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OTHER DOCUMENTED ADVERSE HEALTH EFFECTS FROM FLUORIDE

Fluoridation's adverse health effects are not recognised by most physicians but they are documented in blind and double-blind studies. Allergy, Hypersensitivity, gastrointestinal and skin irritation are known side effects of fluoride ingestion. The toxicity of fluoride is increased in people with inadequate nutrition (sub-standard vitamin-mineral intake) or who are immune-compromised (eg., diabetics, renal disease, etc)

Contraindications and Side Effects of Sodium Fluoride (NaF) supplements

Animal & Human studies
  • Banu Priya CAY, et al., Toxicity of Fluoride to Diabetic Rats, Fluoride, 1997, 30:1
  • Baykov AA, et al., A two-step mechanism of fluoride inhibition of rat liver inorganic pyrophosphatase, Arch Biochem Biophys, 1992, 294:1
  • Eckerlin RH et al., Milk production of cows fed fluoride contaminated commercial feed. Cornell Vet 1986 Oct;76(4):403-14
  • Gibson S, Effects of fluoride on immune system function, Complimentary Med. Res, 1992, 6:3
  • Boros I, et al., Fluoride intake, distribution, and bone content in diabetic rats consuming fluoridated drinking water, Fluoride, 1998, 31:1
  • Chen GL, Experimental study of antagonizing effect of calcium and magnesium against fluoride toxicity in collagen, Chung Hua Yu Fang I Hsueh Tsa Chih, 1992, 26:2
  • Gupta IP, et al., Fluoride as a Possible Etiological Factor in Non-Ulcer Dyspepsia, J. of Gastroenterology and Hepatology, 1992, 7, 355-356
  • Kumari DS, Rao PR, Red cell membrane alterations in human chronic fluoride toxicity, Biochem Int, 23:4, 1991
  • Lantz O, et al., Fluoride-induced chronic renal failure, Am J Kidney Dis, 1987, 10:2
  • Muller P, et al., Sodium fluoride-induced gastric mucosal lesions: comparison with sodium monofluorophosphate, Gastroenterol, 1992 April, 30:4
  • Pillai KS, et al., Effect of subacute dosage of fluoride on male mice, Toxicol Lett, 1988, 44:1-2
  • Li R, et al., Fluoride in Drinking Water and Intracardiac Blood Flow Defects in Iowa, Am. J. of Epidem, 1992 Oct, 136, 1030
  • Shea JJ, et al., Allergy to Fluoride, Annals of Allergy, 1967, 25
  • Shen N, et al., Relationship between height, collagen metabolism, hair zinc and excessive fluoride intake, Hua Hsi I Ko Ta Hsueh Hsueh Pao, 1992, 23:1
  • Sjostrom S, Kalfas S,Tissue necrosis after subgingival irrigation with fluoride solution, J of Clinical Periodontology
  • Spittle B, Allergy and Hypersensitivity To Fluoride, Fluoride, 1993, 26:4
  • Strunecká A, Patočka J, Pharmacological implications of aluminofluoride complexes, A review of the evidence for pathophysiological effects of aluminium and fluoride on living organism.
  • Susheela AK, et al., Fluoride ingestion and its correlation with gastrointestinal discomfort, Fluoride, 1992, 25:l
  • Waldbott GL, The Preskeletal Phase of Chronic Fluoride Intoxication, Fluoride, 1998, 31:1
  • Whitford GM, Pashley DH, Garman RH, Effects of fluoride on structure and function of canine gastric mucosa, Dig Dis Sci, 1997, 42(10)

    Banu Priya CAY, Anitha K, Murali Mohan E, Pillai KS, Murthy PB, Toxicity of Fluoride to Diabetic Rats, Fluoride, 1997 Feb, 30:1, 43-50

    Wistar rats were given 20 ppm fluoride in drinking water, or single administration of 115 mg/kg alloxan i.m. to induce diabetes, or single administration of 115 mg/kg alloxan i.m. followed by 20 ppm fluoride for 31 days. Blood sugar level increased in rats given alloxan and alloxan + fluoride. Body weight gain in rats given alloxan + fluoride decreased significantly compared to other groups. Decrease in haemoglobin and glutamic oxaloacetate transaminase (GOT) was seen only in rats given alloxan + fluoride. In this group alkaline phosphatase, the target enzyme in fluoride toxicosis, increased considerably. The toxicity of fluoride in diabetic rats was further reflected in organ weight data. This investigation shows that fluoride toxicity is greater in diabetic rats.

