Iamandii I, De Pasquale L, Giannone ME, Veneri F, Generali L, Consolo U, Birnbaum LS, Castenmiller J, Halldorsson TI, Filippini T, Vinceti M - "Does fluoride exposure affect thyroid function? A systematic review and dose-response meta-analysis" Environ Res 117759 (2023) doi: 10.1016/j.envres.2023.117759
https://www.sciencedirect.com/science/a ... 512302563X
Abstract
Introduction: Fluoride exposure may have various adverse health effects, including affecting thyroid function and disease risk, but the pattern of such relation is still uncertain.
Methods: We systematically searched human studies assessing the relation between fluoride exposure and thyroid function and disease. We compared the highest versus the lowest fluoride category across these studies, and we performed a one-stage dose-response meta-analysis for aggregated data to explore the shape of the association.
Results: Most retrieved studies (27 of which with a cross-sectional design) were conducted in Asia and in children, assessing fluoride exposure through its concentrations in drinking water, urine, serum, or dietary intake. Twenty-four studies reported data on thyroid function by measuring thyroid-related hormones in blood (mainly thyroid-stimulating-hormone - TSH), 9 reported data on thyroid disease, and 4 on thyroid volume. By comparing the highest versus the lowest fluoride categories, overall mean TSH difference was 1.05 μIU/mL. Dose-response curve showed no change in TSH concentrations in the lowest water fluoride exposure range, while the hormone levels started to linearly increase around 2.5 mg/L, independent of the risk of bias of the included studies. The association between biomarkers of fluoride exposure and TSH was also positive, with little evidence of a threshold. Evidence for an association between fluoride exposure and blood concentrations of thyroid hormones was less evident, though there was an indication of inverse association with triiodothyronine. For thyroid disease, the few available studies suggested a positive association with goiter and with hypothyroidism in both children and adults.
Conclusions: Overall, exposure to high-fluoride drinking water appears to non-linearly affect thyroid function and increase TSH release in children, starting above a threshold of exposure, and to increase the risk of some thyroid diseases.
2023 REVIEW: Does fluoride exposure affect thyroid function? A systematic review and dose-response meta-analysis
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COMMENTARY: 2023 REVIEW: Does fluoride exposure affect thyroid function? A systematic review and dose-response meta-anal
Here we encounter yet another systematic review and meta-analysis conducted by researchers displaying limited comprehension of fluoride's impact on thyroid hormone metabolism and overall thyroid function. Despite a documented history of fluoride's effects on the thyroid now spanning more than 150 years, it appears as if this wealth of knowledge doesn't exist.
Once again, this flawed understanding has resulted in yet another unproductive review. A critical confounder, iodine intake, has once more been inadequately considered.
In the words of the study:
Some original researchers merely stated the absence of "iodine deficiency disorders" (i.e. Zhang et al., 2015; Yu et al., 2018; Wang et al., 2020). As disclosed elsewhere (PFPC 2023), these studies were, in fact, conducted on populations with more-than-adequate/excessive iodine intake.
Shaik et al. (2019) claimed their study was on children with "optimal iodine intake," yet no UIC or intake data is ever presented in the paper.
High Iodine Intake
The authors, Iamandii, Birnbaum et al., here seem oblivious to the basic premise that elevated fluoride intake is necessary when iodine intake is high, to produce similar effects as are normally seen at lower iodine intake levels (May, 1950). This, despite the authors themselves citing numerous animal studies that address this issue in depth (Jiang et al., 2016; Liu et al., 2016).
If this fundamental principle is not grasped, attempting to establish a "threshold level" surely becomes questionable. The authors propose an absurd threshold dose of 2.5 mg/L of fluoride in water, further disregarding the fact that several studies emphasize TOTAL fluoride as the concern, not just fluoride in water.
Studies conducted on populations with more-than-adequate/excessive iodine intake (Hall et al., 2023; Cui et al., 2020; Du et al., 2021; Zhang et al., 2015; Yang et al., 2008; Wang et al. 2020; Xu et al., 2022) are listed with those featuring lower iodine intake or thyroid dysfunction (Epsom et al., 1984; Kheradpisheh et al., 2018), and others at high altitudes (Khandare et al., 2017), where thyroid hormone metabolism differs significantly, and the normal TSH/thyroid feedback mechanism is suspended.
