- McPherson CA, Zhang G, Gilliam R, Brar SS, Wilson R, Brix A, Picut C, Harry GJ - "An Evaluation of Neurotoxicity Following Fluoride Exposure from Gestational Through Adult Ages in Long-Evans Hooded Rats" Neurotox Res 34(4):781-798 (2018) doi: 10.1007/s12640-018-9870-x. Epub 2018 Feb 5. PMID: 29404855; PMCID: PMC
This study was done by scientists of the US National Toxicology Program (NTP), supposedly "to address issues identified in the NTP systematic review (NTP 2016) of determining low to moderate levels of evidence for effects of F− exposure on learning and memory and to address the paucity of quality studies conducted at exposure levels near the recommended level for community water fluoridation in the USA."
Reading through this paper, one gets the distinct impression that this study was specifically designed to avoid showing the adverse effects of fluoride.
This was a study conducted to evaluate the neurotoxicological effects of fluoride.
As neurodevelopment is closely tied to thyroid function, thyroid hormones were to be evaluated, together with TSH, the thyroid-stimulating-hormone.
Thyroid hormones control brain development.
- Thyroid hormone deficiency at critical stages during pregnancy and early childhood results in impaired development of the brain and consequently in impaired mental function. The WHO still considers iodine deficiency, which leads to hypothyroidism, the SINGLE most important preventable cause of brain damage worldwide (Moog et al., 2017; WHO, 2007). An adequate supply of iodine to children and pregnant women is considered a basic human right (Pedraza et al., 2006).
The most vulnerable groups are pregnant and lactating women and their developing fetuses and neonates (Moog et al., 2017). As is the case in fluoride toxicity, the severity and irreversibility of thyroid hormone deficiency in humans depend on both the degree of the deficiency and the period during development in which it is suffered (Pedraza et al., 2006).
It is now established that even mild changes in thyroid function in prenatal life can have lasting negative consequences for a child’s development, and be associated with lower full IQ scores, and impaired motor- and neurological function in childhood (Päkkilä et al., 2015; Li et al., 2010; Haddow et al., 1999; Kooistra et al., 2006).
Numerous high-risk windows during pregnancy have been identified. Maternal deficiency in thyroid hormone during the first trimester can result in adverse effects on a child’s intelligence and motor development (Li et al., 2010; Kooistra et al., 2006), and be a risk factor for both verbal and nonverbal cognitive delay in early childhood (Henrichs et al., 2010).
Other studies have shown that children of healthy women who had very high TSH concentrations in the 17th week of pregnancy had significantly lower IQ levels at the age of 7-9 years (Haddow et al., 1999). The IQ in these children was inversely correlated with maternal TSH concentration (Klein et al., 2001).
The number of children at risk for neurodevelopmental deficits related to early maternal thyroid hormone deficiency is 150–200 times greater than that of newborns with congenital hypothyroidism, for which successful screening programs have been instituted in many countries (Lavado-Autric et al., 2003).
More than 15% of women of child-bearing age in the United States are reported to have maternal thyroid hormone deficiency (Hollowell & Haddow, 2007; Perrine et al., 2010).
Rats are usually chosen to investigate the effects of maternal thyroid hormone deficiency on brain development because, like humans, rats have a period early in development where they are wholly dependent on thyroid hormone provided by the mother. The human first trimester-equivalent covers much of the prenatal period in a rat. At gestation day 7 (GD7), rodent embryonic stages are consistent with those in the human 3rd week post-fertilization (Sulik et al., 1981). Because a large part of brain maturation in rodents happens after birth, it is thought that the early postnatal period in rats mimics the last trimester in humans. Postnatal day 21 (PND21) in rodents is considered the equivalent to a child 2-3 years old (Semple et al., 2013).
Did the NTP test for thyroid hormones and TSH?
Yes, ONCE. Male rats only (!) were tested once - at PND56 (late adolescence, young adulthood). More on the actual tests below. What is astonishing here - besides the selections of gender and test date - is that no efforts were made to evaluate thyroid hormones in serum or brain at the crucial times of development. None. Pregnant dams were not tested at all.