    Baykov AA, Alexandrov AP, Smirnova IN, A two-step mechanism of fluoride inhibition of rat liver inorganic pyrophosphatase, Arch Biochem Biophys, 1992 Apr, 294:1, 238-43

    Product formation curves for inorganic pyrophosphatase-catalyzed hydrolysis of pyrophosphate in the presence of fluoride were analyzed in order to get insight into the mechanism of its inhibitory action on this enzyme. The enzymatic reaction was monitored with a phosphate analyzer operating on the time scale of seconds. Inhibition patterns were virtually identical for cytosolic and mitochondrial pyrophosphatases. The effect of fluoride was biphasic: it caused a rapid (t1/2 less than 1 s) decrease in the initial velocity of the reaction followed by slow (t 1/2 greater than or equal to 4 s) inactivation of the enzyme during catalysis. The slow phase resulted in trapping intact substrate at the active site, and the resulting complex could be isolated by gel filtration. Pyrophosphatase remained active when incubated with fluoride in the absence of pyrophosphate or in the presence of its bisphosphonate analogs, which are bound to but not hydrolyzed by this enzyme. These features of the inhibition are consistent with the mechanism in which rapid binding of the inhibitor to the enzyme.substrate complex is followed by its slow isomerization. Kinetic parameters obtained in this work indicate that appreciable inactivation of pyrophosphatase can occur at fluoride concentrations found in human plasma. This effect may therefore be one of the major factors contributing to fluoride toxicity.

    Boros I, Keszler P, Csikós G and Kalász H, Fluoride intake, distribution, and bone content in diabetic rats consuming fluoridated drinking water, Fluoride, 1998, 31:1, 33-41

    SUMMARY: The aim of this study was to determine how metabolic and functional changes in diabetes affect the fluoride intake, distribution, and concentration in bone tissue; and whether alterations in fluoride metabolism in diabetes may influence the severity of the disorder. Two groups of rats received 0 (D) or 10 ppm (DF10) fluoride via drinking water for three weeks, ad libitum. Two other groups were treated with a single dose of streptozotocin to induce diabetes, and also received 0 (D) or 10 ppm fluoride (DF10). The quantity of fluoride consumed via water by the DF10 animals was calculated daily and an equal amount was added to the drinking water of another group of non-diabetic animals (FF).

    In the diabetic group (DF10) the intake of fluoride gradually increased, hyperglycemia was more severe, and renal hypertrophy was expressed less than in the diabetic group (D) which consumed deionized water. The femoral fluoride concentration increased in proportion to fluoride intake. The high fluoride intake of FF animals resulted, when compared to DF10 ones, in a further increase in the bone tissue and in relatively less elevation in plasma fluoride concentrations. It is concluded that (i) fluoride supply via drinking water may enhance the severity of diabetes in rats, and (ii) due to diabetic metabolic and functional imbalance, the fluoride metabolism may also change.

    Chen GL, Experimental study of antagonizing effect of calcium and magnesium against fluoride toxicity in collagen, Chung Hua Yu Fang I Hsueh Tsa Chih, 1992 Mar, 26(2), 80-82 (Article in Chinese)

    SD rats were given fluoride 20 mg/kg for 14 days through a gastrointestinal tube, body weight growth depressed obviously, the ratio of the Liver and Kidney weight to body weight increased significantly, hemoglobin concentration dropped and morphology and metabolism of collagen all became abnormal. All these effects can be antagonised by giving calcium (100 mg/kg), magnesium (100 mg/kg) or calcium and magnesium combined (50 mg/kg each). When Ca and Mg is given combined, the antagonizing effect is even better.

    Eckerlin RH, Maylin GA, Krook L, Milk production of cows fed fluoride contaminated commercial feed. Cornell Vet 1986 Oct;76(4):403-14

    A commercial feed concentrate and a mineral mix with excessive amounts of fluoride were introduced into a Holstein dairy herd with an average milk production well above national standards. Milk production decreased drastically, and during the following 6 years the deficit in milk production in the herd ranging from 52 to 120 milking cows was 1.5 million Kg (3 1/4 million lbs.). The tolerance levels set by the National Academy of Sciences for fluoride ingestion by lactating cow were found to be inadequate.

    Kumari DS, Rao PR, Red cell membrane alterations in human chronic fluoride toxicity, Biochem Int, 23:4, 1991 Mar, 639-48

    Red cells from humans exposed chronically to toxic levels of fluoride through drinking water showed significant increase in lipid peroxidation and membranous cholesterol and phospholipids. Additionally, electrophoretic patterns of ghost membrane proteins revealed the presence of a new band in the range of congruent to 66 Kd and increase in the high molecular weight protein and predominance of bands with a molecular weight of congruent to 93 Kd and congruent to 20 Kd. The activities of total, Na(+)-K(+)-, Mg(2+)- and Ca(2+)-ATPases were significantly decreased in the red cell ghosts of fluorotic patients.

    Lantz O, Jouvin MH, De Vernejoul MC, Druet P, Fluoride-induced chronic renal failure, Am J Kidney Dis, 1987 Aug, 10:2, 136-9

    Renal fluoride toxicity in human beings is difficult to assess in the literature. Although experimental studies and research on methoxyflurane toxicity have shown frank renal damage, observations of renal insufficiency related to chronic fluoride exposure are scarce. We report a case of fluoride intoxication related to potomania of Vichy water, a highly mineralized water containing 8.5 mg/L of fluoride. Features of fluoride osteosclerosis were prominent and end-stage renal failure was present. The young age of the patient, the long duration of high fluoride intake, and the absence of other cause of renal insufficiency suggest a causal relationship between fluoride intoxication and renal failure.

