Fluoride Neurotoxicity

Topic Summary

By Center for Fluoride Research Analysis / Fluoride Science Editorial Board
Last updated: October 26, 2017
INSUFFICIENT EVIDENCE ON FLUORIDATION AND NEUROBEHAVIORAL DISORDER

Summary on fluoride neurotoxicity: Neurobehavioral disorders such as learning disabilities, attention deficit hyperactivity disorder (ADHD), autism, reduced intelligence quotient (IQ), dementia, and Alzheimer’s Disease are commonly reported in industrialized countries. Wide variations in prevalence across populations and the reporting years are often due to differences in diagnostic and reporting behaviors. Although some cases are linked to identified exposures, specific etiology is unknown in most cases.1

FLUORIDE NEUROTOXICITY CELLULAR AND ANIMAL STUDIES

On the basis of information derived from cellular studies, it appears that fluoride has the ability to interfere with the functions of the brain (i.e. disruptions of aerobic metabolism, reduced effectiveness of acetylcholine as a transmitter, and an increase in free radicals) by direct and indirect means.2 However, the clinical outcomes and significance of such biochemical changes potentiated by the exposures to fluoride in animals and humans are yet to be well understood.

The National Toxicology Program recently published a systematic review of studies testing the impact of fluoride in drinking water and diet on neurobehavioral function in mice or rats.3 Their conclusion was that there is a low-to-moderate level of evidence that suggests a potential adverse effect on learning and memory at fluoride concentrations higher than 0.7ppm.3 However, they acknowledged that the relevance of the doses of fluoride exposures as well as the measurements of memory and learning used in the available laboratory studies and thus the findings to humans are largely unknown, especially as many of those studies were determined to be at high risk of bias.

HUMAN STUDIES

Available human epidemiological studies almost entirely focus on global IQ, a measure based on tests that is correlated with important indicators of human cognitive ability such as knowledge retention, abstract reasoning, and visual-spatial processing. In 2012, Choi and her colleagues conducted a systematic review and meta-analysis of 27 studies conducted in fluoride-endemic counties such as China and reported the weighted-pooled-standardized mean difference of -0.45, which showed a faintly lower IQ in the high-fluoride group relative to the reference/lower-fluoride group.5 These studies included in the meta-analysis are of cross-sectional design, originally written in non-English languages, used various measures of fluoride exposure and IQ outcome, and did not address critical biases or report important methodological details, and thus largely are of unknown or limited quality on the question of fluoride neurotoxicity.4

Broadbent et al. (2015) conducted a prospective cohort study providing evidence against fluoride neurotoxicity in New Zealand where natural levels of fluoride in drinking water are generally less than 0.2 mg/L and fluoride levels in areas with community water fluoridation are adjusted upward to 0.7-1.0 mg/L.6 The cohort of 1037 children born between April 1, 1972 and March 31, 1973 (91% of eligible birth cohorts) was constituted at age 3 years as part of the Dunedin Multidisciplinary Health and Development Study and followed longitudinally.6 Fluoride exposures from drinking water, the use of tablets or toothpaste were not associated with IQ scores measured at 7-13 years and at age 38 years after controlling for confounders such as sex, socioeconomic status in childhood, low birth weight, breastfeeding, and educational achievement (controlled only for adult IQ).6

Broadbent and colleagues also investigated how subsets of IQ scores were associated with fluoride exposures and found no significant difference in verbal comprehension, perceptual reasoning, working memory, and processing ability by fluoride exposure level.6 Choi and her colleagues also attempted to study what domains of cognitive ability would be most affected by fluoride exposures using a small sample of first graders (N=51) in China and found lower digit span scores among children with moderate-severe fluorosis relative to children with normal-questionable fluorosis after adjusting for potential confounders such as child’s sex, age, parity, early childhood illness, and caretakers age, education, and income.7 The authors reported that 60% of this small pilot study subjects were affected by moderate or severe fluorosis,7 which indicates that the study participants had much greater level of fluoride exposures during early childhood than US children of similar age group (i.e. the prevalence of moderate-severe fluorosis in the US is less than 5%).8