When the serum thyroid hormone levels were evaluated, fluoride levels were not tested at the same time. Those were done on adult rats only, presumably >PND90. The actual date is unclear from the information supplied. How can this be considered appropriate? No serum levels are available from PND25 when brain and femur were investigated.
Before we discuss the thyroid tests a bit further below, a few words on the iodine in the rat feed. Iodine is essential for the formation of thyroid hormones.
Iodine in the Feed
While the amount of fluoride in the chow was considered in this study (as fluoride toxicity depends on TOTAL intake), the iodine content was not. It is very hard to understand how the top toxicologists in the US could possibly commit such a blunder - while conducting a neurotoxicity assessment involving thyroid function. This matter becomes even more worrisome when one considers that there are many hundreds of studies showing the antagonistic relationship of fluoride and iodine, including over 200 reports from China alone (PFPC, 2007). The NTP was made aware of all these studies BEFORE this experiment started (PFPC, 2016).
However - that is not all. Instead of using the regular NTP-2000 rodent chow that is normally employed in NTP toxicity assessments, McPherson et al. actually chose a chow with iodine content of 6 mg/kg, over 25 times the amount that is in the standard NTP-2000 rodent chow, reported to be 0.2 mg/kg (NTP, 2016). [3rd party vendors of the NTP-2000 chow list an iodine content of 0.33 mg/kg (Zeigler), far below 6 mg/kg.]
With iodine intake this high, it requires much more fluoride to produce similar effects as is observed with a normal iodine intake. Fluoride toxicity is directly related to iodine and thyroid status. For an iodine-deficient person/animal, far less amounts of fluoride are toxic (Lin Fa-Fu et al., 1991; Guan et al., 1988; Zhao et al., 1998).
Obvious questions: Why was the standard NTP-2000 rat chow not used? Why was a chow selected with such high iodine content? Why was there no accounting for iodine in the diet?
- Rat Chow used by McPherson et al.:
Teklad 2918 (irradiated; Envigo, Madison, WI) (6 mg/kg iodine content)
Low - fluoride chow: Teklad Custom Diet TD.160173 (Presumably the same as 2918, but with low fluoride content)
Teklak 2918 Data Sheet:
https://insights.envigo.com/hubfs/resou ... ?hsLang=en
NTP-2000 Datasheet (0.33 mg/kg iodine content)
https://www.zeiglerfeed.com/Literature/ ... P-2000.pdf
Looking now at the rat strain used in this study, one can see a pattern emerging - a pattern to deceive, most regrettably.
McPherson et al. used Long-Evans rats in their study. Besides the work by Varner et al. (1994; 1998) we know of no other study reviewed by the NTP that used this rat model. Out of the many China studies, for example, not one animal study used Long-Evans rats, but rather other, established, strains in toxicology. The studies reviewed by McPherson et al. were all done on either Wistar or Sprague Dawley (SD) rats.
- NOTE: Since the 1930s it has been known that there are differences in Long-Evans rats when it comes to the thyroid (Freudenberger, 1932). Long-Evans rats are known to have a lower sensitivity to iodine deficiency - it takes higher amounts and a longer exposure time to anti-thyroid agents to produce similar effects as in other rat species (Ruiz et al, 2013; Gilbert et al., 2011; Okamura et al., 1981). Changes in thyroid hormone levels in Long Evans rats do not result in the same magnitude of changes in serum TSH as they do in albino rats (Gilbert et al., 2011). The normal TSH level in a Long-Evans rat is almost twice as high as that of a Sprague-Dawley rat (Rybnikova et al., 2018). It has been alleged that the NTP was aware of the higher resistance of Long-Evans rats to fluoride poisoning (Spencer & Limeback, 2018).
Considering the other tests employed in this study: it has been documented in the past that Long-Evans rats perform better in motor tasks than other strains (Yanai, et al., 1979), which of course is not surprising when one considers the lower sensitivity to iodine deficiency. Other studies have shown that standard behavioral assays with Long-Evans rats do not readily detect the neurotoxicity induced by modest developmental thyroid hormone deficiency (Gilbert et al., 2013).
Thyroid Tests - Methods
As mentioned above, there are no data on thyroid hormone or TSH levels at the beginning or the end of the experiment, in pups, pregnant dams, nor any female rat.
