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according to NAS 2006

Fluoride occurs in drinking water primarily as free fluoride.


When ingested some fluorides combine with hydrogen ions to form hydrogen fluoride (HF), depending on the pH of the contents of the stomach (2.4% HF at pH 5; 96% HF at pH 2).


HF easily crosses the gastric epithelium, and is the major form in which fluoride is absorbed from the stomach (see Chapter 3).


Upon entering the interstitial fluid in the mucosa where the pH approaches neutrality, HF dissociates to release fluoride and hydrogen ions which can cause tissue damage.


Whether damage occurs depends on the concentrations of these ions in the tissue.


It appears that an HF concentration somewhere between 1.0 and 5.0 mmol/L (20 and 100 mg/L), applied to the stomach mucosa for at least 15 minutes, is the threshold for effects on the function and structure of the tissue (Whitford et al. 1997).


Reported GI symptoms, such as nausea, may not be accompanied by visible damage to the gastric mucosa. Thus, the threshold for adverse effects (discomfort) is likely to be lower than that proposed by Whitford et al.


This review is concerned primarily with the chronic ingestion of fluoride in drinking water containing fluoride at 2-4 mg/L.


Single high doses of ingested fluoride are known to elicit acute GI symptoms, such as nausea and vomiting, but whether chronic exposure to drinking water with fluoride at 4 mg/L can elicit the same symptoms has not been documented well.

The primary symptoms of GI injury are nausea, vomiting, and abdominal pain (see Table 9-1). Such symptoms have been reported in case studies (Waldbott 1956; Petraborg 1977) and in a clinical study involving double-blind tests on subjects drinking water artificially fluoridated at 1.0 mg/L (Grimbergen 1974).


In the clinical study, subjects were selected whose GI symptoms appeared with the consumption of fluoridated water and disappeared when they switched to nonfluoridated water.


A pharmacist prepared solutions of sodium fluoride (NaF) and sodium silicofluoride (Na2SiF6) so that the final fluoride ion concentrations were 1.0 mg/L.


Eight bottles of water were prepared with either fluoridated water or distilled water. Patients were instructed to use one bottle at a time for 2 weeks.


They were asked to record their symptoms throughout the study period. Neither patients nor the physician administering the water knew which water samples were fluoridated until after the experiments were completed.


The fluoridation chemicals added to the water at the time of the experiments were likely the best candidates to produce these symptoms.


Despite those well-documented case reports, the authors did not estimate what percentage of the population might have GI problems. The authors could have been examining a group of patients whose GI tracts were particularly hypersensitive.


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).

Perhaps it is safe to say that less than 1% of the population complains of GI symptoms after fluoridation is initiated (Feltman and Kosel 1961). The numerous fluoridation studies in the past failed to rigorously test for changes in GI symptoms and there are no studies on drinking water containing fluoride at 4 mg/L in which GI symptoms were carefully documented.


Nevertheless, there are reports of areas in the United States where the drinking water contains fluoride at concentrations greater than 4 mg/L and as much as 8 mg/L (Leone et al. 1955b).


Symptoms of GI distress or discomfort were not reported.


In the United Kingdom, where tea drinking is more common, people can consume up to 9 mg of fluoride a day (Jenkins 1991). GI symptoms were not reported in the tea drinkers. The absence of symptoms might be related to the hardness of the water, which is high in some areas of the United Kingdom. Jenkins (1991) reported finding unexpectedly high concentrations of fluoride (as high as 14 mg/L) in soft water compared with hard water when boiled.

In contrast, in India, where endemic fluorosis is well documented, severe GI symptoms are common (Gupta et al. 1992; Susheela et al. 1993; Dasarathy et al. 1996).


One cannot rule out the influence of poor nutrition (the absence of dietary calcium in the stomach) contributing to the GI upset from fluoride ingestion. Chronic ingestion of drinking water rich in fluoride on an empty stomach is more likely to elicit symptoms.

GI Symptoms Relating to the Concentration of Fluoride Intake

It is important to realize that GI effects depend more on the net concentration of the aqueous solution of fluoride in the stomach than on the total fluoride dose in the fluid or solid ingested. The presence of gastric fluids already in the stomach when the fluoride is ingested can affect the concentration of the fluoride to which the gut epithelium is exposed. The residual volume of stomach fluid ranges between 15 and 30 mL in people fasting overnight (Narchi et al. 1993; Naguib et al. 2001; Chang et al. 2004). Such volumes would decrease the fluoride concentration of a glass of drinking water by only about 10%. In Table 9-1, the concentrations of fluoride in the stomach were estimated from the mean reported fluoride exposures. A dilution factor was used when it was clear that the subjects already had fluid in their stomach. The results from the water fluoridation overfeed reports (concentrations of fluoride in the stomach between 20 and 250 mg/L) indicate that GI symptoms, such as nausea and vomiting, are common side effects from exposure to high concentrations of fluoride.