    Muller P, Schmid K, Warnecke G, Setniker I, Simon B, Sodium fluoride-induced gastric mucosal lesions: comparison with sodium monofluorophosphate, Gastroenterol, 1992 April, 30:4 252-4

    In a randomized double-blind study with two parallel groups of 10 male healthy volunteers each the response of gastric mucosa after a 7 days ingestion of sodium fluoride tablets (NaF) or sodium monofluorophosphate tablets (MFP) was compared. Gastroscopic evaluations were preformed before treatment, day 1 and day 7. Simultaneously blood samples were collected for determination of laboratory data and serum fluoride values. In the MFP-group no severe gastric lesions were observed, whereas in the NaF-group in 7 of the 10 subjects significant gastric mucosal lesions including acute hemorrhages and free blood in the gastric lumen were found. The differences of the lesions scores in both groups were statistically significant (p = 0.0015). The serum fluoride content was comparable in both treatment groups. Possible adverse drug reactions were reported in 4 subjects with NaF and in 1 subject with MFP. In summary, under the experimental conditions used MFP is well tolerated by the stomach while NaF produces significant gastric mucosal lesions.

    Pillai KS, Mathai AT, Deshmukh PB, Effect of subacute dosage of fluoride on male mice, Toxicol Lett, 1988 Nov, 44:1-2, 21-9

    A sublethal concentration (one-tenth of the LD50) of fluoride (F) (5.2 mg F/kg body weight) was administered to Swiss albino mice (male) daily for 35 days. These mice showed a decrease in body weight gain, and food and water consumption. A significant decrease in red blood cell counts and an increase in white blood cell counts were seen in fluoride-administered mice. These animals also showed a decline in albumin, total protein, cholesterol, glucose and alkaline phosphatase activity in the serum. The fluoride content significantly increased in different organs of these animals. Sperm did not show any abnormalities due to fluoride toxicity in this specific instance

    [editor's note: recently, the 5.2 mg F/kg body weight has been classified as the "Probably Toxic Dose" (PTD) for Humans]

    Shea JJ, Gillespie SM, Waldbott GL, Allergy to Fluoride, Annals of Allergy, 1967 July, 25, 388- 391

    [Abstract -- Six children and one adult exhibited various allergic reactions after the use of toothpaste and vitamin preparations containing fluoride. The following conditions were encountered: Urticaria, exfoliative dermatitis, atopic dermatitis, stomatitis, gastro-intestinal and respiratory allergy.]

    The literature contains little information concerning allergic reactions to the fluorine ion. Indeed some have questioned the possibility that fluoride in such a small amount as is present in vitamin tablets, toothpastes or water could act as a sensitizer. Two other halogens, iodine and bromine are recognized as sources of allergic manifestations.

    Feltman and Kosel1 noted atopic dermatitis, urticaria, epigastric distress, emesis and headache in one per cent of 672 pregnant women and children to whom they had administered fluoride tablets as a prevention of dental caries. Waldbott reported urticaria2 and dermatitis3 due to fluoride in drinking water. The causal relationship of these diseases to fluoride was established by blind and double blind tests. Epstein4 encountered a case of general dermatitis in one out of 20 patients with acne to whom he administered, on an experimental basis, 1 mg of fluoride per day for one to eleven weeks.

    Douglas presented an account of stomatitis in 133 cases due to fluoride-containing dentifrices. The patients' ages ranged from 2½ to 92 years. His series included a family of six and another of four, every member of which was adversely affected by fluoride toothpaste. Several of these patients had gastro-intestinal disturbances. The ulcers in the mouth were refractory to antibiotic therapy and to local medication, but cleared up promptly when nonfluoride toothpaste was substituted for the fluoride toothpaste. In 32 patients Douglas reproduced the stomatitis by reapplying the dentifrice, in some cases as often as six times. [case reports omitted]

    Comment
    [...] Of special interest are the gastro-intestinal manifestations in five of the seven children, particularly the presence of blood in stool in three of the cases. Gastric hemorrhages are a major feature in acute fluoride intoxication8 and gastro-intestinal disturbances such as gastritis and spastic bowels, have been reported by Fradà and Mentesana9 in about one half of their 62 cases of hydrofluorosis. Gastric symptoms must be anticipated especially in subjects who have hyperacidity of the stomach. When inorganic fluoride compounds combine with gastric HCl, hydrofluoric acid (HF) is formed which exerts an irritating action upon the mucosa of the stomach and the upper gastro-intestinal tract.10 [...references not scanned]

    Shen N, Li X, Wei S, Relationship between height, collagen metabolism, hair zinc and excessive fluoride intake, Hua Hsi I Ko Ta Hsueh Hsueh Pao, 1992 Mar, 23(1), 83-86 (Article in Chinese)

