Embarrassing knock-back of second draft review of possible cognitive health effects of fluoride

We have come to expect exaggeration of scientific findings in media reports and institutional press releases. But it can also be a problem is original scientific publications where findings are reported in an unqualified or exaggerated way. Image Credit: Curbing exaggerated reporting

This is rather embarrassing for a US group attempting to get the science right about possible toxic effects of fluoride. It’s also embarrassing for the anti-fluoride activists who have “jumped the gun” and been citing the group’s draft review as if it was reliable when it is not.

The US National Academies of Sciences, Engineering, and Medicine (NAS) have released their peer-review of the revised US National Toxicity Program (NTP) draft on possible neurodevelopmental effects of fluoride (see Review of the Revised NTP Monograph on the Systematic Review of Fluoride Exposure and Neurodevelopmental and Cognitive Health Effects).

This is the second attempt by the NTP reviewers to get acceptance of their draft and it has now been knocked back by the NAS peer reviewers for a second time.

Diplomatic but damning peer-review

Of course, the NAS peer reviewers use diplomatic language but the peer review is quite damning. It criticises the NTP for ignoring some of the important recommendations in the first peer review. One which is quite critical was the lack of response to the request that NTP explains how the monograph can be used (or not) to inform water fluoridation concentrations. The second NAS peer review firmly states that the NTP:

“should make it clear that the monograph cannot be used to draw any conclusions regarding low fluoride exposure concentrations, including those typically associated with drinking-water fluoridation.”

And:

“Given the substantial concern regarding health implications of various fluoride exposures, comments or inferences that are not based on rigorous analyses It seems to me that there is soime internal politicsshould be avoided.”

It seems to me there is some internal politics involved and some of the NTP authors may be promoting their own, possibly anti-fluoride, agenda. Certainly, the revised NTP draft monograph continues to obfuscate this issue. It continues to state that “fluoride is presumed to be a cognitive neurodevelopmental hazard to humans” – a clause which anti-fluoride campaigner consistently quote out of context. Yes, it does state that this is based on findings 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.” But this is separated from the other fact that the findings on cognitive neurodevelopment for “exposures in ranges typically found in drinking water in the United States (0.7 mg/L for optimally fluoridated community water systems)” are “are inconsistent, and therefore unclear.”

Monograph exaggerates by enabling unfair cherry-picking

So, you see the problem. The draft NTP monograph correctly refers to IQ and other cognitive effects in children exposed to excessive levels of fluoride. The draft also correctly refers to that lack of evidence for such effects at lower fluoride exposure levels typical of community water fluoridation. But in different places in the document.

The enables activist cherry-picking to support an anti-fluoride agenda and that is a fault of the document itself. It should clearly state that the monograph should not be used to draw any conclusion at these low exposure levels. This is strongly expressed in the peer-reviewers’ comments.

I find the blanket “presumed to be a hazard for humans” quite misleading. For example, no one says that calcium is “presumed to be a cardiovascular hazard to humans.” Or that selenium is “presumed to be a cardiovascular or neurological hazard to humans.” Or what about magnesium – would you accept that it is a “presumed neurological hazard to humans?” Would you accept that iron is a “presumed cardiovascular, cancer, kidney or erectile dysfunction hazard to humans?” Yet all those problems have been reported for humans at high intake levels of these elements.

No, we sensibly accept that various elements and microelements have beneficial, or essential benefits, to humans at reasonable intake levels., Then we sensibly warn that these same elements can be harmful at excessive intake. To proclaim that any of these elements are “presumed” to be hazardous – without clearly saying at excessive intake levels, is simply distorting or exaggerating the data.

What does “presumed” mean?

A lot of readers find the use of “presumed” strange. But it’s meaning is related to the levels of evidence found by reviewers.

No, don’t believe those anti-fluoride activists who falsely claim that “presumed” is the highest level of evidence and that the finding should be treated as factual. They are simply wrong.

Some idea of the word’s use is presented in this diagram from the NTP revised draft monograph.

So “presumed” means that the evidence for the effect is moderate. That the effect is not factual or known. But as further evidence comes in the ranking of fluoride as a hazard may increase, or decline.

As the monograph bases this “presumed” rating solely on evidence from areas of endemic fluorosis where fluoride intake levels are high it is correct to avoid stating the effects as factual. For example, consider these images from areas of endemic fluorosis in China (taken from a slide presentation by Xiang 2014):

Clearly, people in these areas suffer a range of health effects related to the high fluoride intake. The cognitive effects like IQ loss from these areas could result from these other health effects, not directly from fluoride (although excessive fluoride intake leads to the health effects).

So we can “presume” that fluoride (in areas of endemic fluorosis where fluoride intake is excessive) is a “cognitive neurodevelopmental hazard for humans” but we can not factually state that the neurodevelopment effects are directly caused by fluoride. That would require further scientific work to elucidate the specific mechanisms involved in creating that effect.

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Anti-fluoridationists put faith in new “strong” studies to provide evidence missing in draft NTP review

The US National Academies of Science (NAS) found the National Toxicity Programme’s (NTP) conclusion in their recent draft report that fluoride is neurotoxic was not supported by the reviewed evidence (see Another embarrassment for anti-fluoride campaigners as neurotoxic claim found not to be justified). This was a huge defeat for anti-fluoride activists who had been roundly promoting the conclusion of the draft report – despite the warning on every page that it “should not be construed to represent any NTP determination or policy” and that the draft had been “distributed solely for the purpose of pre-dissemination peer review.”

