Fluoride and Neurobehavioral Disorders

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

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.

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. These studies are of cross-sectional design and are conducted in fluoride-endemic countries, such as China. Many of these studies are originally written in non-English languages and did not address critical biases or report important methodological details, and thus are largely of unknown or limited quality.4 In 2012, Choi and her colleagues conducted a systematic review and meta-analysis of 27 of these studies 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 While the direction of the association seems to be consistent across in-vitro, animal, and human observational studies, small IQ reduction such as this synthesized from pooled cross-sectional studies with deficiencies and methodological limitations should be interpreted with caution.

Broadbent et al. conducted a prospective cohort study 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 Despite limitations (i.e. the total exposure to fluoride at the individual level was unknown) this study offers evidence of better quality and relevance to the US population than any other studies in the peer-reviewed literature .

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.

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.9 While the authors argued that the finding warrants further study, the recommendation is weak, since their 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.

While there are a fair number of studies that have examined the potential effect of fluoride on intelligence and neurobehavioral health, the majority of them use research designs which are inherently weak and/or have serious limitations, thus do not offer sufficient evidence to determine any risk of neurotoxicity attributable to fluoride in humans, especially at the concentrations commonly seen in countries with CWF. There are often a number of plausible explanations and genetic, environmental, sociocultural, and medical risk factors for neurobehavioral disorders, and it is imperative to rule them out before drawing conclusions about cause and effect.

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

 

Systematic Reviews that discuss Neurobehavioral Disorders and Water Fluoridation

National Toxicology Program 20163

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 AL et al. 20125

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 QQ et al. 200810

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 bullet-pointed 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 sight fluorosis area.” when it actually should be stated “children living in high-fluoride areas had a reduction of 5 IQ points compared with low-fluoride areas.”

 

NRC Report 20062

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. 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
  10. 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