    After eliminating confounding factors, the study was made on the relationship between height, collagen metabolism, hair zinc and excessive fluoride intake. 140 schoolchildren aged 12-13 years born and reared in endemic fluorosis areas were surveyed. The results were as follows: 1. The average height of children with dental fluorosis III degree (DF III degree) was appreciably smaller than that of children without dental fluorosis. Among children with excessive fluoride intake, a negative correlation between the height and fluoride level in staple foods was seen. 2. The more the fluoride ingested, the higher the urinary THP excreted, showing that fluoride intoxication interfered with the collagen metabolism. 3. Among children with excessive fluoride intake, the height showed negative correlation with urinary THP/Cr, suggesting that the effect of fluoride on collagen metabolism indicated the mechanism of height retardation. 4. As compared to control group with the excessive fluoride intake but without dental fluorosis group, there was a significant reduction in hair zinc in group with DF III degree, suggesting that the zinc in the body decreased because of zinc metabolism disturbance by excessive fluoride intake. But among cases with excessive fluoride intake, no appreciable correlation between hair zinc and height was found. Therefore, it could not be confirmed that the effect of fluoride on zinc metabolism affected the height development.

    [editor's note: collagen is a major structural component of skin, ligaments, tendons, muscles, cartilage, bones and teeth]

    Sjostrom S, Kalfas S, Tissue necrosis after subgingival irrigation with fluoride solution, J of Clinical Periodontology 26(4):257-260, 1999

    Irrigation of periodontal pockets with fluoride solution after scaling and root planing is occasionally recommended to inhibit the growth of pathogenic bacteria in the periodontal pocket. At the same time, irrigation enables mechanical removal of loosely adhering plaque and debris. Due to its toxicity, fluoride solution deposited in the periodontium may lead to tissue damage. We report in this paper, a case of extensive periodontal tissue necrosis and permanent loss of alveolar bone after irriga-tion of periodontal pockets with stannous fluoride solution. The literature on the toxic effects of fluo-ride on the local tissues is briefly reviewed and arguments for a re-evaluation of the use of stannous fluoride for pocket irrigation are provided. [References: 27]
    Reprint Sjostrom S, Umea Univ, Sch Dent, Dept Oral Biol S-90185 Umea Sweden

    Spittle B, Allergy and Hypersensitivity to Fluoride, Fluoride, 1993, 26:4, 267-273

    A review of the literature was undertaken in response to four recent reviews which found that the evidence that fluoride was an allergen was unconvincing. Reports were found of urticaria, contact dermatitis and stomatitis occurring in response to fluoride, settling on the withdrawal of fluoride and recurring with appropriate challenges. It is concluded that the four reviews were seriously incomplete in their coverage of the literature, and that when a more complete examination is made there are reasonable grounds for concluding that there are individuals in whom allergy or hypersensitivity to fluoride has been demonstrated. The sources of fluoride included those used in the fluoridation of community water supplies

    A review of the literature was undertaken in response to four recent reviews which found that the evidence that fluoride was an allergen was unconvincing. Reports were found of urticaria, contact dermatitis and stomatitis occurring in response to fluoride, settling on the withdrawal of fluoride and recurring with appropriate challenges. It is concluded that the four reviews were seriously incomplete in their coverage of the literature, and that when a more complete examination is made there are reasonable grounds for concluding that there are individuals in whom allergy or hypersensitivity to fluoride has been demonstrated. The sources of fluoride included those used in the fluoridation of community water supplies.

    Introduction
    Four recent reviews, from the United States of America (1,2), Australia (3) and New Zealand (4), have concluded that claims that fluoride is an allergen could not be supported from studies undertaken to date, and that the weight of evidence shows that fluoride is unlikely to produce hypersensitivity and other immunological effects. Although the two US subcommittees involved were different, the sections dealing with the effects of fluoride on hypersensitivity and the immune system are almost the same. Thus although all four reports reached a similar conclusion that fluoride was unlikely to produce allergic or hypersensitivity effects, the 1993 reports (2,4) refer to those published in 1991 (1,3) and are not completely independent. The present review was undertaken to see if the same conclusion was reached.

    Literature Review
    In dismissing the occurrence of allergic reactions to fluoride, the New Zealand report (4) refers to the earlier United States (1) and Australian (3) reviews both of which in turn cite a statement by Austen et al (5) on behalf of the American Academy of Allergy. The Academy reviewed reports of fluoride allergy and found no evidence of allergy or intolerance to fluorides as used in the fluoridation of community water supplies (5).

    Waldbott made a rebuttal of the findings of Austen et al in 1971 (6) and noted that in 1978 this was still unrefuted (7). He observed that the statement by Austen et al cited only seven references, of which only five referred to fluoride (6). He commented that the committee had referred to a book of his, A Struggle with Titans (8), which was written for lay persons, but had apparently not given attention to 19 articles of his in scientific journals (6).