So the anti-fluoridationists declared belief that the NTP draft was going to mean the end of community water fluoridation (CWF) was dashed. But that has not stopped Paul Connett, head of the main US anti-fluoride group Fluoride Action Network (FAN) from putting his own spin on the NAS peer review report. In his attempt to present this huge defeat as somehow positive he issued a press release where he claims:

“If the recommendations are adopted, they will make the final report ‘iron-clad’ against criticisms. The NAS suggestions should strengthen the draft report’s conclusion that fluoride is a presumed neurotoxin in children, which is based on 149 human studies. This finding brings into question the long-standing assurances from public health officials that water fluoridation is safe.”

The NAS peer review is very critical – and not just about the fact that the draft conclusion was not supported by the reviewed evidence. There are criticisms of biased study selection, insufficient consideration of the effect of confounders and problems with statistical analyses used. But besides playing with words to misrepresent the peer review, Paul Connett has declared a belief that the NTP will now consider new studies, published since the draft report was released, and these will provide the evidence missing in the original draft. He is hoping the revised review will include new “strong” (in his opinion) studies which will finally swing things his way:

“Multiple strong scientific studies, at exposures relevant to fluoridation, have been published after the NTP’s review. They link fluoridation in Canada to greatly lowered IQ in formula-fed infants (Till 2020) and 300% higher rates of ADHD (Ridell 2019); fluoridation in USA with sleep disturbances in adolescents (Malin 2020); and fluoride with lower IQ by thyroid disruption (Wang 2020).”

Notably, Connett actively ignores, yet again, a new study which does not fit his bias because it reports a positive relationship between maternal prenatal urinary F and child IQ – the complete opposite of what he wishes (see The anti-fluoride brigade won’t be erecting billboards about this study). But Connett has been specific so we can objectively consider just how strong or weak these new studies are and evaluate for ourselves the likelihood that they can be used to provide support for the unwarranted conclusion expressed in the draft NTP report.

I have discussed several of these studies in previous articles but briefly consider them together here.

Till et al (2020) formula-fed child study

I discussed this study in my article Anti-fluoride propagandists appear not to read the articles they promote. It’s citation is:

Till, C., Green, R., Flora, D., Hornung, R., Martinez-mier, E. A., Blazer, M., … Lanphear, B. (2020). Fluoride exposure from infant formula and child IQ in a Canadian birth cohort. Environment International, 134(September 2019), 105315.

This has been blindly promoted by anti-fluoride propagandists as finding a decrease in IQ for children formula-fed as babies and a negative relationship of IQ for these children with drinking water F. However, the relationships are not statistically significant. It’s possible those anti-fluoride activists claiming a significant relationship had been influenced by Till’s previous conference paper where she indulged in special pleading for a non-significant relationship.

The findings reported by Till et al (2020) are summarised below:

While there are no significant relationships for IQ (FSIQ – Full-Scale IQ), the authors did report a significant negative relationship of performance IQ (PIQ) with water fluoride for children both breastfed and formula-fed as babies (and also for estimated F-intake for formula). Strangely, the anti-fluoride promoters of this paper generally don’t refer to this – perhaps because very few of them actually read the papers they promote.

Why there is a difference between IQ and PIQ is a bit of a mystery but there is a recommendation that PIQ, a subset of IQ tests, should not be used for clinical decision making because it is not consistent with current standards (see Beware of scientific paper abstracts – read the full text to avoid being fooled).

Riddell et al (2018) ADHD study

My article ADHD and fluoride – wishful thinking supported by statistical manipulation? discussed this study. Its citation is:

Riddell, J. K., Malin, A., Flora, D., McCague, H., & Till, C. (2019). Association of water fluoride and urinary fluoride concentrations with Attention Deficit Hyperactivity Disorder in Canadian Youth. Submitted to Environment International, 133(May), 105190.

The authors expressed disappointment that they could not find any relationship of ADHD prevalence to urinary F which they considered the best measure of F exposure. However, they were able to squeeze out some significant relationships with water F when the data was divided according to youth age. Significant for older youth but not younger. The findings of Riuddell et al (2019) are summarised in this figure.

The relationships are tenuous with large confidence intervals indicating their weakness. Manipulation of the data by age to find significant relationships reminds me of the saying that if data is tortured enough it will produce the answer you want

So, again, hardly a “strong” study and I cannot see Connett’s wish that the NTP will be able to justify its unwarranted draft conclusion with this.

Malin et al (2020) sleep “disturbances” study

I reviewed this study in my article Sleep disorders and fluoride: dredging data to confirm a bias. The paper citation is:

Malin, A. J., Bose, S., Busgang, S. A., Gennings, C., Thorpy, M., Wright, R. O., … Arora, M. (2019). Fluoride exposure and sleep patterns among older adolescents in the United States: a cross-sectional study of NHANES 2015 – 2016. Environmental Health, 1–9.

First of all, this paper has been poorly peer-reviewed. Effectively just an “in-house” review by coworkers all involved in publishing the same work (see Some fluoride-IQ researchers seem to be taking in each other’s laundry). This figure illustrates the relationships between the authors and their coworkers working with the same and similar data:

Relationships between Malin and her peer reviewers as indicated by joint publications. Links to the papers listed from the top are: Malin & Till (2015),  Thomas et al (2014), Bashash et al (2017), Marlin et al (2018), Malin et al (2018), Bashash et al (2018), Thomas et al (2018), and Riddell et al (2018)

I think this sort of self-selected peer-review during journal publication is almost scientifically corrupt. In my article, I concluded that the journal was chosen for publication and the absence of genuine peer review, together with the weak findings, indicated  “this is another poor quality paper on fluoride and health effects which make unwarranted claims – and which will be used by anti-fluoride activists in their campaign against community water fluoridation.”

