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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Developmental fluoride neurotoxicity: a systematic review and meta-analysis

AL Choi, G Sun, Y Zhang, and P Grandjean.

Review published: 2012.

CRD summary

This review found there was a possibility of an adverse effect of high fluoride exposure on children’s neurodevelopment. The varied and observational nature of the included studies meant that there was a high risk of bias due to confounding factors, so the results may not be reliable. Therefore, the authors’ cautious conclusions and recommendations for further research are appropriate.

Authors' objectives

To investigate the effect of increased fluoride exposure on delayed neurobehavioral development in children.


MEDLINE, EMBASE, TOXNET, Water Resources Abstracts (ProQuest) and China National Knowledge Infrastructure (CNKI) were searched from 1980 to 2011. Reference lists of included articles were also searched.

Study selection

To be included studies had to compare a high fluoride exposure group to a reference exposure group, report IQ scores or other cognitive function measures, and present a measure of the association between fluoride exposure and cognitive function measures.

All but two of the included studies were conducted in China. Children ranged in age from four to 16 years. Fluoride exposure was mostly through drinking water, but three studies assessed exposure due to coal burning. The Rural Chinese version of the Combined Raven Test (CRT-RC) and other Raven tests (to measure reasoning ability) were the most commonly used outcome measure; IQ tests and the Wechsler intelligence test were also used.

The authors did not state how many reviewers performed the study selection.

Assessment of study quality

No quality assessment of included studies was reported.

Data extraction

It appeared that the estimate of association between IQ or other cognitive function score and fluoride exposure was extracted from each study (however this was reported) along with its 95% confidence interval. Relative risks that compared low or marginal intelligence versus normal intelligence based on CRT-RC were also extracted (where reported).

The authors did not state how many reviewers performed the data extraction.

Methods of synthesis

Estimates of effect were converted into standardised mean differences (SMD) and pooled in Mantel-Haenszel fixed-effect and DerSimonian-Laird random-effects meta-analyses. Relative risks for the CRT-RC test were pooled using random-effects meta-analysis. Heterogeneity was assessed using Ι². Potential for publication bias was assessed using funnel plots and Begg and Egger tests. The effect of age and year of publication were investigated using meta-regression. Further subgroup analyses were reported in the paper.

Results of the review

Twenty-seven studies were included in the meta-analysis with sample sizes that ranged from 60 to 956 children.

Fluoride exposure reduced intelligence test scores in the meta-analysis (SMD -0.45, 95% CI -0.56 to -0.34; Ι²=80%). The effect was slightly smaller in studies reporting only CRT-RC scores (SMD -0.36, 95% CI -0.48 to -0.25; Ι²=78%; 16 studies) and in studies of drinking water fluoride exposure only (SMD -0.29, 95% CI -0.44 to -0.14; Ι²=82%; nine studies). More recently published studies gave smaller effect sizes (SMD 0.02 per year, 95% CI 0.006 to 0.03), but child age had no impact on the results.

Fluoride exposure increased the risk of low or marginal CRT-RC scores (RR 1.93, 95% CI 1.46 to 2.55; Ι²=59%; 16 studies); results were similar for studies that included only drinking water fluoride exposure (RR 1.75, 95% CI 1.16 to 2.65; Ι²=71%; nine studies).

There was no evidence of publication bias.

Authors' conclusions

The results supported the possibility of an adverse effect of high fluoride exposure on children’s neurodevelopment.

CRD commentary

This review addressed a relevant public health issue with reasonable broad inclusion criteria. A suitable search was performed which included a relevant Chinese database. It was unclear whether action was taken to avoid reviewer error or bias. Study quality was not formally assessed but the authors noted many quality deficiencies of the studies.

All included studies were observational in nature and no adjustment for potential confounding factors was reported, so the analyses appeared to be at high risk of bias due to confounding. Studies were combined in suitable meta-analyses. The authors noted that there was considerable diversity in the studies, leading to substantial unexplained heterogeneity in the results, which meant that the generalisability of the results was unclear. Nearly all studies were conducted in China, so it was unclear if these findings would apply in other countries.

The diversity across the included studies and the substantial potential for bias due to confounding by unidentified factors meant that the results of this review may not be reliable. Given this, the authors’ cautious conclusions and recommendations for further research are appropriate.

Implications of the review for practice and research

Practice: The authors made no recommendations for public health practice.

Research: The authors suggested that future research should focus on evaluating dose-response relationships using individual-level measures of exposure, make use of standardised measures of neurobehavioral performance, and improve control of potential confounders.


No external funding.

Bibliographic details

Choi AL, Sun G, Zhang Y, Grandjean P. Developmental fluoride neurotoxicity: a systematic review and meta-analysis. Environmental Health Perspectives 2012; 120(10): 1362-1368. [PMC free article: PMC3491930] [PubMed: 22820538]

Indexing Status

Subject indexing assigned by NLM


Adolescent; Child; Child, Preschool; China /epidemiology; Developmental Disabilities /chemically induced /epidemiology; Drinking Water /chemistry; Environmental Exposure; Environmental Monitoring; Fluorides /toxicity; Humans; Intelligence Tests; Models, Biological; Neurotoxicity Syndromes /epidemiology /etiology



Database entry date


Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 22820538


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