NTP 2019-2020: Two Draft Systematic Reviews of Fluoride’s Neurotoxicity
The review by the National Toxicology Program (NTP) of fluoride’s neurotoxicity was initiated in response to a nomination from the Fluoride Action Network (FAN). The NTP began the review in 2016 and released its first draft in September 2019. This draft was sent to the National Academies of Sciences, Engineering and Medicine (NASEM) for peer-review.
The NASEM committee held a meeting for the public on November 6, 2019, to discuss NTP’s first review and to accept public comment. Fluoride Action Network’s research director, Chris Neurath, and senior advisor, Bill Hirzy, PhD, attended the meeting. An excerpt from a news report by Pat Rizzuto in Bloomberg Law, noted:
Risk Greater Than Recognized
Fluoride poses a greater risk than NTP’s draft report suggests, Chris Neurath, research director for the Fluoride Action Network, told the committee.
NTP’s report consistently paid less attention to studies that found low concentrations of fluoride could be harmful, he said.
The scientific evidence showing fluoride can harm children’s developing brains is as strong or stronger than was the data that emerged in the 1990s—and faced fierce criticism—showing low levels of lead were neurotoxic, Neurath said.
It took two decades for public health officials to accept that at a low level lead was indeed neurotoxic. “Millions of children suffered loss of IQ and behavioral problems during those two decades of critical indecision,” he said.
The academies should pay heed, he said.
The NASEM committee recommended that NTP make several changes.
On September 16, 2020, NTP sent their second draft review to NASEM, incorporating the changes they requested. (NASEM committee members are listed here.)
Conclusion of NTP’s 2019 first draft Review (page 2):
NTP 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. However, the consistency is based primarily on higher levels of fluoride exposure (i.e., >1.5 ppm in drinking water).
Conclusion of NTP’s 2020 second draft Review, page 2:
NTP concludes that fluoride is presumed to be a cognitive neurodevelopmental hazard to humans. This conclusion is based on a moderate level of evidence that shows a consistent and robust pattern of findings in human studies across several different populations demonstrating that higher fluoride exposure (e.g., >1.5 mg/L in drinking water) is associated with lower IQ and other cognitive effects in children. Limited and weaker evidence is considered to provide an inadequate level of evidence that fluoride is associated with cognitive effects in adults.
What is a “presumed” rating?
The NTP used the OHAT* method for rating fluoride’s hazard. The five ratings are: Known, Presumed, Suspected, Not classifiable, or Not identified to be a hazard to humans.
The NTP rating of “presumed” is the highest confidence rating without doing a controlled human experiment, which would be illegal.
Comparison of NTP monographs for other chemicals found only the chemical warfare agent Sarin to receive the confidence rating “known hazard” and that was because there were controlled human experiments.
* OHAT is the abbreviation for Office of Health Assessment and Translation, which is within the Division of the National Toxicology Program at the National Institute of Environmental Health Sciences.
Fluoride Action Network’s submissions
The Director of FAN, Paul Connett, PhD, noted in his comments submitted to NASEM,
Chris Neurath, research director for FAN submitted substantive comments to both NASEM and the NTP on the 2020 Review (see all submissions at the end).
Chris identifies with specificity the downgrading of evidence in the NTP Review in his full submission with tables and figures. It will shock those who have read the literature to learn that the NTP Review excluded the Bashash et al., 2017 study.
Downgraded evidence in the 2020 NTP Review:
• Excluded the largest effect in the strongest study: Bashash 2017.
• Excluded strongest low-dose studies from dose-response meta-analysis.
• Unnecessary division of studies lowers power in dose-response meta-analyses.
• Simplistic exposure assessment underestimates hazard at doses relevant to US.
• NTP’s simplistic dose-response meta-analysis methods underestimated effects at low doses because they used the mean exposure while most studies had individual-level exposures that ranged well below the mean.
• Improperly downgraded the animal evidence to “inadequate” despite the NTP 2016 review of the animal evidence concluding it was “low to moderate”.
• The NTP monograph deviated from the OHAT guidelines in its section “Generalizability to the U.S. Population”.
• Meta-analyses have inadequate documentation.
Connett noted in his comments,
Chris Neurath identified the following strengths and weaknesses of the 2020 Review:
• The revised and updated review has identified substantially more higher quality studies with the number going from 18 to 29.
• Of the 29 higher quality studies, 27 found statistically significant adverse effects, which is a very high degree of consistency.
• The NTP has addressed recommendations of both NASEM and FAN to improve the clarity and validity of quality scoring methods.
• The addition of meta-analyses also improves clarity of the evidence.
• The conclusion of “presumed developmental neurotoxity” has thus grown substantially stronger and is solidly supported by the body of evidence.
• Our written submission has detailed discussion of weaknesses.
• By far the greatest weakness is the ad hoc section titled “Generalizability to the US Population”. This is, in effect, a risk assessment requiring a valid exposure assessment and dose-response assessment, but NTP has done neither. The NTP’s methods led to an underestimate of the confidence that fluoride causes harm at exposures below 1.5 mg/L.
• The NTP made the fundamental error of equating drinking water concentration with internal dose.
• The NTP’s exposure assessment consisted of a single one-sentence footnote referenced to a CDC database that is restricted and not available to the public.
• There was no proper dose-response assessment. The only planned dose-response assessment was a dose-response meta-analysis, yet it was not carried out for the 10 highest quality studies with individual-level exposure data. These 10 highest quality studies were also those finding affects at the lowest doses. The failure to conduct a dose-response meta-analysis on the strongest studies at low doses leads to a severe underestimate of the confidence of adverse effects at low doses.
• For the dose-response meta-analysis of group-level studies, NTP improperly used just the mean doses to define doses, even though many studies had a wide range of exposures in each exposure group, including exposures that fell below the cut-off level 1.5 mg/L.
• We are conducting a dose-response meta-analysis with the 10 individual-level studies and will supply it to the NAS.
• When proper dose-response assessments are made with the 29 higher quality studies, we found remarkable consistency of adverse effects. 18 studies were at exposures below 1.5 mg/L and 17 of those found adverse effects.
• Therefore, the evidence below 1.5 mg/L is as strong and consistent as that above 1.5 mg/L.
• Finally, a fundamental goal of the OHAT systematic review method is to ensure consistency of NTP evaluations across different chemicals.
Chris concluded this list with,
• When comparing the fluoride monograph to those for other chemicals we find a dramatic double standard, with fluoride needing to pass a far higher bar to reach a conclusion of presumed hazard than other chemicals.
• We believe the NASEM committee and NTP must take a larger perspective and ensure fluoride is treated in the same way as any other chemical being evaluated by NTP.
See Neurath’s Dose-Response Assessment of Fluoride Neurotoxicity Studies submitted to the NAS and NTP.
This short video is a good introduction to the NTP’s Systematic Review of Fluoride’s Neurotoxicity
More Public Comments from Chris Neurath on the Fluoride Review (October 2020)
Documents and Submissions on NTP’s Review