    Austen et al conclude that in the review of the cases reported there was insufficient evidence to state that true syndromes of fluoride allergy or intolerance existed (5). This included the cases reported by Feltman and Kosel (9). They had reported that l% of their cases reacted adversely to fluoride tablets (9). Atopic dermatitis and urticaria occurred with the use of fluoride tablets, disappeared with the use of placebo tablets, and recurred when the fluoride tablets were, unknowingly to the patient, given again (9). Kaplan (10) notes that when an urticarial drug reaction is suspected, this diagnosis may be tested by eliminating the agent. If it is correct, gradual resolution of the urticaria is anticipated. He notes that all medications should be considered a potential cause of urticaria. Except for penicillin, it is stated that no routine tests are available that can reliably confirm or refute the diagnosis of drug-induced urticaria or angioedema, and an empirical approach is therefore indicated (10). The empirical approach adopted by Feltman and Kosel of withdrawal of the fluoride tablets, substitution with placebo tablets and later a blind challenge with fluoride tablets (9) appears to be in keeping with the guidelines of Kaplan (10). Contrary to the view of Austen ct al, the results suggest that there is clinical evidence that a syndrome of fluoride allergy exists.

    Another paper reviewed by Austen et al, by Shea, Gillespie and Waldbott (11), reported allergy to fluoride in toothpaste and drops. In one case, involving a 48-year-old man with giant urticaria, double-blind testing was used to confirm the etiologic relationship with fluoride (11). The lesions had involved mainly the hands and feet but sometimes the entire body surface. They usually occurred about one hour after breakfast. He had been using a fluoridated toothpaste at the time. Six days after discontinuing this he was completely free of symptoms. Three years later he experienced another episode of generalized urticaria. This occurred within an hour of his inadvertently brushing his teeth with a fluoridated toothpaste. The double-blind testing involved taking a tablespoonful of water each morning from three bottles labelled 1, 2 and 3 with each bottle being used in turn for a week at a time. Bottle 2 contained 1 mg of fluoride per tablespoonful, this code being known only by the pharmacist who prepared the bottles. On the fourth day on bottle 2 he developed generalized pruritis and oedema in the distal joints of his extremities. Nevertheless he continued taking the water from bottle 2 for another three days during which time he developed hives on the right elbow and pains in the lumbo-sacral area followed by an outbreak of generalized urticaria. These symptoms disappeared 2 days after the patient discontinued the use of bottle 2 (11).

    In a second case the aetiological role of fluoride was confirmed using a patch test (11). The patient, a 9-year-old female, had frequent urticaria, allergic conjunctivitis and minor asthmatic attacks. There had been constant episodes of ulcers distributed throughout the oral cavity. Slight abdominal tenderness was present. A fluoridated toothpaste had been used since the onset of the oral lesions. A patch test gave a two plus reaction to the fluoride toothpaste but not to chewing gum, Lifesavers, or a non-fluoride toothpaste. During the development of the positive patch test reaction the patient experienced a flare-up of the oral lesions associated with severe abdominal pain. After changing to a non-fluoride toothpaste the oral lesions as well as the abdominal pains subsided completely. One year later a recurrence of the stomatitis occurred within 15 minutes of inadvertently brushing her teeth with a fluoridated toothpaste. Severe abdominal pain also occurred (11). Again in this case the guidelines of Kaplan (10) appear to have been followed and indicate that there is clinical evidence to show that a syndrome of fluoride allergy exists. Although the above cases refer to the use of fluoride tablets and toothpaste in contrast to the mention in the statement by Austen et al of fluorides as used in the fluoridation of community water supplies, this qualification is not mentioned earlier in the article by Austen et al (5). There it is stated that there is not sufficient clinical evidence to state that a true syndrome of fluoride allergy exists (5).

    Urticaria is characterized by the appearance of pruritic, erythematous, cutaneous elevations that blanch with pressure, indicating the presence of dilated blood vessels and oedema (10). Urticaria, both local and generalized, was described with acute sodium fluoride poisoning by Lidbeck, Hill and Beeman (13). In 1959 Waldbott described six cases of urticaria due to fluoridated water (13). In one case, Mrs PO aged 40 years, the relation of the urticaria to fluoride in water was substantiated by a double-blind test (14). The patient was required to take a tablespoonful of water daily from three bottles labelled 1, 2 and 3, using each for a week at a time. One bottle contained 1 mg of fluoride per tablespoonful but neither the patient nor her attending physician knew which one it was. The urticaria reappeared on the third day of using the fluoride solution. Another patient, Mrs HP aged 48 years, had generalized urticaria which began three weeks after moving to a fluoridated area. On using water with a low amount of fluoride in hospital (0.1 ppm) the urticaria subsided. Within 24 hours of resuming using fluoridated water the urticaria recurred. An intradermal skin test with a 1:100 dilution of a 1% aqueous solution of sodium fluoride gave a 3-plus wheal reaction. This was followed by a generalized outbreak of urticaria within ten minutes. Control tests with a 1% solution of sodium bromide and sodium iodide were negative. With double-blind testing involving three bottles of water only one of which contained fluoride, urticaria recurred within two days of taking the water from the fluoride-containing bottle (14).