The study used a range of parameters which facilitated dredging of the data to find apparently statistically significant relationships (see  Statistical manipulation to get publishable results). None of the relationships with blood plasma F were statistically significant (despite a bit of special pleading by the authors). They did report significant relationships with water F for sleep apnea, snoring, bedtime and waketime. An apparent reduction of snoring with an increase in water F baffled the authors. The confidence interval for sleep apnea was very large and small differences in bedtime and wake time are easily understood as connected with social differences between rural and city residents. There were no relationships with sleep duration.

So much for Connett’s description of this as a “strong scientific study” capable of reinstalling NTP confidence in their unsupported draft conclusion of a neurotoxic effect of fluoride.

Wang et al (2020) IQ study

This study is reported in:

Wang, M., Liu, L., Li, H., Li, Y., Liu, H., Hou, C., … Wang, A. (2020). Thyroid function, intelligence, and low-moderate fluoride exposure among Chinese school-age children. Environment International, 134(September 2019), 105229. https://doi.org/10.1016/j.envint.2019.105229

Although Connett claims the study was “at exposures relevant to fluoridation” this is not so. The study was aimed at measuring “low-moderate fluoride exposure affects” in the Chinese context and involved comparison of children from areas of “endemic and non-endemic fluorosis areas in Tianjin, China.” Water fluoride concentrations ranged from 0.20 to 3.90 mg/L and urinary F from 0.01 to 5.54 mg/L. Not at all comparable to the concentration where community water fluoridation (CWF) is present.

However, the study did separate results into different quartiles according to water F and urinary F concentrations and the data for the lowest quartiles are worth considering because they are for concentrations similar to that present where CWF is used.

I have extracted that data for quartile 2 of water F (0.7 to 1.00 mg/L) – a bit high compared with CWF but the data for the more relevant quartile 1 was not presented. Also the data for the second and third quartile of urinary F (UF) with the ranges 0.15 to 0.41 mg/L and 0.451 top 2.28 mg/L. Again these values are high.

Linear regression in these ranges showed no significant relationship of child IQ with either water F or Urinary F (UF) (see figure below). So much for Connett’s claim that this is a “strong scientific studies, at exposures relevant to fluoridation” that will lead to the NTP strengthening the NTP’s unsupported draft conclusion of a neurotoxic effect.

The elephant in the room – Santa-marina et al (2019)

Of course, Connett studiously ignores this study because it reported a positive relationship between maternal prenatal urinary F and child IQ (see The anti-fluoride brigade won’t be erecting billboards about this study).

The citation for this study is:

Santa-Marina, L., Jimenez-Zabala, A., Molinuevo, A., Lopez-Espinosa, M., Villanueva, C., Riano, I., … Ibarluzea, J. (2019). Fluorinated water consumption in pregnancy and neuropsychological development of children at 14 months and 4 years of age. Environmental Epidemiology, 3.

I have summarised the findings reported by Santa Marina et al (2019) below. These are certainly not going to provide any hope to Connett that the unsupported NTP conclusion will somehow be retrieved.

Conclusions

Connett is simply attempting, in his press release, to put a brave face on the embarrassment of the NAS peer review report. He and his supporters had been actively promoting the unsupported conclusion of the draft report – even suggesting it would shortly lead to the end of CWF. So a public embarrassment and he responds by holding out hope that his position will be retrieved by new studies.

His reliance on new studies is effectively an acknowledgement that the studies considered by the NTP were not adequate for the draft conclusion presented. However, he is wrong to describe these studies as “strong.” They are actually very weak and are hardly likely to change the final NTP assessment. He has also actively ignored, and hidden, the fact that the new studies are contradictory (Santa-marina et al 2019 produced the opposite result to what Connett wants) and conflicting (the different studies rely on different measures of cognitive ability and fluoride intake as well as manipulation of the data to find significant relationships).

The revised NTP report will not be produced soon as the peer reviewers identified a range of problems which will require major changes. There may well be even newer studies reported in the interim and these may not help Connett’s case any more the ones he cited. On top of that, the NTP may well discover older studies that their biased selection process missed in their original literature search (I still hold out hope that they will this time in include Perrott (2018) which, I believe, raises important issues about the effect of confounders ignored by other studies).

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Industry-funded translation can introduce bias in selection of studies for scientific review

Image credit: Assessing and addressing bias in systematic reviews

The Fluoride Action Network (FAN), in the last decade, paid for translation of a lot of Chinese-language scientific papers linking high fluoride dietary intake to IQ deficits in children. They, of course, selected papers to fit their own ideologically-motivated bias. This is perfectly understandable for an activist group. But has this caused a bias in available English-language sources on this topic? And does this mean recent scientific reviews of this subject unintentionally suffer from selection bias?

I hadn’t considered this possibility before, but it is an issue raised in the recent US National Academies of Sciences (NAS) peer review of the US National Toxicity Program’s (NTP) review of possible neurotoxic effects of fluoride (see Another embarrassment for anti-fluoride campaigners as neurotoxic claim found not to be justified).