In 2016, the report of a study conducted by Uppsala University’s (Sweden) interdisciplinary Psychosocial Care Program (U-CARE) was published on the University’s Library website.  Sweden has natural variation of fluoride in the drinking water similar to the levels in the US (reportedly between 0 and 4 mg/L) which stems foremost from the bedrock under the water sources.9 Aggeborn and Öhman examined the individual-level register data of math tests taken at age 16 as well as cognitive and non-cognitive abilities evaluated for men between 18 and 20 years of age for military enlistment in relation to fluoride exposure.9 Fluoride exposure was estimated based on public water systems and residence from birth to age 16. To assess the process of using water plant data to estimate fluoride exposure, dental outcome data were linked to the fluoride data. This assessment demonstrated the expected pattern of reduced dental need as the measure of fluoride exposure increased. This lends some credibility to the estimation of fluoride exposure. Sample sizes in these analyses were quite large (N>20,000) and care was taken in the presentation of the findings to provide a balanced interpretation of the results. The authors concluded that there were essentially zero effects of fluoride on cognitive ability and non-cognitive ability in young adult males and math score in both males and females.9 There is no fluoride neurotoxicity danger attributable to fluoride in drinking water at levels below 1.5 mg/l.9 When the authors examined the longer range effect of fluoride on the population in economic terms, they found a positive effect of fluoride on log income and employment status (1mg/L increase of fluoride level in drinking water was associated with 4.2% and 2% increase in income and probability of being employed, respectively) which may imply that better dental health owing to fluoride contributes positively to the labor market.9

Bashash and colleagues (2017) examined data collected in the longitudinal birth cohort study called Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT)10 to assess the potential impact of prenatal exposures to fluoride on children’s cognitive functions. While the ELEMENT database offered various maternal and perinatal variables (i.e. birth outcomes, maternal smoking, IQ) as well as childhood neurocognitive outcomes assessed periodically at individual-levels, the study was not planned prior to the data collection thus relied solely on urinary fluoride levels for exposure measurement. Mexico is one of the countries that fluoridate salt (at 250ppm) thus the subjects of the study most likely had exposed to fluoride from salt as well as other background food, dental products, and drinking water with varying degrees of naturally occurring fluoride. The limitations of urinary fluoride as a biomarker are that it reflects only recent exposures and fluctuates during the day. Thus fluoride levels measured in spot urine samples, as done in this study, may be different from usual and/or long-term exposures. Furthermore, there is no reference dose of urinary fluoride during pregnancy or established relationship between external and internal dose of fluoride with respect to biological effect (i.e. neurotoxicity).2

The study found 0.5mg/L increase in maternal urinary fluoride level during pregnancy was associated with a decline in childhood cognitive ability—3.15 and 2.5 points down in General Cognitive Index at 4 years (N=287) and IQ score at 6-12 years (N=211), respectively.10 However there was no clear association between prenatal urinary fluoride and IQ scores below approximately 0.8mg/L urinary fluoride levels indicating possible non-linear relationship between fluoride exposure and cognitive outcomes.10 In addition, a widely spread scatter plot distribution suggests that prenatal fluoride exposure may be a small portion of variations that explain the relationship. The authors found no clear, statistically significant, association between children’s urinary fluoride and IQ at 6-12 years of age.10

Barberio et al. (2017) also used data of urinary fluoride levels measured in spot urine samples obtained from the nationally representative Canadian children and reported no association between creatinine- or specific gravity-adjusted urinary fluoride and reported learning disability in 3-12 year-olds (N≈1100).11 This study was a cross-sectional study and cognitive function was measured in self-reported/parent-reported diagnosis of learning disabilities, however the authors were able to examine the effect of external fluoride using data of residential history, primary source of water, the use of fluoride-containing dental products at home, receipt of fluoride treatments at dental office, and sampled water for testing fluoride concentrations. The authors found no difference in these external fluoride exposure levels among children with and without a reported learning disability diagnosis (N<300).11

The majority of existing studies on hypothesized fluoride neurotoxicity use research designs which are inherently weak and/or have many limitations, thus accumulated evidence does not allow us to reject or accept fluoride’s neurotoxicity in humans or if fluoride in drinking water has any negative effect on children’s neurodevelopment at this time. The association may be non-liner and non-robust at best. There are often a number of plausible risk factors that influence the neurocognitive outcomes in human such as genetics, environmental exposures to known neurotoxins such as lead, mercury, and arsenic, nutrition and iodine intake, maternal and familial sociocultural resources, educational opportunities as well as early childhood interventions. It is imperative to rule them out before drawing conclusions about cause and effect. Furthermore, consensus on the appropriate measure of fluoride exposure for fluoride-IQ research, including issues related to the selection of fluoride biomarkers, methodology of sampling, and analytical strategies, should be established.

