Latest US NRC report: fluoride toxicokinetics & health effects

The following quotes are from the 2006 US National Research Council report Fluoride in Drinking Water: A Scientific Review of EPA’s Standards, which is the most comprehensive review of fluoride toxicity to date. I have read the report in full, and the quotes are my own selection. They are intended to highlight some key points, not provide a complete summary. I have two PDF versions, hence the doubling up on page numbers. Anything inside square brackets is an addition I have made, and does not appear in either of the original documents. A reference list has been omitted here, and may be found in the original document. This page does not include quotes relating to fluoride exposure.

Maximum Contaminant Level Goal (MCLG)

p 2 [p 2/3] “the [12 person] committee concluded unanimously that the present MCLG of 4 mg/L for fluoride should be lowered. Exposure at the MCLG clearly puts children at risk of developing severe enamel fluorosis, a condition that is associated with enamel loss and pitting. In addition, the majority of the committee concluded that the MCLG is not likely to be protective against bone fractures”

p 4 [p 5] “Since 1993, there have been no new studies of enamel fluorosis in US communities with fluoride at 2 mg/L in drinking water. Earlier studies indicated that the prevalence of moderate enamel fluorosis at that concentration could be as high as 15%.”

p 6 [p 7] “There were few studies to assess fracture risk in populations exposed to fluoride at 2 mg/L in drinking water. The best available study, from Finland, suggested an increased rate of fracture in populations exposed to fluoride at concentrations above 1.5 mg/L. However, this study alone is not sufficient to judge fracture risk for people exposed to fluoride at 2 mg/L. Thus, no conclusions could be drawn about fracture risk or safety at 2 mg/L.”

p 7 [p 8] “The chief endocrine effects of fluoride exposures in experimental animals and in humans include decreased thyroid function, increased calcitonin activity, increased parathyroid hormone activity, secondary hyperparathyroidism, impaired glucose tolerance, and possible effects on timing of sexual maturity. Some of these effects are associated with fluoride intake that is achievable at fluoride concentrations in drinking water of 4 mg/L or less, especially for young children or for individuals with high water intake. Many of the effects could be considered subclinical effects, meaning that they are not adverse health effects. However, recent work on borderline hormonal imbalances and endocrine-disrupting chemicals indicated that adverse health effects, or increased risks for developing adverse effects, might be associated with seemingly mild imbalances or perturbations in hormone concentrations. Further research is needed to explore these possibilities.”

p 8 [p 10] “To develop an MCLG that is protective against severe enamel fluorosis, clinical stage II skeletal fluorosis, and bone fractures, EPA should update the risk assessment of fluoride to include new data on health risks and better estimates of total exposure (relative source contribution) for individuals. EPA should use current approaches for quantifying risk, considering susceptible subpopulations, and characterising uncertainties and variability.”

Secondary Maximum Contaminant Level (SMCL)

p 1 [p 1] “The MCLG is a health goal set at a concentration at which no adverse health effects are expected to occur… For some contaminants, EPA also establishes an SMCL, which is a guideline for managing drinking water for aesthetic, cosmetic, or technical effects.”

p 8 [p 10] “From a cosmetic standpoint, the SMCL does not completely prevent the occurrence of moderate enamel fluorosis. EPA has indicated that the SMCL was intended to reduce the severity and occurrence of the condition to 15% or less of the exposed population. The available data indicate that fewer than 15% of children will experience moderate enamel fluorosis of aesthetic concern (discolouration of the front teeth) at that concentration. However, the degree to which moderate enamel fluorosis might go beyond a cosmetic effect to create an adverse psychological effect or an adverse effect on social functioning is not known.”

