Fluoride Drug Interactions, Uses, Effectiveness, Safety & More

Some observational research has found that exposure to high levels of fluoride in utero or during childhood may impact neurodevelopment. These findings are currently exploratory; further research is warranted to determine the presence or absence of a causal relationship and whether any risk is significant at the population level. In addition, although efforts were made to take confounding factors into consideration during the conduct of these studies, more information is needed to determine whether any neurological effects may be related to other exposures during pregnancy or childhood or to other factors such as socioeconomic status, use of formula instead of breast-feeding, lifestyle factors, or the choice of IQ tests used. Also, the actual intake of fluoride is not known in most cases.

Population research that has compared IQ scores between geographic regions with high natural levels of fluoride (e.g. up to 11.5 mg/L) and those with artificially fluoridated water (e.g., concentrations between 0.7-1.2 mg/L) have found that much higher fluoride levels may be associated with a reduced IQ score. A meta-analysis of 30 observational studies including 12,263 children from 7 countries suggests that higher early childhood or prenatal fluoride exposure levels are associated with lower IQ scores. Dose-response analysis indicated a linear decrease in IQ score as water fluoride levels exceeded 1 mg/L, with a 3-point decrement in score for each 1 mg/L increase in water fluoride concentration. However, all but 3 studies were conducted in countries with naturally fluoridated water as opposed to those with artificial water fluoridation programs, within which water fluoride concentrations are monitored and controlled. Additionally, most studies were cross-sectional and heavily confounded, with no information on actual fluoride intake. Furthermore, the relationship between fluoride exposure and IQ score was strongest in the studies determined to be at the highest risk for bias. A subsequent meta-analysis, incorporating many of the same publications in its dose-response analysis, similarly identified an inverse association between IQ score and fluoride exposure when water fluoride levels exceeded 1.5 mg/L.

Research on the impact of optimally fluoridated water on neurodevelopment during infancy or childhood is conflicting. A meta-analysis of eight cross-sectional and cohort studies which evaluated the impact of fluoride levels at or below 1.5 mg/L in China, India, and Iran found no association with childhood IQ scores and fluoride exposure. Two cohort studies in Australia, where water fluoridation programs are common, have found no correlation between childhood fluoride exposure and neurodevelopment. One study found no difference in behavior scores at 17 years of age between children exposed to fluoridated water during the first 5 years of life and those not exposed to fluoridated water. The second study, which utilized the presence of dental fluorosis as a marker for high childhood fluoride intake, found no difference in IQ score at 16-26 years of age between those with and without dental fluorosis. A cohort study using the Canadian Maternal-Infant Research on Environmental Chemicals (MIREC) cohort found an association between IQ score at 4 years and fluoride exposure during infancy, but not early childhood, in males, but not females. However, measures of fluoride intake during infancy were limited by lack of data on use of formula versus breastfeeding and the type of water used to reconstitute formula. Separately, one observational study in Canada found a relationship between urinary fluoride levels and diagnosis of ADHD with higher inattention scores at age 14 years, but not at age 9 years. The findings of this study are limited by the use of urinary fluoride levels, which are considered a potentially unreliable marker for fluoride intake.

There is some concern that reconstitution of infant formula with fluoridated water might result in fluoride intakes above the tolerable upper intake level (UL). One observational study in Canada found that for each 0.5-gram increase in fluoride from reconstituted formula, there is an 8.8-point decrement in performance IQ, which measures non-verbal reasoning and visual-motor coordination, at 3-4 years of age. However, there was no association with global intellectual functioning or verbal reasoning. The Canadian Dental Association recommends that when infant formulas are used as the main source of nutrition, drinking water that contains natural fluoride above recommended levels should not be used to reconstitute the formula.

There is also some concern that levels of fluoride found in optimally fluoridated water sources might impact fetal neurodevelopment. Emerging population research suggests that increased fluoride intake during pregnancy, as measured by urinary fluoride or dietary surveys, might be associated with negative cognitive effects. One cohort study utilizing data from the Canadian MIREC cohort found that for each 1 mg/L increase in maternal urinary fluoride, there is a 3.7-point decrement in IQ in children aged 3-4 years, with a greater reduction in non-verbal abilities than verbal abilities. A sub-analysis revealed a decrement of 4.5 points in males, with no decrement in females. A separate MIREC cohort study identified a potential modulating interaction between iodine exposure and fluoride exposure during pregnancy, as determined via urinary levels. Specifically, low iodine-high fluoride was associated with a greater reduction in IQ score than adequate iodine-high fluoride. A cohort study in Mexico found that higher urinary fluoride levels during pregnancy are associated with symptoms of inattention in the offspring at age 6-12 years. Conversely, a cohort study conducted in Denmark identified no relationship between maternal urinary fluoride levels and IQ score at 7 years of age. The findings of these studies are limited by the use of urinary fluoride levels, which are considered a potentially unreliable marker of fluoride intake. In fact, one study investigating the impact of diet on urinary fluoride levels during pregnancy identified potential variations in impact between trimesters and between the pre- and postpartum states.