WINDOW OF SUSCEPTIBILITY FOR FLUORIDE NEUROTOXICITY?

The question of whether fluoride’s neurotoxicity has a critical window of susceptibility is often raised as the period of fetal development and early childhood are obviously important period for brain development, and fluoride is reportedly transportable to fetus through umbilical cord and placenta. There are only a few studies that looked at the fluoride exposure in pregnant women and its association with neurobehavioral outcomes in their offspring.10,12 One of the co-authors of the recent Mexican study examined the same ELEMENT database for her thesis (https://deepblue.lib.umich.edu/handle/2027.42/110409) and found no evidence of detectable adverse outcome on offspring neurobehavioral development at 1, 2, and 3 years of age associated with maternal fluoride exposure during pregnancy (measured in spot urine and plasma samples). Despite minor differences in analytical methodologies, these two studies used the same cohort and design of data collection but seem to disagree unless the effect of prenatal fluoride exposure has a latent period or the effect is clinically insignificant anyways. Furthermore, a systematic review by the NTP (2016) hinted greater neurobehavioral effect in animals exposed to fluoride as adults than in animals exposed during development.3 The mixed evidence as these begs for further research with refined methodology.

ADHD

In 2015, Malin and Till reported that state-level prevalence of ADHD, a common neurobehavioral disorder in children, was greater in states with a greater proportion of the population receiving fluoridated water from public water supplies based on 51 observations.13 This study failed to adjust for important confounders such as smoking, low birth weight, gender and is at high-risk of suffering from a source of bias known as ecological fallacy.  That is, the individuals with ADHD in this study may not have been exposed to fluoridated water.  Barberio and colleagues of Canadian study analyzed the subset of data to examine whether reported diagnosis of ADHD is associated with any measure of fluoride exposure.11 They found that those with higher creatinine-adjusted urinary fluoride had lower odds of reporting ADD (p=0.003), however this association was reduced to non-significant (p=0.107) in the adjusted model for potential confounders such as age, gender, household income and education.11 Aggeborn and Öhman found zero effects of fluoride on the probability of being prescribed medications for ADHD, depression or psychoses among Swedish population.9

The following section summarizes the findings and recommendations from the frequently referenced systematic reviews on this topic.

SYSTEMIC REVIEWS THAT DISCUSS NEUROBEHAVIORAL DISORDERS AND WATER FLUORIDATION

ENVIRONMENTAL PROTECTION AGENCY (EPA) RESPONSE TO TSCA SECTION 21 PETITION (2017)14
Excerpt of response showing EPA denied fluoride neurotoxicity petition

Responding to the petition under section 21 of the Toxic Substances Control Act (TSCA) submitted by several anti-fluoridation advocacy groups in 2016 for the purpose of pursuant fluoridation chemicals as drinking water additives, EPA made their reviews of scientific evidence and response to the petition’s following 9 claims:

  1. Fluoride neurotoxicity at levels relevant to US population
  2. Recent epidemiological studies corroborate neurotoxic risk in Western populations
  3. Neurotoxic risks supported by animal and cell studies
  4. Susceptible subpopulations are at heightened risk
  5. RfD/RfC derivation and uncertainty factor application
  6. Benefits to public health
  7. Extent and magnitude of risk from fluoridation chemicals.
  8. Consequences of eliminating use of fluoridation chemicals
  9. Link to elevated blood lead levels

