Review of the Draft NTP Monograph: Systematic Review of Fluoride Exposure and Neurodevelopmental and Cognitive Health Effects.

................Rationale for Not Performing a Meta-Analysis

The committee strongly recommends that NTP reconsider its decision not to perform a meta-analysis and, if it still decides not to do a meta-analysis, that it provide a more thorough and convincing justification for its decision. In the monograph, NTP states that a meta-analysis was not performed because of “heterogeneity in dose among the available human evidence, and because a hazard conclusion could be reached without conducting a meta-analysis” (NTP 2019, p. 13). A properly conducted meta-analysis can account for heterogeneity in exposure measurements and other aspects of study design, so it is not clear why heterogeneity was listed as a reason for not performing one. It would be difficult to perform one meta-analysis that includes both relative risk estimates and mean differences (or standardized mean differences), but these could be separated out into two meta-analyses. Potentially, meta-analyses of studies deemed sufficiently similar in their exposure and outcome metrics could also be performed and could address NTP's concern about heterogeneity. However, because NTP did not present the studies in a way that would suggest such groupings, the committee is unclear how feasible such analyses would be. The committee also recommends that NTP explain why it did not update the Choi et al. (2012) meta-analysis. NTP uses the funnel plot in Choi et al. (2012) as evidence of minimal publication bias in its systematic review. However, Choi et al. (2012) considered only a subset of the studies included in the systematic review, so NTP's claim of minimal publication bias would be strengthened by adding recent papers to the meta-analysis and constructing a new funnel plot.

Communication Regarding Lower Exposures

The discussion section of the monograph provides an informal assessment of the evidence with regard to exposure range and declares that the positive results are based largely on exposures greater than those used for fluoridation. The basis of that inference is not apparent, and it seems to contradict the earlier assertion that nearly all the studies are positive, including ones that assessed lower exposures. More important, as discussed in Chapter 2, this discussion gives a false impression that NTP conducted a formal dose–response assessment. NTP should make it clear that the monograph cannot be used to assess what concentrations of fluoride are safe.

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NTP CONCLUSION

The monograph “concludes that fluoride is presumed to be a cognitive neurodevelopmental hazard to humans. This conclusion is based on a consistent pattern of findings in human studies across several different populations showing that higher fluoride exposure is associated with decreased IQ or other cognitive impairments in children” (NTP 2019, p. 59). The committee was tasked with assessing whether NTP satisfactorily supports its conclusion. In light of the issues raised by the committee regarding the analysis of various aspects of some studies and the analysis, summary, and presentation of the data in the monograph, the committee finds that NTP has not adequately supported its conclusion. The committee's finding does not mean that the conclusion is incorrect; rather, further analysis or reanalysis as suggested in the present report is needed to support the conclusion in the monograph.