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11. Taylor KW, Eftim SE, Sibrizzi CA, et al. Fluoride Exposure and Children's IQ Scores: A Systematic Review and Meta-Analysis. JAMA Pediatr 2025.
12. Kumar JV, Moss ME, Liu H, Fisher-Owens S. Association between low fluoride exposure and children's intelligence: a meta-analysis relevant to community water fluoridation. Public Health 2023;219:73-84.
13. Do LG, Spencer AJ, Sawyer A, et al. Early Childhood Exposures to Fluorides and Child Behavioral Development and Executive Function: A Population-Based Longitudinal Study. J Dent Res 2023;102(1):28-36.
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18. Canadian Dental Association. CDA position on use of fluorides in caries prevention. March 2012. Available at: https://www.cda-adc.ca/_files/position_statements/fluoride.pdf. Accessed December 9, 2020.
19. Green R, Lanphear B, Hornung R, et al. Association between maternal fluoride exposure during pregnancy and IQ scores in offspring in Canada. JAMA Pediatr. 2019;173(10):940-8.
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Exposure to fluoride can cause allergic reactions including urticaria, exfoliative dermatitis, atopic dermatitis, stomatitis, and gastrointestinal allergic reactions. Respiratory allergic reactions occur rarely. A case of dermatitis around the mouth was thought to be related to the high fluoride levels in a specific toothpaste (NeutraFluor 5000 Plus). In another case report, lip inflammation occurred in reaction to the amine fluoride in a toothpaste product. Lip inflammation and urticaria were also reported in reaction to a specific brand of toothpaste (Crest Pro-Health). However, it is not clear if this reaction occurred in response to the fluoride or tin component of stannous fluoride.

1. McEvoy GK, ed. AHFS Drug Information. Bethesda, MD: American Society of Health-System Pharmacists, 1998.
2. Peters P, Drummond C. Perioral dermatitis from high fluoride dentifrice: a case report and review of literature. Aust Dent J. 2013 Sep;58(3):371-2.
3. Foti C, Romita P, Ficco D, Bonamonte D, Angelini G. Allergic contact cheilitis to amine fluoride in a toothpaste. Dermatitis. 2014 Jul-Aug;25(4):209.
4. Enamandram M, Das S, Chaney KS. Cheilitis and urticaria associated with stannous fluoride in toothpaste. J Am Acad Dermatol. 2014 Sep;71(3):e75-6.

Fluoride can cause enamel fluorosis, a condition in which the ingestion of excessive amounts of fluoride during the development of permanent teeth may cause discoloration and pitting. This is a cosmetic effect only; tooth enamel may be stronger and more resistant to caries with enamel fluorosis. Topically, use of stannous fluoride in toothpaste has caused staining of the teeth.

1. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy Press, 1999. Available at: http://books.nap.edu/books/0309063507/html/index.html.
2. Sälzer S, Slot DE, Dörfer CE, Van der Weijden GA. Comparison of triclosan and stannous fluoride dentifrices on parameters of gingival inflammation and plaque scores: a systematic review and meta-analysis. Int J Dent Hyg. 2015 Feb;13(1):1-17.

Orally, sodium fluoride 40-65 mg daily can cause lower extremity pain and stress fractures. Fluoride at high doses for prolonged periods, over 10 mg daily for 10 or more years, can cause skeletal fluorosis. Skeletal fluorosis initially presents as joint stiffness and pain, followed by crippling, osteosclerosis, muscle wasting, and neurological defects due to hyper calcification of the vertebra. Crippling skeletal fluorosis is extremely rare in the US.

1. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy Press, 1999. Available at: http://books.nap.edu/books/0309063507/html/index.html.

A meta-analysis shows that exposure to drinking water high in fluoride is associated with increases in both systolic and diastolic blood pressure, and possibly an increased risk of developing hypertension, when compared with exposure to drinking water with low to normal levels. High levels of fluoride were defined as 1.02-4.06 mg/L and low to normal levels were defined as 0.18-0.84 mg/L.

1. Davoudi M, Barjasteh-Askari F, Sarmadi M, et al. Relationship of fluoride in drinking water with blood pressure and essential hypertension prevalence: a systematic review and meta-analysis. Int Arch Occup Environ Health 2021;94(6):1137-1146.