Use of FAN sources introduces biased study selection

The NAS peer reviewers are harshly critical of the NTP draft review. A central concern was the way the NTP evaluated the literature on the subject. The NAS peer reviewers say on page 3 of their report:

“The committee had substantive concerns regarding NTP’s evaluation of the human evidence as noted below. The strategy used for the literature search indicated that NTP used FAN as a source to identify relevant literature. The process by which FAN identified and selected studies is unclear, and that uncertainty raises the question of whether the process could have led to a biased selection of studies. Such a concern raises the need for a formal evaluation of any potential bias that might have been introduced into the literature-search process.”

OK, I am not impressed that the NTP used FAN as a source. FAN is hardly a reliable source and its “study tracker” certainly does not pick up anywhere near the full literature available (see Cherry-picking and ring-fencing the scientific literature). But, at first thought, I imagined that the FAN source simply produced a subset of anything that is picked up using a more reliable source like PubMed to do literature searches.

Injection of study bias into English-language scientific literature

But the NAS peer reviewers raise an important problem with reliance on FAN as a source and its effect on the available English-language scientific literature. On page 24 of their report they say:

“. . the process by which FAN identified and selected studies is not clear. FAN identified a number of studies published in Chinese language journals—some of which are not in PubMed or other commonly used databases—and translated them into English. That process might have led to a biased selection of studies and raises the question of whether it is possible that there are a number of other articles in the Chinese literature that FAN did not translate and about which NTP is unaware. NTP should evaluate the potential for any bias that it might have introduced into the literature search process. Possible ways of doing so could include conducting its own searches of the Chinese or other non–English-language literature and conducting subgroup analyses of study quality and results based on the resource used to identify the study (for example, PubMed vs non-PubMed articles). As an initial step in such evaluations, NTP should consider providing empirical information on the pathway by which each of the references was identified. That information would also improve understanding of the sources that NTP used for evidence integration and the conclusions drawn in the monograph.”

In a nutshell, FAN arranged and paid for translation of quite a large number of Chinese papers on this issue (fluoride intake and child IQ deficits). Naturally, they have selected papers supporting their political cause (the abolition of community water fluoridation) and ignored papers which they could not use to that end. It is therefore likely they have introduced into English-language scientific literature a biased selection of Chinese papers because FAN effectively “republished” the translated papers in the journal “Fluoride” – a well-known repository of anti-fluoride material.

Maybe I was wrong to assume anything from FAN would simply be a subset of what is available through more respectable searching sources. But, according to the peer reviewers, some of the translated papers may be picked up when FAN is used as a source of studies but not when PubMed or similar respected sources are used. A warning, though – many of the FAN-promoted translated studies have only been partly translated, maybe only the abstract is available. This is not sufficient for a proper scientific review (see Beware of scientific paper abstracts – read the full text to avoid being fooled).

I am not saying this bias introduction into the English-language scientific literature was intentional, but it is a likely end-result of their actions. Importantly, it is also a likely end-result of funding from big money sources (the “natural”/alternative health industry which funds FAN and similar anti-fluoride and anti-vaccination groups – see Big business funding of anti-science propaganda on health).

So, is this a way that big industry can inject their bias into the available scientific literature? A way to ensure that reviewers will, maybe unintentionally, convey this industry bais into their own summary of scientific findings?

Reviewers should make a critical assessment of studies

The FAN-promoted Chinese studies really do not contribute to any rational discussion of issues with CWF because they were all made in areas of endemic fluorosis. Ironically they often compare child IQ in villages where fluoride intake is high, with that in villages where the fluoride intake is low. It is the low -fluoride villages which are relevant to areas of CWF because their drinking water F concentrations are comparable.

In reality, these Chinese studies could be used to support the idea that CWF is harmless. Even if that is an inherent assumption for low fluoride intake in these studies.

So, perhaps the bias introduced to the literature by translation of the FAN-promoted studies really is of no consequence to the evaluation of CWF. However, consideration of reviews like the recent one by Grandjean (2019) indicates there is a tendency to simply extrapolate from high concentration studies to make unwarranted conclusions about CWF. In this case, the tendency is understandable as Grandjean is well known for his opposition to CWF and is often used by FAN to make press statements raising doubts about this health policy (see Special pleading by Philippe Grandjean on fluoride, Some fluoride-IQ researchers seem to be taking in each other’s laundry, and Fluoridation not associated with ADHD – a myth put to rest).

This was also a problem with the draft NTP review which produced the (unwarranted) conclusion “that fluoride is presumed to be a cognitive neurodevelopmental hazard to humans.” The draft did actually mention that the conclusion “is based primarily on higher levels of fluoride exposure (i.e., >1.5 ppm in drinking water” and “effects on cognitive neurodevelopment are inconsistent, and therefore unclear”  for “studies with exposures in ranges typically found in the water distribution systems in the United States (i.e., approximately 0.03 to 1.5 ppm according to NHANES data).” But, of course, it is the unwarranted conclusion that gets promoted.

Conclusions

Reviewers need to be aware of this and other ways activist groups and big business can inject bias into the scientific literature.

This problem underlines the responsibility reviewers have of recognising all possible ways that biased selection of studies they consider can occur. It also means they should make every effort to include negative studies (not supporting the effect they may personally prefer) as well as positive studies. They also need to include all the findings (positive and negative) included in the individual studies they review.

In cases like the FAN-promoted Chinese studies, there is an obligation to at least note the possibility of bias introduced by activists and industry-funded translations. Even better, to ensure that the reviewer undertakes to independently search for all studies on the subject and arrange for translations where necessary.