Additionally, included evidence shows fluoride effects on TSH at fluoride water concentrations below 0.5 mg/L (Kheradpisheh et al., 2018). Apparently, that study was not included in the threshold analysis because it dealt with adults, not children. (Quantitative analysis here included children up to 18 years old, while Kheradpisheh et al. investigated adults 20 years and older. Reason enough for exclusion? It doesn't make much sense, as - on the other hand - no attention is given to the fact that thyroid hormones may change greatly between 8 and 18 years, puberty being a key event.)
As the companion study by some of the same authors was a review on "Fluoride Exposure and Cognitive Neurodevelopment" (Veneri et al., 2023), published in March of this year, the study by Kheradpisheh et al. should have been discussed and extra attention given to it, as it shows that even at fluoride water concentrations below 0.5 mg/L, TSH was increased from 2.2 to 2.8 mIU/L in adults with normal thyroid function. The upper limit threshold for TSH for the first trimester of pregnancy is 2.5 mIU/L in many countries - specifically set to prevent potential adverse birth outcomes associated with thyroid dysfunction during early pregnancy, and developmental issues in the baby.
Table by Kheradpisheh et al.:
Effects on Thyroid Disease
Despite the study by Kheradpisheh et al. demonstrating the exacerbating effects of fluoride on untreated hypothyroidism (see the TSH levels in the table above) at fluoride water concentrations below 0.5 mg/L, that is not even mentioned in the discussion on fluoride effects on thyroid disease in children and adults.
Other data is entirely misinterpreted.
For example, the study by Wang et al. (2022) showed that fluoride was protective on goiter formation in children that carry the TSHR rs2268458 polymorphism or the PTPN22 rs3765598 polymorphism. Both of these are closely associated with Graves disease, or iodine-induced hyperthyroidism (Basedow Disease) - the very condition fluoride was effectively used for as medical treatment, for over three decades (May, 1950).
There is no mention at all of this historical application of fluoride in hyperthyroidism. Instead, authors claim that "the availability of data with reference to fluoride overexposure and its effects on the thyroid gland is unfortunately very poor." Considering that there are hundreds of studies easily available (PFPC 2023), including all the pharmacological data documenting the effectiveness of fluoride in the treatment of Basedow Disease, it is hard to take this review seriously.
There simply is no real understanding.
Susheela's pivotal study from 2005 is erroneously listed as "Andezhath et al." Sigh.
There are many other flaws in this review, but time constraints prevent a more comprehensive examination. Updates will be posted as they become available.
REFERENCES
Chen Diqun, Meng Fangang, Liu Lixiang, Zhao Rencheng, Du Yang, Jiao Lisha, Liu Shoujun, Liu Yuan, Huang Jumei, Wang Xin, Liang Na, Sun Guodong, Xi Jianguo - "A Typical Survey on Thyroid Nodules in Adults in Juye County, Shandong Province, China" Chin J Ctrl Endem Dis 29(1):5-8 (2014) PFPC Library
"Within the water iodine range of 200–300 μg/L, an increase in water fluoride from (0.99±0.29) mg/L to (1.67±0.19) mg/L led to a significant decrease in both thyroid nodule detection rates and TPOAb positivity rates."
Dechairo BM, Zabaneh D, Collins J, Brand O, Dawson GJ, Green AP, Mackay I, Franklyn JA, Connell JM, Wass JA, Wiersinga WM, Hegedus L, Brix T, Robinson BG, Hunt PJ, Weetman AP, Carey AH, Gough SC - "Association of the TSHR gene with Graves' disease: the first disease specific locus" Eur J Hum Genet 13(11):1223-30 (2005) doi: 10.1038/sj.ejhg.5201485
https://www.nature.com/articles/5201485
Jiang Y, Guo X, Sun Q, Shan ZY, Teng W - "Effects of excess fluoride and iodine on thyroid function and morphology" Biological Trace Element Research 170(2):382–389 (2016)
https://link.springer.com/article/10.10 ... 015-0479-0
"These results suggest that iodide causes the most damage but that fluoride can promote specific changes in the function and morphology of the thyroid, either alone or in combination with iodide."
