Developmental Fluoride Neurotoxicity: A Systematic Review and Meta-Analysis
Department of Environmental Health, Harvard School of Public Health, Boston, MA, USAAnna L. Choi, Department of Environmental Health, Harvard School of Public Health,Landmark Center 3E, 401 Park Dr., Boston, MA 02215 USA. Phone 617-384-8646; fax 617-384-8994; firstname.lastname@example.org
Background: Although fluoride may cause neurotoxicity in animal models and acute fluoride poisoning causes neurotoxicity in adults, very little is known of its effects on children’s neurodevelopment.
Objective: We performed a systematic review and meta-analysis of published studies to investigate the effects of increased fluoride exposure and delayed neurobehavioral development.
Methods: We searched the MEDLINE, EMBASE, Water Resources Abstracts, and TOXNET databases through 2011 for eligible studies. We also searched the China National Knowledge Infrastructure (CNKI) database, as many studies on fluoride neurotoxicity have been published in Chinese journals only. In total, we identified 27 eligible epidemiological studies with high and reference exposures, endpoints of IQ scores or related cognitive function measures with means and variances for the two exposure groups. We estimated the standardized mean difference (SMD) between exposed and reference groups across all studies using random effects models. We conducted sensitivity analyses restricted to studies using the same outcome assessment and having drinking water fluoride as the only exposure. Cochran test for heterogeneity between studies, Begg’s funnel plot and Egger test to assess publication bias were performed. Meta-regressions to explore sources of variation in mean differences among the studies were conducted.
Results: The standardized weighted mean difference in IQ score between exposed and reference populations was -0.45 (95% CI -0.56 to -0.35) using a random-effects model. Thus, children in high fluoride areas had significantly lower IQ scores than those who lived in low fluoride areas. Subgroup and sensitivity analyses also indicated inverse associations, although the substantial heterogeneity did not appear to decrease.
Conclusions: The results support the possibility of an adverse effect of high fluoride exposure on children’s neurodevelopment. Future research should include detailed individual-level information on prenatal exposure, neurobehavioral performance, and covariates for adjustment.
A recent report from the U.S. National Research Council (NRC 2006) concluded that adverse effects of high fluoride concentrations in drinking water may be of concern and that additional research is warranted. Fluoride may cause neurotoxicity in laboratory animals, including effects on learning and memory…
To summarize the available literature, we performed a systematic review and meta-analysis of published studies on increased fluoride exposure in drinking water and neurodevelopmental delays. We specifically targeted studies carried out in rural China that have not been widely disseminated, thus complementing the studies that have been included in previous reviews and risk assessment reports…
Findings from our meta-analyses of 27 studies published over 22 years suggest an inverse association between high fluoride exposure and children’s intelligence… The results suggest that fluoride may be a developmental neurotoxicant that affects brain development at exposures much below those that can cause toxicity in adults…
Serum-fluoride concentrations associated with high intakes from drinking-water may exceed 1 mg/L, or 50 Smol/L, thus more than 1000-times the levels of some other neurotoxicants that cause neurodevelopmental damage. Supporting the plausibility of our findings, rats exposed to 1 ppm (50 Smol/L) of water-fluoride for one year showed morphological alterations in the brain and increased levels of aluminum in brain tissue compared with controls…
In conclusion, our results support the possibility of adverse effects of fluoride exposures on children’s neurodevelopment.
Future research should formally evaluate dose-response relations based on individual-level measures of exposure over time, including more precise prenatal exposure assessment and more extensive standardized measures of neurobehavioral performance, in addition to improving assessment and control of potential confounders.