Above all, reviewers should critically consider the quality of the studies they include in their reviews and not simply rely on their own confirmation bias.

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Another embarrassment for anti-fluoride campaigners as neurotoxic claim found not to be justified

Anti-fluoride campaigners have made the classic mistake of promoting claims based on a draft report. Now peer reviewers have found the claim unjustified and the report will be rewritten. But will the anti-fluoride brigade stop making the claim?

Anti-fluoride campaigners have just lost another of their propaganda claims with the release of a US National Academies of Science (NAS) peer review of the recent National Toxicity Program’s (NTP) draft monograph discussing fluoride exposure and neurotoxicity.

Ever since the release of this draft last October anti-fluoride campaigners have been making hay out of this statement on page 2 of the draft (and repeated several times in its text):

“Conclusions: NTP concludes that fluoride is presumed to be a cognitive neurodevelopmental hazard to humans.”

In general, these campaigners have presented this conclusion as a finding of the NTP, even though the draft includes this statement on every page:

“This DRAFT Monograph is distributed solely for the purpose of pre-dissemination peer review under the applicable information quality guidelines. It has not been formally disseminated by NTP. It does not represent and should not be construed to represent any NTP determination or policy.”

In a clear case of counting eggs before they hatch, the anti-fluoride campaigners now face the embarrassment of losing this claim because the NAS peer reviewers have found the conclusion is not supported by the evidence presented in the draft report. The NAS press release announcing the results of their peer review clearly says:

It “does not find that NTP has adequately supported its conclusion that “fluoride is presumed to be a cognitive neurodevelopmental hazard to humans.”

For readers wanting more detail these are the relevant documents:

• DRAFT NTP MONOGRAPH ON THE SYSTEMATIC REVIEW OF FLUORIDE EXPOSURE AND NEURODEVELOPMENTAL AND COGNITIVE HEALTH EFFECTS
• National Academies of Sciences press release 
• Review of the Draft NTP Monograph

Anti-fluoride activists response to the NAS peer review

The peer review has been out for only a few days and the anti-fluoride propagandists on social media have already denounced it (without reading it in most case) as only one committee’s opinion. Or they have indulged in the straw-clutching of quoting the NAS peer review’s sentence after the one that found the conclusion fo the NTP report was not supported. This says.

“The committee emphasized its finding does not mean that the NTP’s conclusion is incorrect; rather, further analysis or reanalysis is needed to support conclusions in the monograph.”

Perfectly normal for a scientific assessment and, in this case, a bit of a face-saver for the NTP (in many of its details the NAS peer review is quite scathing). And if the NTP has done a reasonable job of accessing the literature we all know that no “further analysis or reanalysis” will magically support the draft claim.

But, as an indication of the embarrassment of these people the “authoritative” comment on the peer review from Paul Connett, leader of the anti-fluoride US activist group Fluoride Action Network (FAN) almost reads like an endorsement of the peer review. Despite FAN having originally stressed the faulty NTP draft conclusion that “fluoride is presumed to be a cognitive neurodevelopmental hazard to humans” Connett does not even mention the NAS finding in his press release (see “Federal report finding fluoride lowers IQ of children reviewed by National Academy of Sciences.“) Strangely he quotes: “The NAS emphasized its finding ‘… does not mean that the NTP’s conclusion is incorrect.'” without even saying what that conclusion was.

The rest of Connett’s comments amount to spin – putting a brave face on his disappointment at this major loss. His claim that “The NAS suggestions should strengthen the draft report’s conclusion that fluoride is a presumed neurotoxin in children” is fanciful given that the material reviewed by the NTP simply does not support this claim.

He is also attempting diversion with his claim “The NAS review has been misinterpreted by fluoridation defenders. The NAS did not independently review the scientific evidence but instead limited itself to comments on whether the NTP clearly and thoroughly explained their methods” The fact is very few comments have been made by “fluoridation defenders” yet – the peer review has been public for only a few days – barely enough time for busy scientists to get around to reading it. And I have not seen a single person claim that the NAS peer reviewers “independently reviewed the evidence.”

What was required of the peer review?

The peer review report makes their action and purpose very clear. They were not tasked with making an independent review of the literature but their job went a lot further than limiting themselves to “comments on whether the NTP clearly and thoroughly explained their methods”

The NTP Project Information document Peer Review of the NTP Monograph on Systematic Review of Fluoride Exposure and Neurodevelopmental and Cognitive Health Effects) provided a list of requirements for the peer reviewers who were asked to “address the following questions:

• Has the systematic review protocol been followed and modifications appropriately documented and justified?
• Does the monograph accurately reflect the scientific literature?
• Are the findings documented in a consistent, transparent, and credible way?
• Are the report’s key messages and graphics clear and appropriate?  Specifically, do they reflect supporting evidence and communicate effectively?
• Are the data and analyses handled in a competent manner?  Are statistical methods applied appropriately?
• What other significant improvements, if any, might be made in the document?
• Does the scientific evidence in the NTP Monograph support NTP’s hazard category conclusions for fluoride in children and adults?”

The NAS peer reviewers clearly answered the last question with an emphatic No! This is not changed by the desperate straw clutching of propagandists who quote the (inevitable and polite) qualification that a further “further analysis or reanalysis” might provide support. Nor is it changed by Connett simply refusing to acknowledge or comment on that very important finding of the peer review committee.