Khandare AL, Gourineni SR, Validandi V - "Dental fluorosis, nutritional status, kidney damage, and thyroid function along with bone metabolic indicators in school-going children living in fluoride-affected hilly areas of Doda district, Jammu and Kashmir, India" Environ Monit Assess 189: 579 (2017)
https://link.springer.com/article/10.10 ... 017-6288-5
Kheradpisheh Z, Mirzaei M, Mahvi AH, Mokhtari M, Azizi R, Fallahzadeh H, Ehrampoush MH - "Impact of Drinking Water Fluoride on Human Thyroid Hormones: A Case- Control Study" Scientific Reports Volume 8, Article number: 2674 (2018)
doi:10.1038/s41598-018-20696-4
https://www.nature.com/articles/s41598-018-20696-4
Leporati P, Groppelli G, Zerbini F, Rotondi M, Chiovato L - "Etiopathogenesis of Basedow's disease. Trends and current aspects" Nuklearmedizin. 54(5):204-10 (2015) doi: 10.3413/Nukmed-0739-15-04
https://www.thieme-connect.com/products ... 0739-15-04
Lin Fa-Fu, Aihaiti, Zhao Hong-Xin, Lin Jin, Jiang Ji-Yong, Maimaiti, Aiken - "High-fluoride and Low-iodine Environment and Subclinical Cretinism in Xinjiang" Endem Dis Bul 6(2):62-67 (1991)
https://poisonfluoride.com/dir/wp-conte ... F-1991.pdf
English Translation in: ICCIDD Newsletter, Volume 7 Number 3 (August 1991)
https://poisonfluoride.com/pfpc/lin-1991.pdf
Liu H, Hou C, Zeng Q, Zhao L, Cui Y, Yu L, Wang L, Zhao Y, Nie J, Zhang B, Wang A - "Role of endoplasmic reticulum stress-induced apoptosis in rat thyroid toxicity caused by excess fluoride and/or iodide" Environmental Toxicology and Pharmacology 46:277-285 (2016)
DOI: 10.1016/j.etap.2016.08.007
http://www.sciencedirect.com/science/ar ... 8916302083
PFPC - Letter to Richard Woychik, Director, NTP & NIEHS (2023)
https://pfpc.substack.com/p/pfpc-letter ... k-director
PFPC - Fluoride Effects on the Thyroid - Recent Research (2023)
viewtopic.php?f=7&t=1345
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10047067/
Veneri F, Vinceti M, Generali L, Giannone ME, Mazzoleni E, Birnbaum LS, Consolo U, Filippini T - "Fluoride exposure and cognitive neurodevelopment: Systematic review and dose-response meta-analysis" Environ Res 221:115239 (2023). doi: 10.1016/j.envres.2023.115239
https://www.sciencedirect.com/science/a ... 5123000312
Wang M, Liu L, Li H, Li Y, Liu H, Hou C, Zeng Q, Li P, Zhao Q, Dong L, Zhou G, Yu X, Liu L, Guan Q, Zhang S, Wang A - "Thyroid function, intelligence, and low-moderate fluoride exposure among Chinese school-age children" Environ Int 134:105229 (2020) NTP #4
https://www.sciencedirect.com/science/a ... 2019301370
"None of the study sites was ...delimitated into endemic areas of iodine deficiency disorders which were determined by thyroid status examination and the median urinary iodine concentration in the population (World Health Organization, 2007)."(no "median urinary iodine concentrations" (UIC) nor info on thyroid status is ever presented in the paper!)
Yu X, Chen J, Li Y, Liu H, Hou C, Zeng Q, Cui Y, Zhao L, Li P, Zhou Z, Pang S, Tang S, Tian K, Zhao Q, Dong L, Xu C, Zhang X, Zhang S, Liu L, Wang A - "Threshold effects of moderately excessive fluoride exposure on children's health: A potential association between dental fluorosis and loss of excellent intelligence" Environ Int 118:116-124 (2018) NTP #3
https://www.sciencedirect.com/science/a ... 201830480X
"None of the study sites was in the areas endemic for iodine deficiency disorders..."