EPA denied the TSCA section 21 petition, primarily because the petition did not set forth a scientifically defensible basis to conclude that any persons have suffered neurotoxic harm as a result of exposure to fluoride in the US through the purposeful addition of fluoridation chemicals to drinking water or otherwise from fluoride exposure in the US. The petition cited studies to support their claims without accounting for strengths, limitations, and risk of bias of each study or providing any criteria or rationale for selecting the particular studies from the overall database of available studies. Take home messages for any future petition submitted to EPA include:

  • EPA values weight and quality of evidence, and the claims should be supported by compelling scientific evidence.
  • EPA considers that establishing a dose-response relationship between exposure to a toxicant and an effect is the most fundamental and pervasive concept of toxicology.
  • EPA is mindful of the public health significance of reducing the incidence of dental caries in the US population.

The full EPA response is available for public viewing at https://www.federalregister.gov/documents/2017/02/27/2017-03829/fluoride-chemicals-in-drinking-water-tsca-section-21-petition-reasons-for-agency-response

NATIONAL TOXICOLOGY PROGRAM (2016)3

NTP conducted this systematic review of literature published up to January 14, 2016 to investigate whether fluoride exposure has detrimental impacts on neurobehavior in laboratory animals. NTP identified 68 studies that tested drinking water or dietary concentrations of 0.45 to 277 ppm fluoride (0.12 to 40 mg/kg/day) using mice or rats; 48 studies addressed learning and memory, 16 of which assessed exposure during development. Based the analysis of 32 studies, NTP concluded that “there is a low-to-moderate level of evidence that suggests a potential adverse effect on learning and memory at concentrations higher than 0.7 ppm from laboratory studies. The evidence is strongest in animals exposed as adults and weaker in animals exposed during development.”

NTP expresses the following limitations in the literature base:

  • Very few studies assessed learning and memory effects in experimental animals at exposure levels near 0.7ppm and had information on alternative sources of fluoride (i.e. food, water supply) available, thus relevance of the findings to human exposure levels in the optimally fluoridated communities (0.7ppm fluoride concentration) is unknown.
  • The outcome endpoint in the majority of studies was a simple latency measurement of learning or memory in the final training session rather than an evaluation of the acquisition of the task to demonstrate learning. Thus, interpretation of the data is hindered by inability to exclude alterations from baseline levels or differences in motor-related performance over the training session as contributing factors.
  • In many studies, there was a lack of reporting of 1) randomization and blinding, 2) specification of test methodologies to assess the outcomes, and/or 3) controlling of confounders such as litter effects, sex, life-stage at exposure, and duration of exposure. Of 68 studies reviewed by NTP, 19 studies were considered to have a very severe risk of bias. Meta-analysis was not conducted because the small number of studies had comparable study designs.
  • Studies appear statistically underpowered to detect a <10% or <20% change from controls for most behavioral endpoints.
CHOI ET AL. (2012)5

The authors conducted meta-analyses of 27 epidemiological studies carried out from 1989 through 2011 on the relationship between high fluoride exposure and delayed neurobehavioral development among children in rural areas of China, including 2 studies from Iran. The outcome measured for the individual studies was general intelligence determined by various IQ tests: 16 of the studies used the Combined Raven’s Test – The Rural edition in China (CRT-RC) and other tests were used as follows: the Weschler Intelligence Tests (3 studies), Binet IQ Test (2 studies), Raven’s Test (2 studies), Japan IQ Test (2 studies), the Chinese Comparative Intelligence Test (1 study), and the Mental Work Capacity Index (1 study). A standardized weighted mean difference (SMD) was computed using both fixed-effects and random-effects models, determining the presence of heterogeneity, and performing sensitivity analyses on studies that used similar tests to measure the outcome.

