"Fluoride is 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."
THE ENDOCRINE SYSTEM
In 2007, Harris and Pass published newborn-screening data from New York and the United States that showed an increase in the incidence (birth prevalence) rates of primary congenital hypothyroidism (CH) over the past 2 decades
New York: 1 in 3378 to
1 in 1414 births;
United States: 1 in 4098 to
1 in 2370 births).
Harris KB, Pass KA Increase in congenital hypothyroidism in New York State and in the United States. Mol Genet Metab. 2007; 91(3):268–277
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Effects on the Endocrine System
The Agency for Toxic Substances and Disease Registry (ATSDR 2003) discussed four papers on thyroid effects and two papers on parathyroid effects and concluded
“data suggest(s) that fluoride ... adversely affects some endocrine glands.”
THYROID FOLLICULAR CELLS
The follicular cells of the thyroid gland produce the classic thyroid hormones thyroxine (T4) and triiodothyronine (T3); these hormones modulate a variety of physiological processes, including but not limited to normal growth and development (Larsen et al. 2002; Larsen and Davies 2002; Goodman 2003).
Between 4% and 5% of the U.S. population may be affected by deranged thyroid function (Goodman 2003), making it among the most prevalent of endocrine diseases (Larsen et al. 2002).
The prevalence of subclinical thyroid dysfunction in various populations is
1.3-17.5% for subclinical hypothyroidism and
0.6-16% for subclinical hyperthyroidism;
the reported rates depend on age, sex, iodine intake, sensitivity of measurements, and definition used (Biondi et al. 2002).
Normal thyroid function requires sufficient intake of iodine (at least 100 micrograms/day [μg/d]),and areas of endemic iodine deficiency are associated with disorders such as
endemic goiter and
cretinism (Larsen et al. 2002; Larsen and Davies 2002; Goodman 2003).
Iodine intake in the United States (where iodine is added to table salt) is decreasing (CDC 2002d; Larsen et al. 2002), and an estimated 12% of the population has low concentrations of urinary iodine (Larsen et al. 2002)
The principal regulator of thyroid function is the
pituitary hormone thyroid-stimulating hormone (TSH),
which in turn is controlled by positive input from the
hypothalamic hormone thyrotropin-releasing hormone (TRH)
TSH binds to G-protein-coupled receptors in the surface membranes of thyroid follicular cells (Goodman 2003),
which leads to increases in both the cyclic adenosine monophosphate (cAMP) and diacylglycerol/inositol trisphosphate second messenger pathways (Goodman 2003).
T3, rather than T4, probably is responsible for the feedback response for TSH production (Schneider et al. 2001).
Some T3, the active form of thyroid hormone, is secreted directly by the thyroid along with T4, but most T3 is produced from T4 by one of two deiodinases (Types I and II ) in the peripheral tissue (Schneider et al. 2001; Larsen et al. 2002; Goodman 2003). T3 enters the nucleus of the target cells and binds to specific receptors, which activate specific genes.
In 1923, the director of the Idaho Public Health Service, in a letter to the Surgeon General, reported enlarged thyroids in many children between the ages of 12 and 15 using city water in the village of Oakley, Idaho (Almond 1923);
In addition, the children using city water had severe enamel deficiencies in their permanent teeth.
The dental problems were eventually attributed to the presence in the city water of 6 mg/L fluoride, and children born after a change in water supply (to water with <0.5 mg/L fluoride) were not so affected (McKay 1933); however, there seems to have been no further report on thyroid conditions in the village. (italtics added)
McLaren (1976), however, pointed out the complexity of the system, the difficulties in making adequate comparisons of the various studies of fluoride and the thyroid, and evidence for fluoride accumulation in the thyroid and morphological and functional changes (e.g., changes in activity of adenylyl cyclase), suggesting that analytical methods could have limited the definitiveness of the data to date.
His review suggested that physiological or functional changes might occur at fluoride intakes of 5 mg/day.
Although fluoride does not accumulate significantly in most soft tissue (as compared to bones and teeth), several older studies found that fluoride concentrations in thyroid tissue generally exceed those in most other tissue except kidney (e.g., Chang et al. 1934; Hein et al. 1954, 1956); more recent information with improved analytic methods for fluoride was not located.
Several studies have reported no effect of fluoride treatment on thyroid weight or morphology (Gedalia et al. 1960; Stolc and Podoba 1960; Saka et al. 1965; Bobek et al. 1976; Hara 1980),
while others have reported such morphological changes as
mild atrophy of the follicular epithelium (Ogilvie 1953),
distended endoplasmic reticulum in follicular cells (Sundstrom 1971), and
“morphological changes suggesting hormonal hypofunction”(Jonderko et al. 1983).
Fluoride was once thought to compete with iodide for transport into the thyroid, but several studies have demonstrated that this does not occur (Harris and Hayes 1955; Levi and Silberstein 1955; Anbar et al. 1959; Saka et al. 1965).