Zhang S, Zhang X, Liu H, Qu W, Guan Z, Zeng Q, Jiang C, Gao H, Zhang C, Lei R, Xia T, Wang Z, Yang L, Chen Y, Wu X, Cui Y, Yu L, Wang A - "Modifying effect of COMT gene polymorphism and a predictive role for proteomics analysis in children's intelligence in endemic fluorosis area in Tianjin, China" Toxicol Sci 144(2):238-45 (2015) NTP #110
https://academic.oup.com/toxsci/article ... 38/1716015
"None of these 2 sites was...delimitated into endemic areas of iodine deficiency disorders."
All other references are available at:
viewtopic.php?f=7&t=1345
Once again, this flawed understanding has resulted in yet another unproductive review. A critical confounder, iodine intake, has once more been inadequately considered.
In the words of the study:
Similar to the recent NTP review, assumptions were made about "iodine adjustment" without any supporting data in the original papers."Iodine status is accounted for as 'adjustment' if the fluoride analyses were adjusted for iodine status or the study population had a homogeneous iodine exposure" (Supplement info).
Some original researchers merely stated the absence of "iodine deficiency disorders" (i.e. Zhang et al., 2015; Yu et al., 2018; Wang et al., 2020). As disclosed elsewhere (PFPC 2023), these studies were, in fact, conducted on populations with more-than-adequate/excessive iodine intake.
Shaik et al. (2019) claimed their study was on children with "optimal iodine intake," yet no UIC or intake data is ever presented in the paper.
High Iodine Intake
The authors, Iamandii, Birnbaum et al., here seem oblivious to the basic premise that elevated fluoride intake is necessary when iodine intake is high, to produce similar effects as are normally seen at lower iodine intake levels (May, 1950). This, despite the authors themselves citing numerous animal studies that address this issue in depth (Jiang et al., 2016; Liu et al., 2016).
If this fundamental principle is not grasped, attempting to establish a "threshold level" surely becomes questionable. The authors propose an absurd threshold dose of 2.5 mg/L of fluoride in water, further disregarding the fact that several studies emphasize TOTAL fluoride as the concern, not just fluoride in water.
Studies conducted on populations with more-than-adequate/excessive iodine intake (Hall et al., 2023; Cui et al., 2020; Du et al., 2021; Zhang et al., 2015; Yang et al., 2008; Wang et al. 2020; Xu et al., 2022) are listed with those featuring lower iodine intake or thyroid dysfunction (Epsom et al., 1984; Kheradpisheh et al., 2018), and others at high altitudes (Khandare et al., 2017), where thyroid hormone metabolism differs significantly, and the normal TSH/thyroid feedback mechanism is suspended.
Additionally, included evidence shows fluoride effects on TSH at fluoride water concentrations below 0.5 mg/L (Kheradpisheh et al., 2018). Apparently, that study was not included in the threshold analysis because it dealt with adults, not children. (Quantitative analysis here included children up to 18 years old, while Kheradpisheh et al. investigated adults 20 years and older. Reason enough for exclusion? It doesn't make much sense, as - on the other hand - no attention is given to the fact that thyroid hormones may change greatly between 8 and 18 years, puberty being a key event.)
- Notably absent from this 'review' is the 3-year UNICEF-funded study by Lin et al. (1991) on children with iodine deficiency, which also demonstrated significant increases in TSH levels at fluoride water concentrations of 0.88 mg/L, similar to the findings by Kheradpisheh et al. in adults (2018).
As the companion study by some of the same authors was a review on "Fluoride Exposure and Cognitive Neurodevelopment" (Veneri et al., 2023), published in March of this year, the study by Kheradpisheh et al. should have been discussed and extra attention given to it, as it shows that even at fluoride water concentrations below 0.5 mg/L, TSH was increased from 2.2 to 2.8 mIU/L in adults with normal thyroid function. The upper limit threshold for TSH for the first trimester of pregnancy is 2.5 mIU/L in many countries - specifically set to prevent potential adverse birth outcomes associated with thyroid dysfunction during early pregnancy, and developmental issues in the baby.
Table by Kheradpisheh et al.:
Effects on Thyroid Disease
Despite the study by Kheradpisheh et al. demonstrating the exacerbating effects of fluoride on untreated hypothyroidism (see the TSH levels in the table above) at fluoride water concentrations below 0.5 mg/L, that is not even mentioned in the discussion on fluoride effects on thyroid disease in children and adults.