Dental fluorosis

p 27 [p 33] “Moderate and severe dental fluorosis have been reported in diabetes insipidus patients in other countries with drinking water containing fluoride at 0.5 mg/L (Klein 1975) or 1 mg/L (Seow and Thomsett 1994), and severe dental fluorosis with skeletal fluorosis has been reported with fluoride at 3.4 mg/L (Mehta et al. 1998 ). Greenberg et al. (1974) recommended that children with any disorder that gives rise to polydipsia and polyuria be supplied a portion of their water from a nonfluoridated source.” [The version with larger page numbers uses the term “enamel fluorosis” instead of “dental fluorosis” in the quoted paragraph.]

p 85 [p 103] “Excessive intake of fluoride during enamel development can lead to enamel fluorosis, a condition of the dental hard tissues in which the enamel covering of the teeth fails to crystallize properly, leading to defects that range from barely discernable [sic] markings to brown stains and surface pitting.”

p 86 [p 105] “The improper mineralization that occurs with enamel fluorosis is thought to be due to inhibition of the matrix proteinases responsible for removing amelogenin fragments. The delay in removal impairs crystal growth and makes the enamel more porous (Bronckers et al. 2002). … Fluoride apparently interferes with protease activities by decreasing free Ca2+ [calcium ion] concentrations in the mineralizing milieu (Aoba and Fejerskov 2002).”

p 87 [p 106] “There appears to be general acceptance in today’s dental literature that enamel fluorosis is a toxic effect of fluoride intake that, in its severest forms, can produce adverse effects on dental health, such as tooth function and caries experience.”

Fluoride complexes

p 42 [p 52] “Further research should include characterization of both the exposure conditions and the physiological conditions (for fluoride and for aluminum or beryllium) under which aluminofluoride and beryllofluoride complexes can be expected to occur in humans as well as the biological effects that could result.”

p 43/44 [p 53] “PJ Jackson et al. (2002) have calculated that at pH 7, in the presence of aluminum, 97.46% of a total fluoride concentration of 1 mg/L is present as fluoride ion, but at pH 6, only 21.35% of the total fluoride is present as fluoride ion, the rest being present in various aluminum fluoride species”

p 108 [p 132] “Do fluoroaluminate complexes exist in biological fluids? The answer to this question depends in large part on pH, protein concentration, and cell composition. However, in general, in the acid environment of the stomach much of the aluminum and fluoride exist in a complex of AlF3 or AlF4⁻. These forms (mostly AlF3) have been purported to cross the intestine and enter cells (Powell and Thompson 1993). Once inside a bone cell the AlFx form appears to activate a specific protein tyrosine kinase through a G protein and evoke downstream signals.”

Bone quality

p 5/6 [p 7] “Fracture risk and bone strength have been studied in animal models. The weight of evidence indicates that, although fluoride might increase bone volume, there is less strength per unit volume.… Biochemical and physiological data indicate a biologically plausible mechanism by which fluoride could weaken bone. In this case, the physiological effect of fluoride on bone quality and risk of fracture observed in animal studies is consistent with the human evidence.”

p 108/9 [p 133] “the general conclusion is that, although there may be an increase in skeletal density, there is no consistent increase in bone strength [in humans]. A carefully performed comparison study between the effects of fluoride (2mg/kg/day) and alendronate in minipigs likely points to the true effect: ‘in bone with higher volume, there was less strength per unit volume, that is, … there was a deterioration in bone quality’ (Lafage et al. 1995)”

p 113 [p 139] “fluoride did not prove to be an effective treatment [for osteoporosis]”

Skeletal fluorosis

p 66 [p 80] “the National Research Council (NRC 1993) indicated that crippling (as opposed to mild) skeletal fluorosis ‘might occur in people who have ingested 10-20 mg of fluoride per day for 10-20 years.’ A previous NRC report (NRC 1977) stated that a retention of 2 mg of fluoride per day (corresponding approximately to a daily intake of 4-5 mg) ‘would mean that an average individual would experience skeletal fluorosis after 40 yr, based on an accumulation of 10,000 ppm fluoride in bone ash.'”