The authors found the suggestion of an inverse relationship between high fluoride exposure and children’s intelligence: The random-effects SMD was -0.45 (95% CI= -0.56, -0.34) with an I2 of 80% and homogeneity test p-value

  • Most of studies included in the meta-analysis were conducted in rural areas of China, and their exposed groups had access to drinking water with fluoride concentrations up to 11.5 mg/L. Thus in many cases concentrations were much above the levels recommended (0.7 mg/L) or allowed (4 mg/L) in public drinking water in the United States. It is also important to note that there was overall overlap in the cut-off points of fluoride exposures between studies: High fluoride group ranged 0.88-11.5 mg/L and reference groups 0.2-2.35 mg/L.
  • Most studies included in the meta-analysis were of insufficient quality. In some reports, there were serious deficiencies/ limitations on methodology. Many reports did not provide complete information on variables and/or potential confounders of the relationship between children’s IQ and high fluoride in drinking water, such as co-exposures to environmental pollutants such as lead and arsenic, other sources of fluoride (foods may also contain high level of fluoride in fluoride-endemic region), perinatal and early childhood nutrition (i.e. iodine, breastfeeding), and poverty.
  • The actual exposures to fluoride and possible routes of fluoride exposure of the individual children were unknown.
  • The estimated decrease in average IQ in high exposure group found in this meta-analysis (SMD=-0.45) is small. Such small shift in IQ points could be within the measurement error of IQ testing and unlikely to have any functional significance at both individual and population levels.
TANG ET AL. (2008)15

The authors identified 16 “case-control” studies conducted in China that were published between 1988 and 2008 and included in meta-analysis to investigate the relationship between fluoride and low IQ. They found summarized weighted mean difference of -4.97 (95% CI=-5.58, -4.36) using a fixed-effect model and -5.03 (95% CI=-6.51, 3.55) using a random-effect model.

This paper has serious flaws both in methodology and interpretation of the results that are highlighted below, and the findings must be either interpreted very cautiously or be discredited.

  • The Materials and Methods section lacks critical information such as inclusion and exclusion criteria. Thus it is impossible to determine whether the authors had a clear rule-based process to objectively summarize the evidence.
  • The authors say “16 case-control studies were included in the review”, however Bazian Ltd, which examined each of included studies, reports that they are actually all cross-sectional studies.4
  • The authors do not report what type of IQ test was used in each study or how fluoride exposures were measured and categorized into “fluorosis-based” exposure groups (slight vs. medium vs. severe fluorosis area or non-fluorosis vs. fluorosis area).
  • The authors say “children who live in a fluorosis area have five times higher odds of developing low IQ than those who live in a non-fluorosis area or a slight fluorosis area.” when it actually should be stated “children living in high-fluoride areas had IQ measured 5 points lower than those in low-fluoride areas.”
NRC REPORT (2006)2

NRC committee evaluated the human epidemiologic data and individual case studies as well as laboratory studies to evaluate fluoride’s potential neurotoxicity and neurobehavioral effects at the concentrations of 2-4 mg/L. The summaries of their findings and recommendations include:

  • Available human studies lacked sufficient detail to fully assess their quality and relevance to US populations. The consistency of the collective results, however, warrants additional research. The committee recommends experimental and clinical investigations to further examine fluoride’s potential effect on broad yet specific neurobehavioral outcomes including mental confusion, lethargy, problem solving, reasoning ability, and short- and long-term memory using proper testing methods and paying attention to associated neurochemical changes as well as individual susceptibility.
  • No animal studies were available to determine fluoride’s effect on higher order mental functions or neurotoxicity. Fluoride’s potential biochemical effects on the brain include disruptions of aerobic metabolism, reduced effectiveness of acetylcholine as a transmitter, and an increase in free radicals but yet to be clearly understood. Future animal studies must be carefully designed to measure cognitive skills beyond rote learning or acquisition of simple associations, and test environmentally relevant doses of fluoride.

NRC Committee concluded “At the present time, questions about the effects of the many histological, biochemical, and molecular changes caused by fluoride cannot be related to specific alterations in behavior or any known disease.”