There is only data on male rats from PND56, a day long past the crucial risk periods. No conclusions can be drawn if those levels are elevated or reduced compared to prior or later levels, as those tests were not conducted. No reference levels are given for normal values in Long-Evans rats.
As is apparent from the paper's table 3 - McPherson et al. did not evaluate Free T3 (FT3) and Free T4 (FT4), but Total T3 and Total T4. Values are reported in ng/dl for T3 and μg/dl for T4, indicating that free fractions were not investigated. FT3 is normally indicated in pg/dl, FT4 in ng/dl. The free (unbound) hormone is the biologically active one.
https://www.ncbi.nlm.nih.gov/pmc/articl ... able/Tab3/
- SIDEBAR: The free thyroid hormone should always be measured in fluoride investigations. The levels of Total T3 or Total T4 do not reflect the true extent of fluoride disruption of thyroid hormone metabolism. Fluoride interferes with the activities of the three deiodinases (D1, D2, D3) which mediate the activation and inactivation of thyroid hormone - they regulate the conversion from T4 into T3, the biologically active form of thyroid hormone. Fluoride may disturb all aspects of deiodination. D3, which is not normally expressed in adults but is expressed in the placenta and in newborn babies, produces rT3. rT3 is a biologically inactive form of T3, crucial during the times of gestation, as it is involved in all timing aspects in neurodevelopment. Fluoride-induced increases in rT3 levels - even at low concentrations - have been well documented, leading to the suggestion that rT3 be used as a biomarker in fluoride poisoning (Lin Fa-Fu et al., 1991; 1992; Sashi & Singla, 2013). During gestation, it is FT4 and TSH that need to be measured, at a minimum. In humans, even a slight deficiency in FT4 ("hypothyroxinemia") during the first trimester can have serious adverse consequences. Excessive levels are also detrimental. This is why trimester-specific reference intervals for TSH and FT4 levels in pregnant women have been issued in guidelines around the world to reduce the risk of brain damage (Stagnarro-Green et al., 2011).
It is important to note that the NTP also failed to differentiate between studies investigating total vs free fractions in their 2016 literature review, as well as in the 2019 Draft. Studies are simply lumped together, without any apparent understanding on the matter.
The test used by McPherson et al. to assess TSH levels in this study was the Rat Pituitary Magnetic Bead Panel Kit. While this test might be efficient - we have no idea - we know of no other study reviewed by the NTP that has used this method. As a matter of fact, we don't know of ANY study investigating fluoride effects on TSH that has used this test. Again, no reference levels are given.
No information is given if the authors conducted even a basic test method validation, or why this test was chosen.
Thyroid Hormone - Test Results
McPherson et al. claim that T3, T4, and TSH levels "were not altered as a function of 10 or 20 ppm F− in the drinking water". They have no right to come to this conclusion as they did not conduct a proper investigation, far from it.
It is also not true, based on the very limited data that is available from PND56.
When the TH data supplied by McPherson et al. in Table 3 is closer investigated, one can clearly identify a pattern showing that T3 levels rise with increasing fluoride intake from Group 2 through to Group 4, while TSH levels slightly decrease. The T3/T4 ratio rises with increasing fluoride intake.
However, as McPherson et al. do not supply any reference ranges, or any information as to how the TSH test method used compares to regular methods, results must be interpreted with great caution. The mean TSH, T4 and T3 levels in this study differ greatly from reports on Long-Evans rats in the literature (Rybnikova et al., 2018; Gilbert et al., 2011; Nishimura et al., 2003). For example, in Nishimura's study mean T4 levels in Long-Evans rats at approximately similar ages were 3.7 ug/dl, while in this study they are almost twice as high. Similarly, in Gilbert's study on iodine deficiency in Long-Evans rats, the control rats on normal iodine intake at PD56 had a T4 of 3.8 ug/dl, a T3 of 100 ng/dl, and a TSH of 1.3 ng/ml. In this study, all the values are higher, in all fluoride groups.
Further, it is important to remember that these results are from PND56 only. In rodents, as in humans, effects of fluoride upon thyroid hormones depend on dose, time and duration, just like in iodine deficiency. For this reason, rodent studies on thyroid hormones in brain development often include TH assays during gestation, as well as numerous crucial time points in the post-natal period (i.e. Gilbert et al., 2013; van Wijk et al., 2008). PND3, PND7, PND14 and PND21 are standard in many investigations, because the critical period of the developmental actions of thyroid hormones in rodents is confined to 2–3 weeks postpartum (van Wijk et al., 2008; Kobayashi et al. 2005).