Other data is entirely misinterpreted.
For example, the study by Wang et al. (2022) showed that fluoride was protective on goiter formation in children that carry the TSHR rs2268458 polymorphism or the PTPN22 rs3765598 polymorphism. Both of these are closely associated with Graves disease, or iodine-induced hyperthyroidism (Basedow Disease) - the very condition fluoride was effectively used for as medical treatment, for over three decades (May, 1950).
There is no mention at all of this historical application of fluoride in hyperthyroidism. Instead, authors claim that "the availability of data with reference to fluoride overexposure and its effects on the thyroid gland is unfortunately very poor." Considering that there are hundreds of studies easily available (PFPC 2023), including all the pharmacological data documenting the effectiveness of fluoride in the treatment of Basedow Disease, it is hard to take this review seriously.
There simply is no real understanding.
Susheela's pivotal study from 2005 is erroneously listed as "Andezhath et al." Sigh.
There are many other flaws in this review, but time constraints prevent a more comprehensive examination. Updates will be posted as they become available.
REFERENCES
Chen Diqun, Meng Fangang, Liu Lixiang, Zhao Rencheng, Du Yang, Jiao Lisha, Liu Shoujun, Liu Yuan, Huang Jumei, Wang Xin, Liang Na, Sun Guodong, Xi Jianguo - "A Typical Survey on Thyroid Nodules in Adults in Juye County, Shandong Province, China" Chin J Ctrl Endem Dis 29(1):5-8 (2014) PFPC Library
"Within the water iodine range of 200–300 μg/L, an increase in water fluoride from (0.99±0.29) mg/L to (1.67±0.19) mg/L led to a significant decrease in both thyroid nodule detection rates and TPOAb positivity rates."
Dechairo BM, Zabaneh D, Collins J, Brand O, Dawson GJ, Green AP, Mackay I, Franklyn JA, Connell JM, Wass JA, Wiersinga WM, Hegedus L, Brix T, Robinson BG, Hunt PJ, Weetman AP, Carey AH, Gough SC - "Association of the TSHR gene with Graves' disease: the first disease specific locus" Eur J Hum Genet 13(11):1223-30 (2005) doi: 10.1038/sj.ejhg.5201485
https://www.nature.com/articles/5201485
Jiang Y, Guo X, Sun Q, Shan ZY, Teng W - "Effects of excess fluoride and iodine on thyroid function and morphology" Biological Trace Element Research 170(2):382–389 (2016)
https://link.springer.com/article/10.10 ... 015-0479-0
"These results suggest that iodide causes the most damage but that fluoride can promote specific changes in the function and morphology of the thyroid, either alone or in combination with iodide."
Khandare AL, Gourineni SR, Validandi V - "Dental fluorosis, nutritional status, kidney damage, and thyroid function along with bone metabolic indicators in school-going children living in fluoride-affected hilly areas of Doda district, Jammu and Kashmir, India" Environ Monit Assess 189: 579 (2017)
https://link.springer.com/article/10.10 ... 017-6288-5
Kheradpisheh Z, Mirzaei M, Mahvi AH, Mokhtari M, Azizi R, Fallahzadeh H, Ehrampoush MH - "Impact of Drinking Water Fluoride on Human Thyroid Hormones: A Case- Control Study" Scientific Reports Volume 8, Article number: 2674 (2018)
doi:10.1038/s41598-018-20696-4
https://www.nature.com/articles/s41598-018-20696-4
Leporati P, Groppelli G, Zerbini F, Rotondi M, Chiovato L - "Etiopathogenesis of Basedow's disease. Trends and current aspects" Nuklearmedizin. 54(5):204-10 (2015) doi: 10.3413/Nukmed-0739-15-04
https://www.thieme-connect.com/products ... 0739-15-04
Lin Fa-Fu, Aihaiti, Zhao Hong-Xin, Lin Jin, Jiang Ji-Yong, Maimaiti, Aiken - "High-fluoride and Low-iodine Environment and Subclinical Cretinism in Xinjiang" Endem Dis Bul 6(2):62-67 (1991)
