Review of the Draft NTP Monograph Systematic Review of Fluoride Exposure and Neurodevelopmental and Cognitive Health Effects (2020) / Chapter Skim
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3 Animal Evidence
3 Animal Evidence
Pages 22-32
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From page 22... ...
RISK-OF-BIAS EVALUATION A concern for the committee was whether NTP's risk-of-bias evaluations adequately captured important threats to internal validity that are specific to neurobehavioral outcomes in animal tests. The guidance in the protocol touched on 1Although the mechanistic evidence is considered separately from the animal evidence, and the committee focused on the animal evidence, the committee questioned whether the literature search strategy for mechanistic evidence was adequate to capture all relevant information, especially with respect to studies that analyzed data derived from new approach methodologies.
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From page 23... ...
-- a study considered by NTP -- reported a 30% decrease in the number of offspring in a fluoride-treated group; this result raises serious concerns about the validity of the study's findings. Given its review of some key studies, the committee is concerned that high mortality was not adequately considered by NTP when it evaluated the animal studies for this risk-ofbias domain.
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From page 24... ...
If NTP acquired information from the study authors, that needs to be clearly documented. Lack of control for litter effects constitutes a critical design and statistical problem in data analyses, and the committee emphasizes the importance of this deficiency for evaluating study validity, particularly in studies that include prenatal exposures.
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Learning and memory assays require testing over days, usually with multiple trials per day; thus, at a minimum, a repeatedmeasures ANOVA is required. Other Potential Threats to Internal Validity The committee found a threat to internal validity that was not adequately captured in the risk-of-bias criteria described in the protocol.
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From page 26... ...
stated that the exclusion criteria should be described in the protocol. The committee found that some studies cited in the monograph had severe methodologic shortcomings that could potentially warrant exclusion from the body of evidence that informs conclusions about hazard.
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In those cases, the use of such post hoc tests for a subset of comparisons would not be possible because the error term from the ANOVA includes error variance from all groups, including ones that involved other treatment combinations. A large proportion of the fluoride studies had one to four additional groups exposed to fluoride and a hypothesized "protective" substance; this makes separating fluoride effects from controls difficult or impossible without access to the raw data for reanalyzing the data relevant to the systematic review.
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From page 28... ...
In the fluoride-neurotoxicity literature, more careful analyses are largely absent, and it is a mistake to dismiss studies of learning and memory because of minor, brief locomotor activity effects or when other assessments can rule out locomotor confounding effects in cognitive assessments. COMMITTEE CONCLUSIONS The committee found that some studies had serious deficiencies that made it question the protocol guidance for rating the internal validity of the studies.
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From page 29... ...
The committee cautions, however, that given the poor quality of the animal studies that it reviewed, revising the systematic review to address the concerns highlighted might not affect the finding that the animal evidence is inadequate to inform conclusions about fluoride exposure and neurodevelopmental and cognitive effects in humans. REFERENCES Amos-Kroohs, R.M., C.P.
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From page 30... ...
2019. Protective effects of Allium sativum extract against sodium fluoride induced neurotoxicity.
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From page 31... ...
2019. Draft NTP Monograph on the Systematic Review of Fluoride Exposure and Neurodevelopmental and Cognitive Health Effects.
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2017. Fluoride and arsenic exposure affects spatial memory and activates the ERK/CREB signaling pathway in offspring rats.
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