[see my calculation of fluoride accumulation in bone]

p 68 [p 81] “Historically, a daily intake of 4-5 mg by an adult (0.057-0.071 mg/kg for a 70-kg adult) was considered a ‘health hazard’ (McClure et al. 1945, cited by Singer et al. 1985). However, the Institute of Medicine (IOM 1997) now lists 10 mg/day as a ‘tolerable upper intake’ for children > 8 years old and adults, although that intake has also been associated with the possibility of mild (IOM 1997) or even crippling (NRC 1993) skeletal fluorosis.”

p 139 [p 170/171] “Stage III has been termed ‘crippling’ skeletal fluorosis because mobility is significantly affected as a result of excessive calcifications in joints, ligaments, and vertebral bodies. This stage may also be associated with muscle wasting and neurological deficits due to spinal cord compression.”

p 143 [p 173] “On the basis of data on fluoride in the iliac crest or pelvis, fluoride concentrations of 4,300 to 9,200 mg/kg in bone ash have been reported in cases of stage II fluorosis, and concentrations of 4,200 to 12,700 mg/kg in bone ash have been reported in cases of stage III fluorosis. The overall ranges for other bones are similar.”

Pharmacokinetics (incl accumulation)

p 74 [p 90] “The pharmacokinetics of fluoride are primarily governed by pH and storage in bone. HF diffuses across cell membranes far more easily than fluoride ion. Because HF is a weak acid with a pKa of 3.4, more of the fluoride is in the form of HF when pH is lower. Consequently, pH—and factors that affect it—play an important role in the absorption, distribution, and excretion of fluoride.”

p 74 [p 90/91] “Fluoride can increase the uptake of aluminum into bone (Ahn et al. 1995) and brain (Varner et al. 1998).

Fluoride concentrations in plasma, extracellular fluid, and intracellular fluid are in approximate equilibrium. The concentrations in the water of most tissues are thought to be 40% to 90% of plasma concentrations, but there are several important exceptions. Tissue fluid/plasma (T/P) ratios exceed one for the kidney because of high concentrations in the renal tubules. T/P ratios can exceed one in tissues with calcium deposits, such as the placenta near the end of pregnancy. The pineal gland, a calcifying organ that lies near the center of the brain but outside the blood-brain barrier, has been found to accumulate fluoride (Luke 2001). Fluoride concentrations in adipose tissue and brain are generally thought to be about 20% of plasma or less (Whitford 1996). The blood-brain barrier is thought to reduce fluoride transfer, at least in short-term experiments (Whitford 1996). It is possible that brain T/P ratios are higher for exposure before development of the blood-brain barrier.”

p 75 [p 91] “Fluoride is cleared from plasma through two primary mechanisms: uptake by bone and excretion in urine. Plasma clearance by the two routes is approximately equal in healthy adult humans. … The relative clearance by bone is larger in young animals and children because of their growing skeletal systems.”

p 75 [p 92] “Fluoride is rapidly absorbed from the gastrointestinal tract, with a half-life of about 30 minutes. After a single dose, plasma concentrations rise to a peak and then fall as the fluoride is cleared by the renal system and bone, decreasing back to (short-term) baseline with a half-life of several hours. Fluoride concentrations in plasma are not homeostatically controlled (Whitford 1996). Chronic dosing leads to accumulation in bone and plasma (although it might not always be detectable in plasma.) Subsequent decreases in exposure cause fluoride to move back out of bone into body fluids, becoming subject to the same kinetics as newly absorbed fluoride. A study of Swiss aluminum workers found that fluoride bone concentrations decreased by 50% after 20 years. The average bone ash concentration in the workers was about 6,400 mg/kg at the end of exposure, estimated via regression (Baud et al. 1978). The bone concentration found in these workers is similar to that found in long-term consumers of drinking water containing fluoride in the range of 2-4 mg/L (discussed later in this chapter). Twenty years might not represent a true half-life. Recent pharmacokinetic models (see below) are nonlinear, suggesting that elimination rates might be concentration dependent.”

p 81 [p 100] “Because of their growing skeleton, infants and children clear relatively larger amounts of fluoride into bones than adults (Ekstrand et al. 1994; Whitford 1999).”

p 83 [p 102] “Research is needed on fluoride plasma and bone concentrations in people with small to moderate changes in renal function as well as patients with serious renal deficiency. Other potentially sensitive populations should be evaluated, including the elderly, postmenopausal women, and people with altered acid-base balance.”