    Contact dermatitis is a term used to describe any rash resulting from a substance touching the skin and as a synonym for allergic contact dermatitis (15). Allergic contact dermatitis is the result of a substance contacting skin that has undergone an acquired specific alteration in its reactivity (l5). This altered reactivity is the result of prior exposure of the skin to the material eliciting the dermatitis or a chemically closely related substance (15). The patch test, whereby the suspected substance is applied to the skin under an occlusive dressing for one to two days and the test site observed after removal, remains the only practical test for demonstrating contact dermatitis (15). In 1948 Abelson reported a typical contact dermatitis with vesiculo-papular pruritic lesions on the hand of a dentist occurring immediately upon application of a 2% solution of sodium fluoride to a patient's teeth (16). Waldbott reports observing repeatedly the same pattern of dermatitis in dentists with confirmation by patch testing (17). Waldbott (14) also described a scaly erythematous pruritic lesion on the thighs of a woman aged 20 years which subsided after moving for observation to a nonfluoridated area. After she had been symptom-free the dermatitis recurred at the same site with papulous, vesicular lesions and intense pruritis within an hour of receiving a test dose of 6.8 mg of fluoride in 300 ml of water. A placebo test with 300 ml of distilled water produced no ill effect (14).

    Aphthous stomatitis and ulcers of the mouth have been described as being not uncommon in persons using fluoride toothpaste and in children who have had topical fluoride applications applied to their teeth (14). Douglas (18) has described 133 cases of stomatitis from fluoride containing toothpaste. All the lesions were refractory to antibiotic therapy and local medication. The lesions cleared up with changing to a nonfluoride toothpaste. In 32 patients the stomatitis was reproduced by applying the fluoride toothpaste, in some as often as six times (18). Waldbott (14) records the case of Mrs LCH aged 62 years who developed a mouth ulcer within three days of starting the use of a fluoride toothpaste. Elimination of the fluoride toothpaste caused the condition to gradually disappear. Application of a saline solution with a cotton swab beneath her tongue produced no ill effect. When a 1% aqueous solution of sodium fluoride was applied, there developed, within five minutes, a hyperaemic oedematous intensely pruritic lesion in the test area which extended into a large portion of the oral mucosa. A smear of the mucus from the area showed marked eosinophilia (14).

    Waldbott (19) also reported the case of Mrs WEA aged 62 years who developed the allergic symptoms of rhinitis, allergic sinus disease and urticaria within hours of using fluoridated water with an intake of 1 to 2 mg a day. A typical allergic appearance of the nasal mucosa eosinophilia and an allergic wheal followed the intradermal injection of 0.1 mg of sodium fluoride. Control injections with horse serum, saline solution and weaker aqueous dilutions of sodium fluoride had no adverse effect (19). Zanfagna (20) has reported on Mrs MET aged 48 years who developed acute generalized urticaria after drinking fluoridated water. A further attack was also traced to fluoridated water. It was stated that sensitivity to fluoride was confirmed by positive challenge tests (20).

    Discussion
    Currently allergy is considered to be synonymous with hypersensitivity in meaning (21). They usually refer to type 1 immediate hypersensitivity, mediated by specific IgE antibodies in genetically predisposed individuals and resulting in symptoms characteristic of eczema, urticaria, rhinitis, asthma and anaphylaxis, although it is noted that several types of allergic states encompass all the mechanisms described by Gell and Coombs (21).

    Waldbott (14) saw a difference between reactions to fluoride due to the toxic action of the fluoride ion and allergic sensitivity. He pointed out that the degree of tissue damage from the toxic action of the fluoride ion has been seen to depend on numerous factors including the dose of the fluoride ion, the duration of the contact with the involved tissue, the pH of the intracellular and extracellular fluids, and the presence of calcium, magnesium and other metals. When in contact with fluids in an acid medium such as gastric juice, fluoride compounds tend to induce undissociated hydrofluoric acid which has a corrosive action. True allergic reactions, on the other hand, can result from relatively insignificant doses and from short exposures. The presence of such allergic symptoms as urticaria, vasomotor rhinitis, dermatitis and eosinophilia, a prompt response to adrenaline, and occasionally positive skin and patch test reactions, point to allergy (l4). As an example of the difference between allergy or hypersensitivity to a drug and intolerance to it, reactions to aspirin can be considered (7). Intolerance to aspirin is characterized by hemorrhages in the stomach whereas allergy to aspirin results in such symptoms as hives, asthma, allergic nasal and sinus disease or even anaphylactic shock (7).

    To establish the existence of allergy to fluoride, community studies which are prone to the ecological fallacy (22) are insufficient and stronger evidence based on the studies of individuals is required. Although in the above discussion reference is made to cases of allergy related to fluoride tablets and toothpaste, there are included cases (Mrs PO, Mrs HP, Mrs WEA, Mrs MET) in which the reaction of allergy has been to fluorides as used in the fluoridation of community water supplies.

