by Paul Connett
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Fluoride and the Endocrine System
We saw in chapter 9 that prior to the start of the fluoridation program there was considerable interest in the possibility that fluoride interfered with the thyroid gland. However, the U. S. Public Health Service (PHS) paid little attention to those concerns before endorsing fluoridation in 1950. Most recent government reviews have given the matter short shrift. 1–5
The Endocrine System
The endocrine system consists of a number of glands (e. g. , thyroid, parathyroid, adrenal) that secrete hormones into the bloodstream. Hormones are responsible for regulating the chemistry of the cells in different tissues. The hormones (e. g. , thyroxin, adrenaline, estrogen, testosterone, insulin) are usually secreted at precise times and circulate in the bloodstream until they reach the tissues they regulate.
Hormones can be subdivided into fat-soluble and water-soluble groups. Solubility in fat or water makes a huge difference to the way hormones interact with the cells in the target tissues. If the hormone is fat soluble, it can cross the cell membrane (which is made up largely of fats) and enter the cell. There it will find a receptor (usually a protein) with a site on its surface, into which the hormone will fit into like a hand fitting into a glove. When the hormone fits into the protein, the protein becomes “activated, ” meaning it is ready to start the first step in a sequence that will ultimately change the activity of the cells in the tissue. In this way, the tissue is regulated; processes inside the cells of the tissue are switched on or off, or existing processes may simply be speeded up or slowed down.
If the hormone is water soluble, it will not be able to cross the cell membrane, so the receptor protein has to be located on the outside surface of the membrane. In this case, once the hormone has attached to the receptor, a process is triggered by which the hormone’s message (not the messenger) is carried across the membrane. The message triggers the production of a second messenger inside the cell that changes cellular activity, and hence the activity of the tissue involved.
A simple example may help clarify this. Most people are familiar with the adrenaline-induced “fight or flight” response. Here is how it works: When something frightens us, the adrenal glands release adrenaline into our bloodstream. This circulates in the blood until it finds the muscles. Being water soluble, it cannot cross the membranes of the cells that make up the muscles, so it finds the receptor molecule on the outside of the membranes. The message is transmitted across the membranes by the G-protein message system (described in chapter 12), producing a second messenger (cyclic AMP) inside the cell. This second messenger then activates a sequence of enzymes, which act as catalysts to break down sugar molecules more quickly—thereby releasing a lot of energy into the muscle cells so we are better equipped to fight or run away.
This is what the NRC report of 2006 had to say about fluoride’s interaction with the endocrine system:
In summary, evidence of several types indicates that fluoride affects normal endocrine function or response; the effects of the fluoride-induced changes vary in degree and kind in different individuals. Fluoride is therefore an endocrine disruptor in the broad sense of altering normal endocrine function or response, although probably not in the sense of mimicking a normal hormone. The mechanisms of action remain to be worked out and appear to include both direct and indirect mechanisms, for example, direct stimulation or inhibition of hormone secretion by interference with second messenger function, indirect stimulation or inhibition of hormone secretion by effects on things such as calcium balance, and inhibition of peripheral enzymes that are necessary for activation of the normal hormone. 6
Fluoride and the Thyroid Gland
The thyroid gland produces two major hormones called T3 and T4, which contain three and four iodine atoms, respectively. Another hormone, the thyroid-stimulating hormone (TSH), is produced in the pituitary gland, and it regulates the production of the hormones by the thyroid gland (see the discussion below). This is a simplified picture, but it will suffice for our purposes.
