Developmental fluoride neurotoxicity: a systematic review and meta-analysis

Abstract

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, 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 random-effects 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 meta-regressions 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 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.

Figure 1

Flow diagram of the meta-analysis.

Figure 2

Random-effect standardized weighted mean difference (SMD) estimates and 95% CIs of child’s intelligence score associated with high exposure to fluoride. SMs for individual studies are shown as solid diamonds (♦), and the pooled SMD is shown as an open diamond (◊). Horizontal lines represent 95% CIs for the study-specific SMDs.

Figure 3

Begg’s funnel plot showing individual studies included in the analysis according to random-effect standardized weighted mean difference (SMD) estimates (x-axis) and the SE (se) of each study-specific SMD (y-axis). The solid vertical line indicates the pooled SMD estimate for all studies combined and the dashed lines indicated pseudo 95% confidence limits around the pooled SMD estimate.