Delayed tooth eruption

p 104 [p 126/127] “Questions have also been raised about the possibility that fluoride may delay eruption of permanent teeth (Kunzel 1976; Virtanen et al. 1994; Leroy et al. 2003). … Delayed tooth eruption could affect caries scoring for different age groups.”


p 139 [p 170/171] “Clinical stage III [the other version of the report says “stage II” – “stage III” is evidently an error, but not just a typo because the paragraph in question has also been altered in other ways] is associated with chronic joint pain, arthritic symptoms, calcification of ligaments, and osteosclerosis of cancellous bones. Stage III has been termed ‘crippling’ skeletal fluorosis because mobility is significantly affected as a result of excessive calcifications in joints, ligaments, and vertebral bodies.”

p 208 [p 247/248] “In the presence of adequate calcium, absorbed fluoride is deposited in the bone as calcium fluorapatite. Bone density increases, urinary fluoride increases, but urinary calcium and phosphorus are not altered. Osteosclerosis and calcification of many tendons and ligaments occur [in the development of skeletal fluorosis].”

p 295 [p 347] “The committee judges that stage II (the stage before mobility is significantly affected) should also be considered an adverse health effect. This stage is characterized by chronic joint pain, arthritic symptoms, slightly calcified ligaments, increased osteosclerosis/cancellous bones, and possibly osteoporosis of long bones (PHS 1991).”

Alzheimer’s disease

p 178 [p 211] “Fluoride produces additional effects on the ACh systems of the brain by its interference with acetylcholinesterase.

Most of the drugs used today to treat Alzheimer’s disease are agents that enhance the effects of the remaining ACh system.”

p 178 [p 212] “In addition to a depletion of acetylcholinesterase, fluoride produces alterations in phospholipid metabolism and/or reductions in the biological energy available for normal brain functions (see section later in this chapter on neurochemical effects). In addition, the possibility exists that chronic exposure to AlFx can produce aluminum inclusions with blood vessels as well as in their intima and adventitia. The aluminum deposits inside the vessels and those attached to the intima could cause turbulence in the blood flow and reduce transfer of glucose and O2 to the intercellular fluids. Finally histopathological changes similar to those traditionally associated with Alzheimer’s disease in people have been seen in rats chronically exposed to AlF (Varner et al. 1998).”

p 186 [p 222] “AlFx not only provides false messages throughout the nervous system but, at the same time, diminishes the energy essential to brain function.

Fluorides also increased the production of free radicals in the brain through several different biological pathways. These changes have a bearing on the possibility that fluorides act to increase the risk of developing Alzheimer’s disease.”


p 187 [p 222] “On the basis of information largely derived from histological, chemical, and molecular studies, it is apparent that fluorides have the ability to interfere with the functions of the brain and the body by direct and indirect means.”


p 189 [p 224] “The endocrine system, apart from reproductive aspects, was not considered in detail in recent major reviews of the health effects of fluoride (PHS 1991; NRC 1993; Locker 1999; McDonagh et al. 2000a; WHO 2002; ATSDR 2003).” [The 2007 Australian NHMRC report can be added to that list.]

p 189 [p 225] “an estimated 12% of the population has low concentrations of urinary iodine (Larsen et al. 2002)”

p 197 [p 234] “As with the animal studies, high fluoride intake appears to exacerbate the effects of low iodine concentrations (Day and Powell-Jackson 1972; Lin et al. 1991). Uncertainty about total fluoride exposures based on water fluoride concentrations, variability in exposures within population groups, and variability in response among individuals generally have not been addressed.”