Fluoride supplements are still routinely used today in areas where natural fluoride in the drinking water falls below 0.7 mg/L. In an early clinical trial using fluoride supplements, Feltman and Kosel (1961) administered fluoride tablets containing 1.2 mg of fluoride or placebo tablets to pregnant mothers and children up to 9 years of age. They determined that about 1% of the subjects complained of GI symptoms from the fluoride ingredient in the test tablets. If it is assumed that the stomach fluid volume after taking the fluoride supplement was approximately 250 mL, the concentration to which the stomach mucosal lining was exposed was in the neighborhood of 5 mg/L. GI effects appear to have been rarely evaluated in the fluoride supplement studies that followed the early ones in the 1950s and 1960s. Table 9-1 suggests that, as the fluoride concentration increases in drinking water, the percentage of the population with GI symptoms also increases. The table suggests that fluoride at 4 mg/L in the drinking water results in approximately 1% of the population experiencing GI symptoms (see Feltman and Kosel 1961).

Chronic Moderate Dose Ingestion of Fluoride

It is clear from the fluoride and osteoporosis clinical trial literature (also see Chapter 5) that gastric side effects were common in these studies (e.g.

Mamelle et al. 1988; Hodsman and Drost 1989; Kleerekoper and Mendlovic 1993). Slow-release fluorides and calcium supplementation helped to reduce GI side effects (Kleerekoper and Mendlovic 1993; Das et al. 1994; Haguenauer et al. 2000). In areas of endemic fluorosis, such as parts of India, most subjects suffer from GI damage and adverse GI symptoms (Gupta et al. 1992; Susheela et al. 1993; Dasarathy et al. 1996). In one study (Susheela et al. 1993), every fourth person exposed to fluoride in drinking water (<1 to 8 mg/L) reported adverse GI symptoms. The results from these studies cannot be compared with the water fluoridation studies summarized in Table 9-1, because in the osteoporosis trials fluoride was nearly always administered as enteric coated tablets along with calcium supplements and the nutrition status of populations in endemic fluorosis areas is different from that in the United States.

Fluoride Injury Mechanisms in the GI Tract

Because 1% of the population is likely to experience GI symptoms, and GI symptoms are common in areas of endemic fluorosis, especially where there is poor nutrition (Gupta et al. 1992; Susheela et al. 1993; Dasarathy et al. 1996), it is important to understand the biological and physiological pathways for the effects of fluoride on the GI system. Those mechanisms have been investigated in many animal studies. In those studies, the concentrations of fluoride used were generally 100- to 1,000-fold higher than what occurs in the serum of subjects drinking fluoridated water. Although some tissues encounter enormous elevations in fluoride concentrations relative to the serum (e.g., kidney, bone), it is unlikely that the gut epithelium would be exposed to millimolar concentrations of fluoride unless there has been ingestion of large doses of fluoride from acute fluoride poisoning. During the ingestion of a large acute dose of fluoride such as fluoride-rich oral care products, contaminated drinking water during fluoridation accidents, and fluoride drugs for the treatment of osteoporosis, the consumption of large amounts of drinking water containing fluoride at 4 mg/L would serve only to aggravate the GI symptoms. Animal studies (see Table 9-2) have provided some important information on the mechanisms involved in GI toxicity from fluoride. Fluoride can stimulate secretion of acid in the stomach (Assem and Wan 1982; Shayiq et al. 1984), reduce blood flow away from the stomach lining, dilate blood vessels, increase redness of the stomach lining (Fujii and Tamura 1989; Whitford et al. 1997), and cause cell death and desquamation of the GI tract epithelium (Easmann et al. 1984; Pashley et al. 1984; Susheela and Das 1988; Kertesz et al. 1989; NTP 1990; Shashi 2002).

Because fluoride is a known inhibitor of several metabolic intracellular enzymes, it is not surprising that, at very high exposures, there is cell death and desquamation of the GI gut epithelium wall. The mechanisms involved in altering secretion remain unknown but are likely the result of fluoride’s ability to activate guanine nucleotide regulatory proteins (G proteins) (Nakano et al. 1990; Eto et al. 1996; Myers et al. 1997). Whether fluoride activates G proteins in the gut epithelium at very low doses (e.g., from fluoridated water at 4.0 mg/L) and has significant effects on the gut cell chemistry must be examined in biochemical studies.

National Academies of Science Report 2006 Chapter 9

Can J Physiol Pharmacol. 2005 Apr;83(4):367-73.

Effects of sodium fluoride on the mechanical activity in mouse gastric preparations.

Amira S1, Mulè F.

Author information 


The aim of the present study was to investigate the responses induced by sodium fluoride (NaF) on gastric mechanical activity, using mouse whole-stomach preparations.


The mechanical activity was recorded in vitro as changes of intraluminal pressure.


In most of the preparations, NaF induced a tetrodotoxin-insensitive biphasic effect characterized by early relaxation followed by slowly developing contractile response.


The contraction was dependent on the concentration of NaF, whereas the relaxation was observed at only 10-30 mmol/L NaF.


The contractile effect was significantly reduced by nifedipine (an L-type Ca(2+) channel blocker), ryanodine or ruthenium red (inhibitors of Ca(2+) release from sarcoplasmic reticulum), and GF109203X (a protein kinase C inhibitor).


Moreover, it was abolished by neomycin (an inhibitor of phospholipase C) and potentiated by SQ22536 (an inhibitor of adenylyl cyclase).


All the drugs significantly increased the relaxation, except SQ22536, which abolished it.


The present results suggest that NaF causes a complex mechanical response in the whole-stomach, which might explain gastric discomfort after fluoride



The relaxation appears owing to production of cAMP, while the contractile effects imply activation of phospholipase C, protein kinase C, influx of Ca(2+), and release of Ca(2+) from ryanodine-sensitive intracellular store.

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