REFERENCES
  1. World Health Organization. Children and Neurodevelopmental Behavioral Intellectual Disorders. October 2011. Available at http://www.who.int/ceh/capacity/neurodevelopmental.pdf
  2. National Research Council. Fluoride in Drinking Water: A Scientific Review of EPA’s Standards. Washington, DC. The National Academies Press. 2006.
  3. NTP (National Toxicology Program). 2016 Systematic literature review on the effects of fluoride on learning and memory in animal studies. NTP Research Report 1. Research triangle Park, NC: National Toxicology Program. Available at: https://ntp.niehs.nih.gov/ntp/ohat/pubs/ntp_rr/01fluoride_508.pdf
  4. Bazian Ltd. Independent critical appraisal of selected studies reporting an association between fluoride in drinking water and IQ: a report for South Central Strategic Health Authority. London, UK: Bazian Ltd; 2009 February 11.
  5. Choi AL, Sun G, Zhang Y, Grandjean P. Developmental Fluoride Neurotoxicity: A Systematic Review and Meta-Analysis. Environ Health Perspect. 2012;120(10):1362-8
  6. Broadbent JM, Thomson WM, Ramrakha S et al. Community water fluoridation and intelligence: Prospective study in New Zealand. Am J Public Health. 2015;105(1):72-6
  7. Choi AL, Zhang Y, Sun G et al. Association of lifetime exposure to fluoride and cognitive functions in Chinese children: a pilot study. Neurotoxicol Teratol. 2015;47:96-101
  8. Beltran-Aguilar ED, Barker L, Dye BA. Prevalence and severity of dental fluorosis in the United States, 1999-2004. NCHS Data Brief. No.53. November 2010. Available at http://www.cdc.gov/nchs/data/databriefs/db53.pdf
  9. Aggeborn L and Öhman M. The Effects of Fluoride in the Drinking Water. Uppsala University Publications. Uppsala, Sweden. November 3, 2016. Available at https://editorialexpress.com/cgi-bin/conference/download.cgi?db_name=EEAESEM2016&paper_id=206
  10. Bashash M, Thomas D, Hu H et al. Prenatal fluoride exposure and cognitive outcomes in children at 4 and 6-12 years of age in Mexico. Environ Health Perspect. 2017;125(9):097017
  11. Barberio AM, Quiñonez C, Hosein FS, McLaren L. Fluoride exposure and reported learning disability diagnosis among Canadian children: Implications for community water fluoridation. Can J Public Health. 2017;108(3):e229-39
  12. Valdez Jiménez L, López Guzmán OD, Cervantes Flores M et al. In utero exposure to fluoride and cognitive development delay in infants. Neurotoxicology. 2017;Mar(59):65-70
  13. Malin AJ, Till C. Exposure to fluoridated water and attention deficit hyperactivity disorder prevalence among children and adolescents in the United States: an ecological association. Environ Health. 2015;Feb 27;14:17
  14. Environmental Protection Agency. Fluoride Chemicals in Drinking Water: TSCA Section 21 Petition; Responses for Agency Response. Available at https://www.federalregister.gov/documents/2017/02/27/2017-03829/fluoride-chemicals-in-drinking-water-tsca-section-21-petition-reasons-for-agency-response
  15. Tang QQ, Du J, Ma HH et al. Fluoride and children’s intelligence: a meta-analysis. Biol Trace Elem Res. 2008;126(1-3):115-20
Other resources
Appraisals
TITLEREVIEWER
Prenatal Fluoride Exposure And Cognitive Outcomes In Children At 4 And 6-12 Years Of Age In MexicoCenter For Fluoride Research Analysis/ Fluoride Science Editorial Board
Exposure To Fluoridated Water And Attention Deficit Hyperactivity Disorder Prevalence Among Children And Adolescents In The United States: An Ecological AssociationShivani Arora, BDS, MPH, CPH
Arsenic And Fluoride Exposure In Drinking Water: Children’s IQ And Growth In Shanyin County, Shanxi Province, ChinaIsmail Jolaoso, BDS, MPH
Relation Between Dental Fluorosis And Intelligence Quotient In School Children Of Bagalkot DistrictMona Haleem, DDS, MPA
Neurodegenerative Changes In Different Regions Of Brain, Spinal Cord And Sciatic Nerve Of Rats Treated With Sodium FluorideGary Whitford, PhD, DMD
Reviews, commentaries, and interviews
TITLEREVIEWER
Fluoride & Neurotoxicity InterviewCenter For Fluoride Research Analysis/ Fluoride Science Editorial Board
An Evaluation Of Neurotoxicity Following Fluoride Exposure From Gestational Through Adult Ages In Long-Evans Hooded RatsCenter For Fluoride Research Analysis/ Fluoride Science Editorial Board