The literature dealing with the interaction between fluoride and the thyroid gland has a long history stretching back to a paper written in 1854 by Maumené, who linked goiter in dogs with exposure to fluoride. 7 The group Parents of Fluoride Poisoned Children (PFPC) provides an extensive summary of that history on its Web site. 8
There are four lines of evidence that fluoride interferes with the thyroid gland:
1. Fluoride-induced goiter. The condition known as goiter (also spelled “goitre”), which involves a gross swelling of the thyroid gland, in turn producing very marked swellings in the neck, is known to be induced by iodine deficiency. Significantly, the condition has also been found by some studies to occur in areas where there are adequate supplies of iodine but an excess of fluoride in the water. 9–15 1 Other studies have failed to find that relationship. 16
2. Treatment of hyperthyroid patients. Between the 1920s and the 1950s, some doctors in Argentina and Europe treated patients suffering from hyperthyroidism with sodium fluoride. 17–23 The treatment was successful in many but not all cases. Doses as low as 0. 9–4. 2 mg fluoride per day were enough to reduce the basal metabolic rate (BMR) of hyperthyroid patients and alleviate their condition. 24 This corresponds to the range of fluoride ingested by many people living in fluoridated areas. The U. S. Department of Health and Human Services estimated that an adult in a fluoridated community ingests between 1. 6 and 6. 6 mg of fluoride a day from all sources combined. 25
This raises an obvious question: If fluoride calms an overactive thyroid, what might it do to a normal or underactive one? Little information has been available until recently. However, a study conducted by Bachinskii et al. in the Ukraine found that prolonged consumption of water with 2. 3 ppm fluoride produced changes in normal thyroid function. The authors described this as “a tension of function of the pituitary-thyroid system that was expressed in TSH [thyroid-stimulating hormone] elevated production, a decrease in the T3 concentration and more intense absorption of radioactive iodine by the thyroid as compared to healthy persons who consumed drinking water with the normal fluorine concentration” and went on to say, “The results led to a conclusion that excess of fluorine in drinking water was a risk factor of more rapid development of thyroid pathology. ”26
These responses were mirrored in a study by Mikhailets et al. 27 In that case, the authors examined the thyroid function of 165 workers in an aluminum plant. They detected thyroid abnormalities that were “characterized by a moderate reduction of iodine-absorbing function of the thyroid, low T3 with normal T4 level, and a slight increase of TSH concentration. ” The authors noted that these changes became more pronounced the longer the workers were exposed to these working conditions. They concluded, “The syndrome of low T3 and reduced absorption of I131[iodine isotope 131] may be considered as diagnostic signs of fluorosis. ”28 We examine the possible mechanisms whereby fluoride may exert its influence in “Possible Mechanisms of Action” below.
3. Low iodide and brain development. It has long been known that one of the consequences of iodine deficiency in mothers is an increased risk of developmental disabilities in their children. With the introduction of iodized salt, this is now a less frequent occurrence in industrialized countries, but the problem has not been eliminated completely. In the United States declines in iodine intake have recently been recorded, and in Australia (a fluoridating country), outright iodine deficiency is still a serious problem. 29, 30
It is well established that the pituitary-thyroid system is important in the early mental development of children. Thus, if fluoride interfered with the thyroid, it could, among other things, result in lowered IQ in children. In this respect, the results of a UNICEF-sponsored study of “the relationship of a low-iodine and high-fluoride environment to sub-clinical cretinism” in China is particularly revealing. In the Xinjiang region of China Lin et al. found that even a modest amount of fluoride in the water (i. e.
, 0. 88 ppm versus 0. 34 ppm) led to a greater reduction in IQ and increased frequency of hypothyroidism (elevated TSH levels with normal T4 and T3 levels) than simply low iodide by itself. IQ and TSH were negatively correlated (as TSH goes up, IQ goes down). 31
4. The thyroid-stimulating hormone. In conjunction with aluminum, fluoride may mimic the action of thyroid-stimulating hormone. See “Possible Mechanisms of Action” below.