Other findings of the NAS peer reviewers

The NAS peer review report is quite extensive (it’s 48 pages long) and covers several other important issues besides its rejection of the main conclusion. Issues related to how good the original protocol was and how closely it was followed, bias resulting from incomplete consideration of all the findings (negative as well as positive) and selection in the literature considered, issues related to statistical analysis and presentation, and problems with accounting for the range of different fluoride exposure measures and outcome parameters.

I might return to some of these issues later as I think they are relevant to other reviews in this area – especially the recent review of Grandjean (2019) – Developmental fluoride neurotoxicity: an updated review. This has similar faults – and some extra faults of its own.

But it is clear that in it’s current form the draft NTP report is not credible. Its conclusion is flawed and there are a number of other problems. It will have to be extensively rewritten to take the peer reviewers comments into account. I look forward to the new, and hopefully much better, version.

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Not just another rat study

A new high-quality study of the effect of fluoride on the memory and learning behaviour of rats has produced definitive results. Anti-fluoride campaigners had great hopes this study would bring an end to community water fluoridation (CWF) – but their hopes have been dashed.

The study showed no effect of fluoride on the memory, learning and motor skills of rats thus reinforcing the consensus that CWF is safe

Animal experiments are commonly used to investigate possible health effects of chemicals like fluoride. This enables strict research protocols without the ethical problems faced by human studies. Consequently, there have been a large number of investigations of the effect of fluoride on animals. Some of these have suggested harmful effects. The US anti-fluoride activist organisation, the Fluoride Action Network (FAN) lists 45 studies “where mice or rats treated with fluoride were found to suffer impairments in their learning and/or memory abilities” (see FLUORIDE AFFECTS LEARNING & MEMORY IN ANIMALS).

FAN claims these and similar studies as irrefutable evidence that CWF is harmful – particularly in their major campaign claiming CWF lowers IQ and should be stopped. However, a more scientific assessment is far less dogmatic.

The US National Toxicity Program (NTP) examined published research of potential neurological effects from fluoride exposures in experimental rodent animals in a systematic review published in 2016 (see Systematic literature review on the effects of fluoride on learning and memory in animal studies). They found many of the studies had limitations due to confounding in the learning and memory assessments and there was a lack of discrimination between motor and learning skills. Very few of the studies were made at drinking water concentrations relevant to CWF and the evidence for adverse effects was “low to moderate,” and weakest for animals during their developmental phase.

The NTP concluded further research was needed and undertook laboratory studies with rodents to fill the research gaps it had identified. Those studies are now complete and have been published in a research paper:

McPherson, C. A., Zhang, G., Gilliam, R., Brar, S. S., Wilson, R., Brix, A., … Harry, G. J. (2018). An Evaluation of Neurotoxicity Following Fluoride Exposure from Gestational Through Adult Ages in Long-Evans Hooded Rats. Neurotoxicity Research. Neurotoxicity Research.

The laboratory experiment

The authors used four treatments for the rats:

• G1: Fed standard rodent chow;
• G2: Fed low-fluoride chow;
• G3: Fed low-fluoride chow + drinking water with 10 ppm F;
• G4 Fed low-fluoride chow + drinking water with 20 ppm F.

Effects of drinking water F were determined by comparing results for G3 and G4 with G2.

The drinking water fluoride concentrations still seem high (compared with the recommended level of 0.75 ppm for CWF) but are lower than used in most earlier studies (often around 100 ppm). However, the basis for these choices was the use of the US secondary drinking water standard (2 ppm) and US UPA maximum contaminant level (4 ppm) and “the conventional wisdom that a 5-fold increase in dose is required to achieve comparable human serum levels.” However, this “wisdom” is debated as blood serum levels fluctuate.

These drinking water concentrations are still far higher than the recommended optimum level for CWF (0.75 ppm) so the results should be seen as more related to the defined upper limits than to CWF itself.

Behavioural assessments

A range of behavioural assessments was made. These included:

“motor, sensory, or learning and memory performance on running wheel, open-field activity, light/dark place preference, elevated plus maze, pre-pulse startle inhibition, passive avoidance, hot-plate latency, Morris water maze acquisition, probe test, reversal learning, and Y-maze.”

The purpose of using such a wide range was to overcome deficiencies of the measurements made in earlier studies and to fill in gaps. Animals at the developmental stage were included as most earlier studies had been made with adult rats.

“No significant differences observed”

One of the most commonly used phrases in this paper as the results are presented and discussed is that there were “no significant differences observed across groups.”

The authors note in their abstract that they “observed no exposure-related differences” in any of the behavioural tests listed above.

This result is important. The study is authoritative. The chosen experimental protocols resulted from an extensive systematic review of the earlier work which identified gaps and deficiencies. A very wide range of behavioural tests was used. And the experimental plans were discussed very widely before the experiments began.

We can conclude, therefore, that rodent experiments are unlikely to show behavioural effects related to fluoride exposure at the concentrations which, the authors argue, are relevant to the recommended maximum drinking water standard (2 ppm) and maximum contaminant level (4 ppm) for humans. The argument that this result is relevant to humans is strengthened by the possibility that ““the conventional wisdom that a 5-fold increase in dose is required” to make results relevant for humans may be inflated.

The argument is further strengthened for humans as the recommended drinking water fluoride concentrations for humans is even lower than the maximum drinking water standard and the maximum contaminant level.

Other assessments

The researchers also analysed thyroid hormones and examined collected tissues. They reported:

“No exposure-related pathology was observed in the heart, liver, kidney, testes, seminal vesicles, or epididymides.”

