Developmental Fluoride Neurotoxicity

A Systematic Review and Meta-analysis

Anna L. Choi; Guifan Sun; Ying Zhang; Philippe Grandjean


Environ Health Perspect. 2012;120(10):1362-1368. 

In This Article

Abstract and Introduction


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 metaanalysis 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, because 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, end points of IQ scores, or related cognitive function measures with means and variances for the two exposure groups. Using randomeffects models, we estimated the standardized mean difference between exposed and reference groups across all studies. We conducted sensitivity analyses restricted to studies using the same outcome assessment and having drinking-water fluoride as the only exposure. We performed the Cochran test for heterogeneity between studies, Begg's funnel plot, and Egger test to assess publication bias, and conducted metaregressions to explore sources of variation in mean differences among the studies.

Results: The standardized weighted mean difference in IQ score between exposed and reference populations was –0.45 (95% confidence interval: –0.56, –0.35) using a randomeffects model. Thus, children in highfluoride areas had significantly lower IQ scores than those who lived in lowfluoride 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 individuallevel information on prenatal exposure, neurobehavioral performance, and covariates for adjustment.


A recent report from the 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 (Chioca et al. 2008; Mullenix et al. 1995). A recent experimental study where the rat hippocampal neurons were incubated with various concentrations (20mg/L, 40mg/L, and 80 mg/L) of sodium fluoride in vitro showed that fluoride neurotoxicity may target hippocampal neurons (Zhang M et al. 2008). Although acute fluoride poisoning may be neurotoxic to adults, most of the epidemiological information available on associations with children's neurodevelopment is from China, where fluoride generally occurs in drinking water as a natural contaminant, and the concentration depends on local geological conditions. In many rural communities in China, populations with high exposure to fluoride in local drinking-water sources may reside in close proximity to populations without high exposure (NRC 2006).

Opportunities for epidemiological studies depend on the existence of comparable population groups exposed to different levels of fluoride from drinking water. Such circumstances are difficult to find in many industrialized countries, because fluoride concentrations in community water are usually no higher than 1mg/L, even when fluoride is added to water supplies as a public health measure to reduce tooth decay. Multiple epidemiological studies of developmental fluoride neurotoxicity were conducted in China because of the high fluoride concentrations that are substantially above 1mg/L in well water in many rural communities, although microbiologically safe water has been accessible to many rural households as a result of the recent 5-year plan (2001–2005) by the Chinese government. It is projected that all rural residents will have access to safe public drinking water by 2020 (World Bank 2006). However, results of the published studies have not been widely disseminated. Four studies published in English (Li XS et al. 1995; Lu et al. 2000; Xiang et al. 2003; Zhao et al. 1996) were cited in a recent report from the NRC (2006), whereas the World Health Organization (2002) has considered only two (Li XS et al. 1995; Zhao et al. 1996) in its most recent monograph on fluoride.

Fluoride readily crosses the placenta (Agency for Toxic Substances and Disease Registry 2003). Fluoride exposure to the developing brain, which is much more susceptible to injury caused by toxicants than is the mature brain, may possibly lead to permanent damage (Grandjean and Landrigan 2006). In response to the recommendation of the NRC (2006), the U.S. Department of Health and Human Services (DHHS) and the U.S. EPA recently announced that DHHS is proposing to change the recommended level of fluoride in drinking water to 0.7mg/L from the currently recommended range of 0.7–1.2mg/L, and the U.S. EPA is reviewing the maximum amount of fluoride allowed in drinking water, which currently is set at 4.0mg/L (U.S. EPA 2011).

To summarize the available literature, we performed a systematic review and meta-analysis of published studies on increased fluoride exposure in drinking water associated with 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.