NRC Report and Fluoride-Thyroid Connection
Fluoride could impact several areas of human health through the mediation of the thyroid. It is unjustifiable that almost no relevant research has been carried out in fluoridating countries. In contrast to most of the other governmental reviews of fluoride’s toxicity, the 2006 NRC panel did express concern about fluoride’s potential to disrupt the endocrine system in general, and about a possible fluoride-thyroid interaction in particular. 32 The authors of the report stated, “Several lines of information indicate an effect of fluoride exposure on thyroid function”33 In terms of specific effects and the dosages at which they occur, they wrote:
Fluoride exposure in humans is associated with elevated TSH concentrations, increased goiter prevalence, and altered T4 and T3 concentrations; similar effects on T4 and T3 are reported in experimental animals. . . In humans, effects on thyroid function were associated with fluoride exposures of 0. 05–0. 13 mg/kg/day when iodine intake was adequate and 0. 01–0. 03 mg/kg/day when iodine intake was inadequate. 34
Such dosages are extremely low; a child would reach them by drinking one or two glasses of water fluoridated at 1 ppm.
Regarding the situation in the United States, the NRC authors showed particular concern about the impact of fluoride on people suffering from iodine deficiency or borderline iodine deficiency: “The recent decline in iodine intake in the United States could contribute to increased toxicity of fluoride for some individuals. ”35–37
In an article published in the January 2008 issue of Scientific American, Dan Fagin wrote the following about the 2006 NRC panel:
The NRC committee concluded that fluoride can subtly alter endocrine function, especially in the thyroid—the gland that produces hormones regulating growth and metabolism. . . Says John Doull, professor emeritus of pharmacology and toxicology at the University of Kansas Medical Center, who chaired the NRC committee: “The thyroid changes do worry me. There are some things there that need to be explored. ”38
Possible Mechanisms of Action
There are at least two plausible mechanisms, supported by some evidence, by which fluoride may influence the activity of the thyroid and its hormones.
Inhibition of Deiodinase
Deiodinase enzymes play an important role in the functioning of the thyroid system. The thyroid hormones thyroxin (T4) and triiodothyronine (T3) contain four and three iodine atoms, respectively. Most of the molecules secreted by the thyroid are T4. A deiodinase is responsible for removing one of the iodines from T4 to form the much more active but shorter-lived T3. T3 in turn is eventually deactivated by another deiodinase. Since T3 stimulates the body’s metabolic rate, its activity needs to be constantly monitored and regulated; otherwise, signs and symptoms of hyper- or hypothyroidism will appear. Deiodinases perform that function, probably at two levels: (1) in the body generally, by directly controlling the concentration of T3 in the blood and tissues (particularly the liver); and (2) by indirectly controlling the output of T4 from the thyroid.
This second control mechanism is more complicated. Briefly, thyroid activity is controlled by another hormone, thyroid-stimulating hormone (TSH), which is produced by the anterior pituitary gland in response to a signal from a part of the brain called the hypothalamus. T3 exercises negative feedback, down-regulating the production of TSH by the pituitary. It appears that deiodination of T4 to T3 within the pituitary plays an important part in that process. 39 Although there is no direct evidence that fluoride can inactivate deiodinases, it is well known as an inhibitor of many enzymes, and the hormonal derangements reported in fluoride-exposed people have been interpreted in terms of effects on deiodinases. 40, 41 According to that interpretation, there are at least three levels at which fluoride could plausibly upset regulation of the thyroid system:
1. Conversion of T4 to T3 in tissues and blood,
2. Local conversion of T4 to T3 in the pituitary gland, resulting in inappropriate continued production of TSH, and
3. Inactivation of T3.
Interpretation of events in the thyroid is further complicated by the existence of other “minor” hormones structurally related to T3 and T4 and by the varied activities and functions of the three deiodinases in different tissues. 42 Interference with deiodinases also affects the availability of free iodide, which may affect not only the brain (see chapter 15) but other tissues as well. 43
Fluoride Mimicking TSH
As suggested in the preceding section, a possible mechanism exists whereby fluoride could bring about an excessive production of TSH from the pituitary. This may help explain why elevated TSH levels have been reported in cases of hypothyroidism with lowered T3 in aluminum workers occupationally exposed to fluoride. 44 But fluoride may itself mimic the action of TSH. TSH is water soluble and sends its message across the membrane of the thyroid via G proteins. Fluoride has a well-established ability, in the presence of a trace amount of aluminum, to switch on G proteins (see chapter 12).