And:

No evidence of neuronal death or glial activation was observed in the hippocampus at 20 ppm F.”

In fact, the only statistically significant effects they found were a “mild inflammation in the prostate gland” and “evidence of mild fluorosis in adults” at 20 ppm F (treatment G4). Remember this level corresponds to the maximum contaminant level for humans and dental fluorosis has also been reported for humans at that concentration.

The anti-fluoride spin

Several years ago I discussed the planned NTP work and the reaction of anti-fluoride campaigners to it in my article Fluoride and IQ – another study coming up.

These campaigners seemed ecstatic about the planned NTP work, although I did comment:

“You wouldn’t think the anti-fluoride crowd would welcome such a careful analysis of the poor-quality articles they promote”

However, Fluoride Free NZ revealed the spin they placed on the NTP document describing the systematic review and the planned work in their press release at the time (see Fluoride-Brain Studies Set to Expose Fluoridation Damage):

“Results could mean the end to fluoridation world-wide, and definitely should put a halt to any plans to start fluoridation in places not currently fluoridated.

Because it is now well established that fluoride affects the brain, the NTP plans to conduct new animal studies to determine the lowest dose at which this damage occurs. They also plan to do a systematic review of all the existing scientific literature. To date, there have been 314 studies that have investigated fluoride’s effects on the brain and nervous system. These include 181 animal studies, 112 human studies, and 21 cell studies.”

I commented on this:

“The confirmation bias and dogmatic agenda stick out like a sore thumb – don’t expect these people to accurately report this study’s findings.”

Well, it seems that these campaigners are still stuck in dumb shock of the denial phase as they have yet to make any comment on these research results. When they do get around to overcoming their speechlessness they are going to be hard put to reconcile this denial with their earlier hopes for the research findings.

There is no way this study can be used to argue for “the end to fluoridation worldwide” or that there “definitely should” be “a halt to any plans to start fluoridation in places not currently fluoridated.

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Local anti-fluoride activists tell porkies yet again

FFNZ confuses lack of low fluoride studies on rats with human studies

Well, I suppose that’s not news. A bit surprising, though, because they are claiming the absence of research on fluoridation and IQ – which sort of conflicts with the previous attempts to actually condemn and misrepresent the actual research on fluoridation and IQ.

Fluoride Free NZ’s (FFNZ) face book page is claiming:

Would you be interested to know that no studies have been conducted on fluoridated water at 0.7ppm to determine whether there is IQ reduction? The National Toxicology Program are currently completing research to fill this gap. You would have thought that they would have done this in the 1950s before starting the fluoridation program wouldn’t you?

There have actually been three recent studies from three different countries which have specifically investigated the claim of an effect of fluoridation on IQ – and, unsurprisingly, all threes studies showed there was no effect.

Here are those studies:

New Zealand

Broadbent, J. M., Thomson, W. M., Ramrakha, S., Moffitt, T. E., Zeng, J., Foster Page, L. A., & Poulton, R. (2014). Community Water Fluoridation and Intelligence: Prospective Study in New Zealand. American Journal of Public Health, 105(1), 72–76.

In fact, anti-fluoride activists in the US, as well as New Zealand, have campaigned against this study. Their major criticism is that the study also included the effect of fluoride tablet use. They argue that this makes the unfluoridated control group useless because many participants will have consumed fluoride tablets. However, they ignore the fact that the statistical analysis corrected for this but still found no statistically significant difference in IQ of children and adults from fluoridated and unfluoridated areas.

Sweden

Other critics of the Broadbent et al. (2014) study have raised the issue of experimental power because of the numbers of people in the study. This could be a valid issue as it would determine the minimum effect size capable of being detected. Aggeborn & Öhman (2016) made that criticism of Broadbent et al., (2016) and all other fluoride-IQ studies. Their study is reported at:

Aggeborn L, Öhman M. (2016) The Effects of Fluoride in the Drinking Water. 2016.

Aggeborn & Öhman (2016) used much larger sample size than any of the other studies – over 81,000 observations compared with around 1000 or less for the commonly cited studies. It was also made on continually varying fluoride concentrations using the natural fluoride levels in Swedish drinking waters (the concentrations are similar to those in fluoridated communities), rather than the less effective approach of simply comparing two villages or fluoridated and unfluoridated regions. The confidence intervals were much smaller than those of other cited fluoride-IQ studies. This makes their conclusion that there was no effect of fluoride on cognitive measurements much more definitive. Incidentally, their study also indicated no effect of fluoride on the diagnosis of ADHD or muscular and skeleton diseases.

Canada

Another recent fluoridation-IQ study is that of Barbario (2016) made in Canada:

Barberio, AM. (2016). A Canadian Population-based Study of the Relationship between Fluoride Exposure and Indicators of Cognitive and Thyroid Functioning; Implications for Community Water Fluoridation. M. Sc. Thesis; Community Health Sciences, University of Calgary.

This study also had a large sample size – over 2,500 observations. This reported no statistically significant relationship of cognitive deficits to water fluoride.

Incidentally, Barberio (2016) also found there was no evidence of any relationship between fluoride exposure and thyroid functioning. That puts another pet claim of anti-fluoride campaigners to rest.

Animal studies

So much for NZFF’s claim that “no studies have been conducted on fluoridated water at 0.7ppm to determine whether there is IQ reduction.” But, just a minute, they are quoting the National Toxicology Program (NTP):

“No studies evaluated developmental exposure to fluoride at levels as low as 0.7 parts per million, the recommended level for community water fluoridation in the United States. Additional research is needed.”