    Although Waldbott found that allergic reactions to fluoride could occur, it was not considered that this was the only mechanism whereby adverse reactions to fluoride were experienced (7). Intolerance to fluoride was seen to occur for example through the formation of corrosive undissociated hydrofluoric acid when fluoride ions were in contact with acidic gastric secretions.

    This potential mechanism for fluoride damaging the gastroduodenal mucosa has been supported by Susheela et al (23) along with other potential mechanisms such as enzyme system inhibition. By studying patients intensively, including by endoscopy and biopsy for histopathological and scanning electron microscope examination, they found that the gastroduodenal mucosa could be severely damaged by the toxic effects of fluoride resulting in dyspeptic symptoms. The changes found included surface abrasions with loss of microvilli in the gastric antrum and duodenum, and a 'cracked-clay' appearance of the duodenal mucosa. Gastrointestinal discomfort, in the form of dyspeptic symptoms was thus seen to be an important diagnostic feature in identifying persons affected by fluoride and it was considered that such symptoms should not be dismissed as non-specific (23).

    Moolenburgh (24) described abdominal discomfort occurring on a double-blind basis with exposure to fluoride. He found in his Dutch general practice patients with illnesses similar to those described by Waldbott. He considered that far from having exaggerated the side-effects, Waldbott had, on the contrary, been inclined to under-statement. Although Moolenburgh expected to find an allergic basis for the adverse effects associated with fluoride, he considered that the symptoms represented poisoning with inhibition of the immune system by a toxic substance in sensitive persons. Where an exacerbation of illnesses with an allergic component such as eczema and asthma occurred, his view was that immune system inhibition by fluoride had resulted in a loss of the ability to cope with the allergy (24). The work by Moolenburgh and his colleagues has been described by Grimbergen (25). By double-blind testing with 60 patients he showed that certain individuals were intolerant to fluoride and that exposure to this could reproduce gastrointestinal symptoms, stomatitis, joint pains, polydipsia, headaches and visual disturbances. Grimbergen noted that Young had found that intracutaneous injections of sodium fluoride gave positive reactions in four persons with urticaria associated with the use of fluoridated water but no such reactions in four persons without urticaria (25).

    Petraborg (26, 27) similarly described a wide spectrum of symptoms in 27 persons exposed to fluoridated water. He considered that since none of the persons were aware that their drinking water was fluoridated or were familiar with the manifestations of fluoride toxicity, that the accounts of their illnesses were equivalent in validity to those associated with double-blind procedures. He noted that several patients were not convinced that something in their drinking water was causing their illness and resumed drinking fluoridated water. Relapses of their illnesses followed. The symptoms included extreme chronic fatigue, polydipsia, general pruritis, headaches and gastrointestinal symptoms (26,27).

    Another adverse effect of fluoride, described by Lee (28), involved an elevation of the serum bilirubin level in six patients with Gilbert's disease. Long-term testing and studying the effect of fluoride tablets in one patient gave evidence that the hyperbilirubinaemia was due solely to fluoride and not to some other ingredient of the water supply. An enzyme-inhibiting action by fluoride was considered to be the most likely mechanism involved (28).

    It is concluded, on the basis of the above examination, that the recent North American, Australian and New Zealand reviews (1-4) were seriously incomplete in their coverage of the literature. There are some individuals in whom allergy or hypersensitivity to fluoride has been demonstrated by appropriate challenge tests. This is seen to be just one of a number of mechanisms whereby adverse reactions to fluoride occur. It is considered that intolerance to fluoride may also follow the formation of corrosive hydrofluoric acid or through enzyme inhibition.

    Dr. Spittle is with the Dept of Psychological Medicine, School of Medicine, University of Otago, Dunedin, NZ.

    References

    • 1 Subcommittee on fluoride of the committee to coordinate environmental health and related programs Review of Fluoride Benefits and Risks. Department of Health and Human Services, Public Health
    • Service Washington 1991
    • 2 Wagner BM, Burt BA, Canter KP et al (Subcommittee on health effects of ingested fluoride, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission on Life Sciences, National Research Council). Health Effects of Ingested Fluoride. National Academy Press, Washington DC 1993 pp 8-9
    • 3 National Health and Medical Research Council. The Effectiveness of Water Fluoridation. Australian Government Publishing Service, Canberra 1991
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    Strunecká A, Patočka J, Pharmacological implications of aluminofluoride complexes, A review of the evidence for pathophysiological effects of aluminium and fluoride on living organism. Charles University, Faculty of Sciences, Department of Physiology, Prague. Department of Toxicology, Purkynì Military Medical Academy, Hradec Králové, Czech Republic

    Susheela AK, Das TK, 2 Gupta IP,2 Tandon RK,2 Kacker SK,2 Ghosh P,3 and Deka,3 Fluoride ingestion and its correlation with gastrointestinal discomfort, Fluoride, 1992, 25:l, pp 5-22