p 197 [p 234/235] “several lines of information indicate an effect of fluoride exposure on thyroid function. However, because of the complexity of interpretation of various parameters of thyroid function (Larsen et al. 2002), the possibility of peripheral effects on thyroid function instead of or in addition to direct effects on the thyroid, the absence of TSH measurements in most of the animal studies, the difficulties of exposure estimation in human studies, and the lack of information in most studies on nutritional factors (iodine, selenium) that are known to affect thyroid function, it is difficult to predict exactly what effects on thyroid function are likely at what concentration of fluoride exposure and under what circumstances”

p 197 [p 235] “Several sets of reported results are consistent with an inhibiting effect of fluoride on deiodinase activity; these effects include decreased plasma T3 with normal or elevated T4 and TSH and normal T3 with elevated T4 (Bachinskii et al. 1985; Guan et al. 1988; Lin et al. 1991; Balabolkin et al. 1995; Michael et al. 1996; Mikhailets et al. 1996; Susheela et al. 2005). The antihyperthyroid effect that Galletti and Joyet (1958) observed in some patients is also consistent with an inhibition of deiodinase activity in those individuals.”

p 198 [p 235/236] “Subclinical hypothyroidism is considered a strong risk factor for later development of overt hypothyroidism (Weetman 1997; Helfand 2004). Biondi et al. (2002) associate subclinical thyroid dysfunction… with changes in cardiac function and corresponding increased risks of heart disease.… subclinical hypothyroidism is associated with increased cholesterol concentrations, increased incidence of depression, diminished response to standard psychiatric treatment, cognitive dysfunction, and, in pregnant women, decreased IQ of their offspring (Gold et al. 1981; Brucker-Davis et al. 2001).”

p 198 [p 236] “The possibility that either dental fluorosis (Chapter 4) or the delayed tooth eruption noted with high fluoride intake (Chapter 4; see also Short 1944) may be attributable at least in part to an effect of fluoride on thyroid function has not been studied.”

p 218 [p 263] “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”

Pineal gland and melatonin

p 214 [p 256] “fluoride is likely to cause decreased melatonin production and to have other effects on normal pineal function, which in turn could contribute to a variety of effects in humans”

Endocrine function (recommendations)

p 224 [p 267] “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 for investigation include the following:

– thyroid disease (especially in light of decreasing iodine intake by the U.S. population);

– nutritional (calcium-deficiency) rickets;

– pineal function (including, but not limited to, melatonin production); and

– development of glucose intolerance and diabetes.”

Hypersensitivity and immunity

p 230 [p 269] “The possibility that a small percentage of the population reacts systemically to fluoride, perhaps through changes in the immune system, cannot be ruled out (see section on the immune system later in this chapter).”

p 249 [p 293/294] “patients who live in either an artificially fluoridated community or a community where the drinking water naturally contains fluoride at 4 mg/L have all accumulated fluoride in their skeletal systems and potentially have very high fluoride concentrations in their bones (see Chapter 3). The bone marrow is where immune cells develop and that could affect humoral immunity and the production of antibodies to foreign chemicals. For example, Butler et al. (1990) showed that fluoride can be an adjuvant, causing an increase in the production of antibodies to an antigen and an increase in the size and cellularity of the Peyer’s patches and mesenteric lymph nodes.”

p 250 [p 295] “Fluoride also augments the inflammatory response to irritants.”

“There is no question that fluoride can affect the cells involved in providing immune responses.”

p 258 [p 303] “Epidemiologic studies should be carried out to determine whether there is a higher prevalence of hypersensitivity reactions in areas where there is elevated fluoride in the drinking water. If evidence is found, hypersensitive subjects could then be selected to test, by means of double-blinded randomized clinical trials, which fluoride chemicals can cause hypersensitivity.”


p 284 [p 334] “The combined literature described above does not clearly indicate that fluoride either is or is not carcinogenic in humans.”

Fluoride in Drinking Water: A Scientific Review of EPA’s Standards

(Free PDF via The National Academies Press)

Water. Text: FLUORIDE Are you pro-choice or pro-poisoning?