Some in vitro and observational research has raised concerns regarding the impact of increased fluoride intake on thyroid function. The available observational research, which has taken place in multiple countries with highly variable water fluoride concentrations, has yielded conflicting findings. Some of these conflicting findings may relate to the use of urinary fluoride levels to estimate fluoride exposure. These levels can be significantly altered by various factors, including individual variability in fluoride pharmacokinetics; lifestyle factors such as smoking and alcohol consumption; and intermittently elevated intake from fluoride-containing dental products or high fluoride foods. Additionally, some population research has identified a potential interaction between iodine intake and fluoride intake on thyroid function, with higher iodine intake increasing the risk for goiter and iodine deficiency increasing the risk for elevated levels of thyroid stimulating hormone (TSH).

A 2023 meta-analysis of the available observational research evaluating fluoride intake and thyroid function identified 33 studies involving 45,000 subjects, the majority of which included children between the ages of 6 to 18. Only 6 of the included studies were considered to be at low risk for bias and only about half of the studies evaluated baseline iodine status. These studies were conducted in Asia (25 studies), Europe (3 studies), Africa (3 studies), and Canada (2 studies). The fluoride levels in drinking water for the regions included in these studies ranged from 0.8 mg/L to 25.1 mg/L; the recommended level of fluoride in U.S. drinking water is 0.7 mg/L. These studies found that water fluoride levels were directly correlated to TSH levels in adults and children; however, this correlation only occurred at water fluoride levels of 2.5 mg/L or more. There were no consistent correlations between thyroid hormone levels (including T3 and T4) and water fluoride levels, or between urinary fluoride levels and any markers of thyroid function.

The impact of fluoride intake on thyroid function during pregnancy is uncertain. One case-control study of 1105 pregnant adults in Canada found that each 0.5 mg/L increase in water fluoride concentration was associated with 1.65 higher odds of primary hypothyroidism during pregnancy. However, water fluoride levels were not associated with risk of subclinical hypothyroidism. Additionally, urinary fluoride levels and estimated fluoride intake were not associated with changes in TSH. It is important to note that 74% of the cases of primary hypothyroidism reported in this study were present prior to pregnancy and study enrollment, confounding any potential association between pregnancy, fluoride intake, and TSH levels.

1. Griebel-Thompson AK, Sands S, Chollet-Hinton L, et al. A Scoping Review of Iodine and Fluoride in Pregnancy in Relation to Maternal Thyroid Function and Offspring Neurodevelopment. Adv Nutr 2023;14(2):317-338.
2. Mou Y, Qu T, Wang R, Zhang Y, He Z, Gu S. The association of high-fluoride and high-iodine combined exposure with dental fluorosis and goiter: a meta-analysis. Environ Geochem Health 2023;45(6):3143-3153.
3. Malin AJ, Riddell J, McCague H, Till C. Fluoride exposure and thyroid function among adults living in Canada: Effect modification by iodine status. Environ Int 2018;121(Pt 1):667-674.
4. Iamandii I, De Pasquale L, Giannone ME, et al. Does fluoride exposure affect thyroid function? A systematic review and dose-response meta-analysis. Environ Res 2024;242:117759.
5. Hall M, Lanphear B, Chevrier J, Hornung R, Green R, Goodman C, et al. Fluoride exposure and hypothyroidism in a Canadian pregnancy cohort. Sci Total Environ 2023;869:161149.

Orally, fluoride can cause gastrointestinal symptoms. Enteric-coated and sustained-release dosage forms of sodium phosphate and sodium monofluorophosphate may cause fewer adverse effects than plain sodium fluoride. Adverse effects appear to be dose related. Sodium fluoride at high daily doses of 40-65 mg can cause nausea, vomiting, and GI bleeding.

1. Grey A, Garg S, Dray M, Purvis L, Horne A, Callon K, Gamble G, Bolland M, Reid IR, Cundy T. Low-dose fluoride in postmenopausal women: a randomized controlled trial. J Clin Endocrinol Metab. 2013 Jun;98(6):2301-7.
2. Brown JP, Josse RG, et al. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. CMAJ 2002;167:S1-S34..
3. Haguenauer D, Welch V, Shea B, et al. Fluoride for treating postmenopausal osteoporosis.(Cochrane Review). Cochrane Database Syst Rev 2002;(4):CD002825..
4. McEvoy GK, ed. AHFS Drug Information. Bethesda, MD: American Society of Health-System Pharmacists, 1998.

Population research in adolescents has found that having plasma fluoride levels of at least 0.32 micromol/L or consuming water with fluoride levels of at least 0.73 mg/L increases the odds of hyperuricemia by approximately 1.8-fold when compared with the lowest quartiles. In addition, serum uric acid levels are increased by 0.212 mg/dL for each micromol/L increase in plasma fluoride levels.

1. Wei Y, Zhu J, Wetzstein SA. Plasma and water fluoride levels and hyperuricemia among adolescents: A cross-sectional study of a nationally representative sample of the United States for 2013-2016. Ecotoxicol Environ Saf 2021;208:111670.