But they omit the next sentence from the quote:

“NTP is conducting laboratory studies in rodents to fill data gaps identified in the systematic review of the animal studies.”

The NTP is discussing the research with animals, mainly rats, where effects of fluoride on the cognitive behaviour of the test animals have been reported but the fluoride concentrations are very high. And NTP’s assessment base on the review of the literature found only “a low to moderate level of evidence that the studies support adverse effects on learning and memory in animals exposed to fluoride in the diet or drinking water.” Hence the need for more research.

As part of the NTP’s research, which is currently underway, there are plans to extend studies to low fluoride concentrations more typical of that used in community water fluoridation.

The high concentrations used in animal studies is a major flaw in the anti-fluoride activist use of them to oppose community water fluoridation. For example, Mullinex et al (1995) (very commonly cited by anti-fluoride campaigners) fed test animals drinking water with up to 125 mg/L of fluoride (concentrations near 0.8 mg/L of fluoride are used in community water fluoridation).

While it is unlikely that the NTP research will find any significant effects of fluoride on the cognitive behaviour of rats at the low concentrations used in community water fluoridation the anti-fluoride campaigners have their fingers (and probably toes as well) crossed.

NTP will begin publishing the results of their new research next year (see Fluoride and IQ – another study coming up).

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Fluoride and IQ – another study coming up

Well, eventually.

It’s basically a systematic review of published scientific literature on fluoride-IQ effects in humans. It’s just at the planning stages and don’t expect anything for a few years – peer review and public consultation of the findings are not planned until 2018.

The review is planned by National Toxicology Program (NTP) which is part of the US National Institute of Environmental Health Sciences. It’s a special project developed in response to requests from the public (guess who?).

Some might question whether such a review will add anything – after all this question has been included in several reviews of possible health effects of community water fluoridation (eg NRC and NZ review), although it has just been one component of most of these reviews. An exception is the review by the Bazian Company

Bazian. (2009). Independent critical appraisal of selected studies reporting an association between fluoride in drinking water and IQ (Vol. 44).

This considered in detail the specific publications used by campaigners against CWF to argue there is a problem (the reviewers found there wasn’t).

But, on the positive side, this will most likely be one more review by a reputable body showing how poor the evidence used by anti-fluoride campaigners is. On the negative side the process and findings will be misrepresented again and again by anti-fluoride campaigners. That has already started – see the press release by Fluoride Free NZ –  Fluoride-Brain Studies Set to Expose Fluoridation Damage. Talk about counting chickens before they hatch!

Here is an extract from the Summary of the NTP proposal (Proposed NTP Evaluation on Fluoride Exposure and Potential for Developmental Neurobehavioral Effects):

“The National Toxicology Program (NTP) proposes to conduct an evaluation of the published literature to determine whether exposure to fluoride is associated with effects on neurodevelopment, specifically learning, memory, and cognition. This evaluation will use systematic review methods and include an examination of data from human (epidemiological), experimental animal, and mechanistic studies. Previous evaluations have found support for an association between fluoride exposure and impaired cognition; however, many of the studies included exposure to high levels of fluoride. Most of the human evidence was from fluoride-endemic regions having high background levels of fluoride, and the animal studies typically included exposure during development to relatively high concentrations of fluoride (>10 mg/L) in drinking water. Thus, the existing literature is limited in its ability to evaluate potential neurocognitive effects of fluoride in people associated with the current U.S. Public Health Service drinking water guidance (0.7 mg/L).” [My emphasis].

The proposal also says:

“A 2015 systematic analysis of the human literature conducted for the Republic of Ireland’s Department of Health (Sutton et al. 2015) concluded that there was no evidence of an association with lowered IQ in studies of community water fluoridation areas based primarily on an analysis of a prospective cohort study in New Zealand (Broadbent et al. 2015). For fluoride-endemic areas, there was a strong suggestion that high levels of naturally occurring fluoride in water (> 1.5 ppm) may be associated with negative health effects, including lowering of IQ. In general, these studies were considered of low quality because they did not fully account for other factors that could also cause a lowering of IQ e.g., nutritional status, socioeconomic status, iodine deficiency, other chemicals in the ground water (arsenic or lead). The conclusions of Sutton et al. (2015) are consistent with findings of a 2012 meta-analysis of 27 epidemiology studies that “supported the possibility of an adverse effect of “high” fluoride exposure on children’s neurodevelopment, specifically for lowered IQ; although the 2012 meta-analysis also identified study quality limitations, mostly related to reporting quality, that limited the strength of conclusions that could be reached (Choi et al. 2012).

The anti-fluoride spin

You wouldn’t think the anti-fluoride crowd would welcome such a careful analysis of the poor-quality articles they promote – but you can get some idea of how they will spin this study over the next few years from the comments in the above press release:

“Results could mean the end to fluoridation world-wide, and definitely should put a halt to any plans to start fluoridation in places not currently fluoridated.

Because it is now well established that fluoride affects the brain, the NTP plans to conduct new animal studies to determine the lowest dose at which this damage occurs. They also plan to do a systematic review of all the existing scientific literature. To date, there have been 314 studies that have investigated fluoride’s effects on the brain and nervous system. These include 181 animal studies, 112 human studies, and 21 cell studies.”

The confirmation bias and dogmatic agenda stick out like a sore thumb – don’t expect these people to accurately report this study’s findings.

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