Review of the Revised NTP Monograph on the Systematic Review of Fluoride Exposure and Neurodevelopmental and Cognitive Health Effects A Letter Report (2021) / Chapter Skim
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Review of the Revised NTP Monograph on the Systematic Review of Fluoride Exposure and Neurodevelopmental and Cognitive Health Effects: A Letter Report.
Review of the Revised NTP Monograph on the Systematic Review of Fluoride Exposure and Neurodevelopmental and Cognitive Health Effects: A Letter Report.
Pages 3-15
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From page 3... ...
.1 The draft monograph summarized the findings of the systematic review and concluded 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 2019a, p.
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From page 4... ...
A brief overview of suggested improvements is provided below; other methodologic issues raised in the previous review that are not discussed here have been adequately addressed in the revised monograph. The committee considers the remaining issues related to the systematic review methods to be minor with the exception of the comment below concerning NTP's process for upgrading and downgrading the body of evidence (NTP 2020b, Table 5)
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From page 5... ...
The committee strongly recommends that NTP revise the monograph text that states that a change in motor activity necessarily complicates interpretation of learning and memory tests and that the absence of an evaluation of motor activity is automatically problematic.2 First, the mere observation of a change in motor activity does not automatically undermine a learning and memory effect, nor does the absence of statements about the general health of the animals undercut validity, as the monograph asserts. Second, the absence of a motor-activity test does not 2 Text that needs to be edited includes p.
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From page 6... ...
. The headings in this section represent the overarching concerns that the committee raised in its previous report, and the text provides the committee's assessment of NTP's responses to the concerns and the revisions made in the draft monograph.
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From page 7... ...
According to the protocol, a crosssectional study is rated as having a probably low risk of bias on confounding if there is direct evidence that appropriate adjustments for arsenic and lead were made; the monograph requires the studies to address arsenic and lead, if applicable. Barberio et al.
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From page 8... ...
Thus, the committee's prior concerns regarding exposure misclassification appear to have been adequately addressed. Need for Further Consideration of Blinding In its previous review, the committee recommended that NTP consider more carefully the effect of not intentionally blinding outcome assessors when evaluating the human studies.
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From page 9... ...
Because the outcome measure is critical for the interpretation of the findings, the committee recommends that NTP apply its criteria in a more consistent manner and specifically address whether there is direct evidence of the sensitivity and precision of self-reported neurodevelopmental outcomes. Lack of Rigorous Statistical Review The committee recognizes that NTP made substantial efforts to improve the statistical reviews of the lower risk-of-bias studies.
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From page 10... ...
Need to Juxtapose Results of Broadly Comparable Studies In its previous review, the committee expressed concern about selective consideration and presentation of results from the various studies. That approach can convey inaccurate impressions regarding consistency unless the findings are derived from studies that are comparable or aligned with respect to study population, exposure measurement, and outcome ascertainment.
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From page 11... ...
Those analyses would include subgroup analyses that separate studies that did and did not blind the outcome assessors, a sensitivity analysis that omits studies with complex sampling designs that did not mention the use of sampling weights, and a sensitivity analysis that omits studies that used community-level exposures but did not account for clustering. Alternatively, NTP could perform a sensitivity analysis in which the standard errors of the studies that did not account for clustering are multiplied by an estimate of the VIF.
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From page 12... ...
Some would consider that a much simpler, more intuitive, and perhaps more useful way of assessing heterogeneity, especially in light of the marked differences between the studies in design, study populations, exposure and outcome assessment methods, and statistical analyses. Although that approach should not be used as the sole basis of conclusions, it can be a useful first step in exploring why heterogeneity might exist.
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From page 13... ...
However, the study also presents prospective results that use maternal prenatal urinary fluoride concentrations, and, unlike the cross-sectional results, the prospective results indicate a fairly strong adverse relationship -- a relationship that is much more consistent with that in the other studies used in the meta-analysis. The rationale for choosing one result over the other should be provided because such decisions can affect the results of the meta-analysis.
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From page 14... ...
Drawing conclusions about the effects of low fluoride exposures (less than 1.5 mg/L) would require a full dose–response assessment, which would include at a minimum more detailed analyses of dose–response patterns, models, and model fit; full evaluations of the evidence for supporting or refuting threshold effects; assessment of the differences in exposure metrics and intake rates; more detailed analyses of statistical power and uncertainty; evaluation of differences in susceptibility; and detailed quantitative analyses of effects of bias and confounding of small effect sizes.
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From page 15... ...
seriously considering the suggestions that are provided in this letter report to improve its clarity and transparency. Attachments A Statement of Task B Committee Membership C Key Issues and NTP Response D Bibliography E Acknowledgment of Reviewers 15
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