined thyroid and fluoride produced a reduction approximately equal to the sum of the two separate effects. Later work by the same group further showed that thiouracil and I-131 increased caries, desiccated thyroid reduced caries, and fluoride’s effects varied depending on thyroid status and route of exposure.
Fluoride’s biological effects were therefore being studied by Crest’s own key developer in relation to thyroid activity and salivary gland physiology decades before this new P&G paper, yet the authors make no mention of that history. Instead, the paper focuses narrowly on selected in vitro endocrine targets, including NIS, TPO, thyroid hormone receptors, steroidogenesis, and nuclear receptors. Negative findings in those assays may argue against simple direct receptor-binding or transporter-inhibition mechanisms, but they do not address the broader indirect endocrine mechanisms by which fluoride has historically been implicated, including thyroid hormone metabolism, deiodinases, TSH/GPCR signaling, iodine-status modification, salivary gland effects, or chronic in vivo HPT-axis responses. The result is a paper framed as probing the “biological plausibility” of fluoride as an endocrine disruptor, while bypassing much of the older endocrine-fluoride literature most directly relevant to Procter & Gamble’s own fluoride-toothpaste history.
Main problem: the paper tests a narrow version of endocrine disruption
The title says the paper is “probing the biological plausibility of fluoride as an endocrine disruptor.” But the assays mostly test direct molecular target activity: receptor binding, enzyme inhibition, transporter inhibition, and steroid hormone production in one adrenal-derived cell model.
That is only one small subset of endocrine biology.
The paper does not test:
deiodinase activity,
thyroid hormone conversion,
TSH receptor signaling,
GPCR/G-protein pathways,
cAMP/PKA signaling,
Gq/11/calcium signaling,
pituitary feedback,
hepatic thyroid hormone metabolism,
thyroid hormone transporters,
iodine-status modification,
renal fluoride handling,
chronic developmental exposure,
pregnancy physiology,
in vivo HPT-axis compensation,
salivary gland effects,
tissue-specific thyroid hormone action.
That matters because fluoride-thyroid mechanisms historically discussed are
not classic receptor-binding mechanisms. A negative receptor panel ceryainly does not rule out endocrine disruption through thyroid hormone metabolism, altered feedback, iodine status, tissue-level hormone action, or chronic systemic adaptation. Fluoride is well established to mimic receptor-activated pathways, not by binding receptors, which makes P&G’s assay selection far too narrow.
A study that tests NIS, TPO, TRα/TRβ, steroidogenesis, and nuclear receptor binding, while ignoring G-protein activation and downstream pathways such as adenylate cyclase/cAMP, PLC/IP3/Ca2+, ERK/MAPK, PI3K/Akt, and thyroid hormone metabolism, has not seriously tested the main historical biochemical basis for fluoride’s thyroid-related endocrine activity.
The mere fact that fluoride is known as a “universal G protein activator” is central. Because thyroid hormone metabolism is regulated through G-protein signaling, fluoride’s broad activation of these pathways is enough to categorize it as one of the worst endocrine disruptors imaginable.
The NIS result is useful but limited
The NIS assay is one of the strongest parts of the paper. It directly addresses the claim that fluoride inhibits NIS - a claim made mainly by Limeback/FAN collaborator Declan Waugh in a much-cited, but highly flawed review from 2019. The results here argue against simple NaF inhibition of NIS-mediated iodide uptake up to 300 μM in HEK293-NIS cells, and thus mirror earlier findings by other researchers
(Buckalew et al., 2020; Jiang et al., 2009; Waltz et al., 2010).
REFERENCES
Buckalew AR, Wang J, Murr AS, Deisenroth C, Stewart WM, Stoker TE, Laws SC - "Evaluation of potential sodium-iodide symporter (NIS) inhibitors using a secondary Fischer rat thyroid follicular cell (FRTL-5) radioactive iodide uptake (RAIU) assay" Arch Toxicol 94(3):873-885 (2020). doi: 10.1007/s00204-020-02664-y
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441586/
Jiang P, Zhang WD, Chai CY, Xiao R, Ding MX, Liu GY - "Effects of fluoride on the expression of genes related to thyroid hormone metabolism in FRTL cells" Chin J Vet Sci 29(7):885–888 (2009)
PFPC Library
Waltz F, Pillette L, Ambroise Y - "A nonradioactive iodide uptake assay for sodium iodide symporter function" Anal Biochem 396(1):91-5 (2010). doi: 10.1016/j.ab.2009.08.038
https://www.sciencedirect.com/science/a ... via%3Dihub
https://pubmed.ncbi.nlm.nih.gov/19733144/
Waugh DT - "Fluoride Exposure Induces Inhibition of Sodium/Iodide Symporter (NIS) Contributing to Impaired Iodine Absorption and Iodine Deficiency: Molecular Mechanisms of Inhibition and Implications for Public Health" Int J Environ Res Public Health 16(6):1086 (2019). doi: 10.3390/ijerph16061086
https://pmc.ncbi.nlm.nih.gov/articles/PMC6466022/