The iodide transporter accepts other negatively charged ions besides iodide (e.g., perchlorate), but they are about the same size as iodide (Anbar et al. 1959); fluoride ion is considerably smaller and does not appear to displace iodide in the transporter.
Bachinskii et al. (1985) examined 47 healthy persons, 43 persons with hyperthyroidism, and 33 persons with hypothyroidism.
Prolonged consumption of “high-fluoride” drinking water (2.3 mg/L, as opposed to “normal” concentrations of 1 mg/L) by healthy persons was associated with statistically significant changes in TSH concentrations (increased), T3 concentrations (decreased), and uptake of radioiodine (increased), although the mean values for TSH and T3 were still within normal ranges (see Appendix E, Table E-6).
The mean value of TSH for the healthy group (4.3 ± 0.6 milliunits/L; Table E-6) is high enough that one expects a few individuals to have been above the normal range (typically 0.5-5 milliunits/L; Larsen et al. 2002).
These results were interpreted as indicating disruption of iodine metabolism, stress in the pituitary-thyroid system, and increased risk of developing thyroidopathy (Bachinskii et al. 1985) (caused by 2.3mg/L of Fluoride).
Lin et al. (1991) examined 769 children (7-14 years old) for mental retardation in three areas of China, including an area with “high” fluoride (0.88 mg/L) and low iodine, an area with “normal” fluoride (0.34 mg/L) and low iodine, and an area where iodine supplementation was routine (fluoride concentration not stated).
Ten to twelve children in each area received detailed examinations, including measuring thyroid 131I uptake and thyroid hormone concentrations.
Children in the first area (0.88ppm F) had higher TSH, slightly higher 131I uptake, and lower mean IQ than children in the second area.
Children in the first area (0.88ppm F) also had reduced T3 and elevated reverse T3, compared with children in the second area. The authors suggested that high fluoride might exacerbate the effects of iodine deficiency.
In addition, the authors reported a difference in T3/rT3 (T3/reverse-T3) ratios between high-(0.88ppmF) and low-fluoride areas (0.34ppmF) and suggested that
excess fluoride ion affects normal deiodination.
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, but TSH has not been measured in most studies.
In animals, effects on thyroid function have been reported at fluoride doses of 3-6 mg/kg/day (some effects at 0.4-0.6 mg/kg/day) when iodine intake was adequate (Table 8-1);
effects on thyroid function were more severe or occurred at lower doses when iodine intake was inadequate.
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 (Table 8-2).
Several sets of results are consistent with inhibition of deiodinase activity, but other mechanisms of action are also possible, and more than one might be operative in a given situation. In many cases, mean hormone concentrations for groups are within normal limits, but individuals may have clinically important situations. In particular, the inverse correlation between asymptomatic hypothyroidism in pregnant mothers and the IQ of their offspring (Klein et al. 2001) is a cause for concern. The recent decline in iodine intake in the United States (CDC 2002d; Larsen et al. 2002) could contribute to increased toxicity of fluoride for some individuals.
Thyroid Parafollicular Cell Function
Only one study has reported calcitonin concentrations in fluoride-exposed individuals. This study found elevated calcitonin in all patients with fluoride exposures above about 0.15 mg/kg/day and in one patient with a current intake of approximately 0.06 mg/kg/day (Table 8-2); these exposures corresponded to plasma fluoride concentrations of 0.11-0.26 mg/L.
Results attributed to altered calcitonin activity have also been found in experimental animals at a fluoride exposure of 2 mg/kg/day (Table 8-1). It is not clear whether elevated calcitonin is a direct or indirect result of fluoride exposure, nor is it clear what the clinical significance of elevated calcitonin concentrations might be in individuals.
In humans, depending on the calcium intake, elevated concentrations of PTH are routinely found at fluoride exposures of 0.4-0.6 mg/kg/day and at exposures as low as 0.15 mg/kg/day in some individuals (Table 8-2).
Similar effects and exposures have been found in a variety of human studies; these studies indicate that elevated PTH and secondary hyperparathyroidism occur at fluoride intakes higher than those associated with other endocrine effects.
In the single study that measured both calcitonin and PTH, all individuals with elevated PTH also had elevated calcitonin, and several individuals had elevated calcitonin without elevated PTH (Teotia et al. 1978).
Elevated concentrations of PTH and secondary hyperparathyroidism have also been reported at fluoride intakes of 9-10 mg/kg/day (and as low as 0.45-2.3 mg/kg/day in one study) in experimental animals (Table 8-1).
One animal study found what appears to be inhibition of the normal parathyroid response to calcium deficiency at a fluoride intake of 5.4 mg/kg/day.
As with calcitonin, it is not clear whether altered parathyroid function is a direct or indirect result of fluoride exposure.