https://poisonfluoride.com/dir/wp-conte ... F-1991.pdf
English Translation in: ICCIDD Newsletter, Volume 7 Number 3 (August 1991)
https://poisonfluoride.com/pfpc/lin-1991.pdf
Liu H, Hou C, Zeng Q, Zhao L, Cui Y, Yu L, Wang L, Zhao Y, Nie J, Zhang B, Wang A - "Role of endoplasmic reticulum stress-induced apoptosis in rat thyroid toxicity caused by excess fluoride and/or iodide" Environmental Toxicology and Pharmacology 46:277-285 (2016)
DOI: 10.1016/j.etap.2016.08.007
http://www.sciencedirect.com/science/ar ... 8916302083
- SEE also: Liu H, Zeng Q, Cui Y, Zhao L, Zhang L, Fu G, Hou C, Zhang S, Yu L, Jiang C, Wang Z, Chen X, Wang A - "The role of the IRE1 pathway in excessive iodide- and/or fluoride-induced apoptosis in Nthy-ori 3-1 cells in vitro" Toxicol Lett 224(3):341-8 (2014). doi: 10.1016/j.toxlet.2013.11.001
https://www.sciencedirect.com/science/a ... 741301391X
Liu H, Zeng Q, Cui Y, Yu L, Zhao L, Hou C, Zhang S, Zhang L, Fu G, Liu Y, Jiang C, Chen X, Wang A -"The effects and underlying mechanism of excessive iodide on excessive fluoride-induced thyroid cytotoxicity" Environ Toxicol Pharmacol 38(1):332-40 (2014)
http://www.sciencedirect.com/science/ar ... 8914001513
PFPC - Letter to Richard Woychik, Director, NTP & NIEHS (2023)
https://pfpc.substack.com/p/pfpc-letter ... k-director
PFPC - Fluoride Effects on the Thyroid - Recent Research (2023)
viewtopic.php?f=7&t=1345
- See also: PFPC - Fluoride use as anti-iodine -> anti-thyroid medication
viewtopic.php?f=7&t=2800
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10047067/
Veneri F, Vinceti M, Generali L, Giannone ME, Mazzoleni E, Birnbaum LS, Consolo U, Filippini T - "Fluoride exposure and cognitive neurodevelopment: Systematic review and dose-response meta-analysis" Environ Res 221:115239 (2023). doi: 10.1016/j.envres.2023.115239
https://www.sciencedirect.com/science/a ... 5123000312
Wang M, Liu L, Li H, Li Y, Liu H, Hou C, Zeng Q, Li P, Zhao Q, Dong L, Zhou G, Yu X, Liu L, Guan Q, Zhang S, Wang A - "Thyroid function, intelligence, and low-moderate fluoride exposure among Chinese school-age children" Environ Int 134:105229 (2020) NTP #4
https://www.sciencedirect.com/science/a ... 2019301370
"None of the study sites was ...delimitated into endemic areas of iodine deficiency disorders which were determined by thyroid status examination and the median urinary iodine concentration in the population (World Health Organization, 2007)."(no "median urinary iodine concentrations" (UIC) nor info on thyroid status is ever presented in the paper!)
Yu X, Chen J, Li Y, Liu H, Hou C, Zeng Q, Cui Y, Zhao L, Li P, Zhou Z, Pang S, Tang S, Tian K, Zhao Q, Dong L, Xu C, Zhang X, Zhang S, Liu L, Wang A - "Threshold effects of moderately excessive fluoride exposure on children's health: A potential association between dental fluorosis and loss of excellent intelligence" Environ Int 118:116-124 (2018) NTP #3
https://www.sciencedirect.com/science/a ... 201830480X
"None of the study sites was in the areas endemic for iodine deficiency disorders..."
Zhang S, Zhang X, Liu H, Qu W, Guan Z, Zeng Q, Jiang C, Gao H, Zhang C, Lei R, Xia T, Wang Z, Yang L, Chen Y, Wu X, Cui Y, Yu L, Wang A - "Modifying effect of COMT gene polymorphism and a predictive role for proteomics analysis in children's intelligence in endemic fluorosis area in Tianjin, China" Toxicol Sci 144(2):238-45 (2015) NTP #110
https://academic.oup.com/toxsci/article ... 38/1716015
"None of these 2 sites was...delimitated into endemic areas of iodine deficiency disorders."
All other references are available at:
viewtopic.php?f=7&t=1345