While often there is at first a stimulation of thyroid hormone production by fluoride at low doses, at higher doses and/or longer duration it turns to inhibition (Zhao et al., 1998). This is the same effect that TSH has on thyroid hormone metabolism. Fluoride is a TSH analogue (Jenq et al., 1993; PFPC 2003).
A general pathology examination was conducted on the heart, kidney, liver, testes, epididymides, prostate, and seminal vesicles - but NOT the thyroid. Why not? Was this not a study involving thyroid function? Thyroids were not even weighed or measured. Thyroid weight increase in iodine deficiency is caused by increased TSH levels resulting in the excessive stimulation of the gland. As mentioned above, fluoride is well-known to cause enlarged thyroids and increase thyroid weight in humans and rodents (PFPC 1996, Zhao et al. 1998, 1989; Li et al., 2011).
Amounts of Fluoride Used
McPherson et al. state:
"In the current study, the top dose of 20 ppm F− was selected based upon the US Environmental Protection Agency’s Maximum Contaminant Level of 4 ppm and the conventional wisdom that a 5-fold increase in dose is required to achieve comparable human serum levels (Dunipace et al. 1995; NRC 2006)."
This has been an issue ever since the NRC published its review of the EPA's MCL standards in 2006. It was based on false assumptions and misinterpretation of data. In rats, concentrations up to 50 ppm water/fluoride concentration are required to produce the fluoride/serum levels that produce dental fluorosis in humans (Denbesten, 2011; Bronckers et al., 2009). In the present study, only the concentration of 20 mg/L in water (plus the F- in the chow) caused mild DF in adult rodents. This is 20 to 40 times higher than the F- in water amount known to cause dental fluorosis in humans. In the study by Lin et al. (1991) - looking at iodine-deficient children, fluoride in water at 0.34 mg/L caused dental fluorosis. The obvious conclusion from this study is that Long-Evans rats require 20 to 40 times the amount of fluoride in water to produce similar dental defects as are observed in children.
The authors further fail to explain why adults rats, drinking fluoridated water at 10 mg/L, have higher fluoride serum levels than those drinking water at 20 mg/L, raising additional concerns.
See Table 2: https://www.ncbi.nlm.nih.gov/pmc/articl ... able/Tab2/
This study was done incorrectly as a toxicological evaluation. There are way too many serious flaws here to consider them just a coincidence, or mere incompetence.
Neither the NTP 2016 Literature Review nor the 2019 NTP Draft Monograph did address ANY of the Chinese studies that evaluated fluoride effects on thyroid hormones in rodents and compared to brain development - including those that investigated effects in pregnant dams and their offspring. Why? These studies were listed in our 2016 submission to the NTP. But this heavily flawed study by McPherson et al. - a study that doesn't satisfy even the most basic requirements for a toxin/thyroid/brain investigation - is now considered THE highest quality animal study on this subject available? There is something very wrong with this picture.
This paper should be withdrawn. A work like this should never be allowed to influence public health policy.
This is also not the first time the NTP has been caught in highly questionable conduct concerning research on fluoride toxicity. Those readers familiar with the 1990 NTP report on the carcinogenesis of sodium fluoride might remember the firing of EPA senior scientist Dr. William Marcus as a result of his criticism of the downgrading of the evidence. Dr. Marcus subsequently filed a wrongful dismissal lawsuit and won his case. The press reported on this extensively at the time (AP, 1994).
Fortunately, there are many studies appearing from all over the world documenting the adverse effects of fluoride on thyroid hormone metabolism, in humans and animals. Close to 200 papers from the last 15 years can be accessed from our website - viewtopic.php?f=7&t=1345 (PFPC 2020). It is only a matter of time until the evidence will simply become too overwhelming to ignore and deny. We can only hope that one day, US Health and Human Services agencies such as the NTP, the ATSDR, and the CDC will be held accountable for having suppressed the truth - knowingly - for so many years.
PFPC Canada, 2020
© 2020 PFPC
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