An indirect effect of fluoride by causing an increased requirement for calcium is probable, but direct effects could occur as well.
Also, although most individuals with skeletal fluorosis appear to have elevated PTH, it is not clear whether parathyroid function is affected before development of skeletal fluorosis or at lower concentrations of fluoride exposure than those associated with skeletal fluorosis.
Recent U.S. reports of nutritional (calcium-deficiency) rickets associated with elevated PTH (DeLucia et al. 2003) suggest the possibility that fluoride exposure, together with increasingly calcium-deficient diets, could have an adverse impact on the health of some individuals.
The single animal study of pineal function indicates that fluoride exposure results in altered melatonin production and altered timing of sexual maturity (Table 8-1).
Whether fluoride affects pineal function in humans remains to be demonstrated.
The two studies of menarcheal age in humans show the possibility of earlier menarche in some individuals exposed to fluoride, but no definitive statement can be made.
Recent information on the role of the pineal organ in humans suggests that any agent that affects pineal function could affect human health in a variety of ways, including effects on sexual maturation, calcium metabolism, parathyroid function, postmenopausal osteoporosis, cancer, and psychiatric disease.
Increased serum glucose and increased severity of existing diabetes have been reported in animal studies at fluoride intakes of 7-10.5 mg/kg/day (Table 8-1).
Impaired glucose tolerance in humans
has been reported in separate studies at fluoride intakes of
0.07-0.4 mg/kg/day, corresponding to serum fluoride concentrations above
about 0.1 mg/L.
The primary mechanism appears to involve inhibition of insulin production.
The clinical significance of fluoride-related endocrine effects requires further attention.
For example, most studies have not mentioned the clinical significance for individuals of hormone values out of the normal range, and some studies have been limited to consideration of “healthy” individuals.
As discussed in the various sections of this chapter, recent work on borderline hormonal imbalances and endocrine-disrupting chemicals indicates that significant adverse health effects, or an increased risk for development of clearly adverse health outcomes, could be associated with seemingly mild imbalances or perturbations in hormone concentrations (Brucker-Davis et al. 2001).
In addition, the different endocrine organs do not function entirely separately: thyroid effects (especially elevated TSH) may be associated with parathyroid effects (Stoffer et al. 1982; Paloyan Walker et al. 1997), and glucose metabolism may be affected by thyroid or parathyroid status.
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.
Further effort is necessary to characterize the direct and indirect mechanisms of fluoride’s action on the endocrine system and the factors that determine the response, if any, in a given individual. Such studies would address the following:
the in vivo effects of fluoride on second messenger function
the in vivo effects of fluoride on various enzymes
the integration of the endocrine system (both internally and with other systems such as the neurological system)
identification of those factors, endogenous (e.g., age, sex, genetic factors, or preexisting disease) or exogenous (e.g., dietary calcium or iodine concentrations, malnutrition), associated with increased likelihood of effects of fluoride exposures in individuals
consideration of the impact of multiple contaminants (e.g., fluoride and perchlorate) that affect the same endocrine system or mechanism
examination of effects at several time points in the same individuals to identify any transient, reversible, or adaptive responses to fluoride exposure.
Better characterization of exposure to fluoride is needed in epidemiology studies investigating potential endocrine effects of fluoride. Important exposure aspects of such studies would include the following:
collecting data on general dietary status and dietary factors that could influence the response, such as calcium, iodine, selenium, and aluminum intakes
characterizing and grouping individuals by estimated (total) exposure, rather than by source of exposure, location of residence, fluoride concentration in drinking water, or other surrogates
reporting intakes or exposures with and without normalization for body weight (e.g., mg/day and mg/kg/day), to reduce some of the uncertainty associated with comparisons of separate studies
addressing uncertainties associated with exposure and response, including uncertainties in measurements of fluoride concentrations in bodily fluids and tissues and uncertainties in responses (e.g., hormone concentrations)
reporting data in terms of individual correlations between intake and effect, differences in subgroups, and differences in percentages of individuals showing an effect and not just differences in group or population means.
examining a range of exposures, with normal or control groups having very low fluoride exposures (below those associated with 1 mg/L in drinking water for humans).
The effects of fluoride on various aspects of endocrine function should be examined further, particularly with respect to a possible role in the development of several diseases or mental states in the United States.
Major areas suggested for investigation include the following:
— thyroid disease (especially in light of decreasing iodine intake by the U.S. population);
— nutritional (calcium deficiency) rickets;
— calcium metabolism (including measurements of both calcitonin and PTH);
— pineal function (including, but not limited to, melatonin production);
— development of glucose intolerance and diabetes.
National Research Council 2006 Fluoride in Drinking Water ENDOCRINE CHAPTER
Number of follow up studies since 2006 on fluoride in drinking water and the incidence of hypothyroidism in the US?