Thus, a mechanism of fluoride’s action here might be an activation of the G-protein messaging system, leading to excess production of the secondary messenger inside the cell (cyclic AMP). Excess production of this secondary messenger may in turn lead to desensitization of the TSH receptor, thereby reducing the stimulus by otherwise normal levels of TSH. Some evidence of this was found in a study of Chinese hamster ovary cells by Tezelman et al. 45
We emphasize that proof that fluoride acts on the thyroid in these ways in vivo is still lacking. Further research is needed, but, meanwhile, the mechanisms are plausible and based on existing science.
Proponents’ Claims
Proponents of fluoridation claim that there is no “credible” evidence that fluoridation harms the thyroid. For example, early in 2006 the British Fluoridation Society (BFS) placed a statement to that effect on the front page of its Web site:
The available medical and scientific evidence suggests an absence of an association between water fluoridation and thyroid disorders.
Many major reviews of the relevant scientific literature around the world support this conclusion. Of particular importance are:
• an exhaustive review conducted in 1976 by an expert scientific committee of the Royal College of Physicians [RCP] of England;
• a systematic review in 2000 by the NHS Centre for Reviews and Dissemination at the University of York; and,
• a 2002 review by an international group of experts for the International Programme on Chemical Safety (IPCS), under the joint sponsorship of the World Health Organisation (WHO), the United Nations Environment Programme (UNEP), and the International Labour Organisation (ILO).
• none have found any credible evidence of an association between water fluoridation and any disorder of the thyroid. 46
This statement remained on the BFS site as of March 2010, though less prominently displayed. It sounds quite impressive, the more so since it goes on to say that the York Review “identified over three thousand references in total” and the IPCS review “included 788 original studies. ”47, 48 But somehow the BFS fails to mention that only a handful (none in the IPCS review) dealt with the thyroid, and that only four short paragraphs of the thirty-year-old RCP review were relevant. 49 In fact, they are talking about a classic case of “no look, no see, ” but cushioning it in verbiage designed to suggest that plenty of work has been performed and reviewed to reassure the reader that fluoridation is no threat to the thyroid system. Such tactics can be persuasive even to supposedly informed and perceptive people. The British Thyroid Association (BTA), no less, was moved to endorse the BF
S statement—not merely the conclusion, but the whole misleading statement. Curiously, neither organization has significantly modified its stance since publication of the 2006 NRC review, which adduced some highly relevant evidence; however, in 2007 the BTA added a rider to its endorsement, implicitly admitting that there might be a significant risk, but merely recommended that thyroid status should be monitored in any new fluoridation program. This reluctance to acknowledge risk is perhaps understandable in the case of the BFS, which exists to promote fluoridation, but one might expect the BTA to exercise more caution on behalf of its own base.
The ADA adopts a quite different approach on its Web site but one equally economical with the truth. Its Fluoride Facts states, “There is no scientific basis that shows that fluoridated water has an adverse effect on the thyroid gland or its function”50 and backs this up by describing a small and, by modern standards, simplistic study by Leone et al. (a questionable source; see chapter 10) that used only very basic parameters and was published forty-five years ago. 51
Both the BFS and the ADA are careful to talk about fluoridated water, perhaps believing that that absolves them from paying attention to any data relating to naturally occurring fluoride—a somewhat legalistic approach.
Our Concerns
At present there is no direct and unassailable proof that fluoridation per se harms anyone’s thyroid. This may be due to the paucity of studies conducted; the 2006 NRC panel identified several areas where more research is needed. Meanwhile, although the evidence is mixed, there are clearly grounds for caution. When one considers the millions of people affected by hypothyroidism (underactive thyroid) in fluoridated countries and the millions more probably suffering from subclinical (undiagnosed) hypothyroidism, the omissions in many government-sponsored reviews are unfathomable.