    SUMMARY: This study was carried out to assess the effect on the human gastroduodenal mucosa of drinking naturally fluoridated water and treating patients with 30 mg sodium fluoride for otosclerosis. Ten cases each of skeletal fluorosis and otosclerosis and twenty cases of non-ulcer dyspepsia (NUD) were investigated through routine clinical investigations, chemical investigations of body fluids and drinking water for fluoride, radiographs, stool examination for ova, cysts and worms, abdominal sonography, upper gastrointestinal endoscopy, jejunal aspirates for Giardia lamblia, histopathology of biopsies of intestinal and gastric mucosa and scanning electron microscopy of the mucosa. Patients of all three groups, compared with a control group of normal healthy volunteers, presented gastrointestinal problems and discomfort. Four patients with non-ulcer dyspepsia also presented radiological evidence of skeletal fluorosis. Analysis of ingested drinking water revealed fluoride concentrations of 0.49 - 11.36 ppm. Histopathological studies revealed non-specific lesions. Stool examination revealed ova of Ascaris lumbricoides in two NUD patients, while the rest had normal stool on examination. Jejunal aspirates were negative for Giardia lamblia in all the subjects. Scanning electron microscopic studies revealed widespread damage to the mucosa, viz. (a) mucus droplets were not visible, (b) loss of microvilli, (c) cracked-clay appearance of the duodenal mucosa and (d) desquamated epithelium of gastric mucosa. It is concluded: 1) Ingested fluoride damages gastroduodenal mucosa. 2) Gastrointestinal discomfort can be an early warning sign of fluorosis. 3) Fluoride toxicity should be considered a possible reason for non-ulcer dyspepsia, especially in fluorosis endemic areas. 4) Gastrointestinal discomfort during sodium fluoride therapy calls for extreme caution and close monitoring. 5) Gastrointestinal discomfort in the form of dyspeptic symptoms should be an important diagnostic feature when identifying fluorosis patients and should not be dismissed as non-specific.

    1Department of Anatomy, 2Department of Gastroenterology, 3Department of Otolaryngology, All India Insitute of Medical Sciences, New Delhi, India

    Waldbott GL, The Preskeletal Phase of Chronic Fluoride Intoxication, Fluoride, 1998, 31:1, 13-20

    Whitford GM, Pashley DH, Garman RH, Effects of fluoride on structure and function of canine gastric mucosa, Dig Dis Sci 1997, 42(10), 2146-2155

    These studies were done to determine the effects of fluoride (F) on the structure and function of the canine gastric mucosa and the possible protective effects of 16,16-dimethyl-prostaglandin E2 (dmPGE2). A portion of the stomach with its vascular supply intact was mounted in a two-compartment chamber, one side of which contained a control solution. Minor effects were caused by exposure to 1 mmol/liter F. Both 5 and 10 [190 ppm] mmol/liter F caused marked increases in the fluxes of water and Na, K, and H ions; mucus secretion; and tissue swelling and redness. The extent of these changes did not increase appreciably upon exposure to 50 or 100 mmol/liter F. Histological findings included marked thinning of the surface cell layer, reduced uptake of PAS stain, localized exfoliation and necrosis of surface cells, acute gastritis, and edema. It was concluded that: (1) the threshold F concentration for effects on the structure and function of the gastric mucosa was approximately 1 mmol/liter; (2) the maximum or near-maximum effects were caused by 10 mmol/liter F; (3) the effects persisted for at least 6 hr after the exposure; and (4) dmPGE2 (0.5 microg/ml) did not attenuate the effects induced by F.

    CONTRAINDICATIONS AND SIDE EFFECTS OF NaF

    Health Canada's Drugs Directorate warning -- "should not be given to infants under 6 months of age and not consumed in areas with fluoridated water supplies" -- is woefully inadequate. The following information (not exhaustive) has appeared in various pharmaceutical books and is consistent with the medical research on NaF (including blind and double-blind studies and/or clinical evidence):

    Those indicating need for medical attention [United States Pharmacopoeia, 1986]

    • Skin rash (allergic reaction)
    • Sores in the mouth and on the lips (mucous membrane ulceration)

    Signs of chronic fluoride overdose [United States Pharmacopoeia, 1986]

    • Constipation or
    • Loss of appetite or
    • Nausea or vomiting or
    • Pain and aching of bones or
    • Stiffness or
    • Weight loss or
    • White, brown, or black discoloration of teeth (fluorosis, osteosclerosis)
    Adverse Reactions [Physicians Desk Reference 1994]

    In hypersensitive individuals, fluorides occasionally cause skin eruptions such as atopic dermatitis, eczema or urticaria, Gastric distress, headache and weakness have also been reported. These hypersensitivity reactions usually disappear promptly after discontinuation of the fluoride. In rare cases, a delay in the eruption of teeth has been reported.

    Precautions/Contraindications/Adverse Effects [Canadian Compendium of Pharmaceuticals and Specialties, 1989 --TRI-VI-FLUOR and/or SODIUM FLUORIDE]

    • Should not be administered to infants and children using other fluoride-containing drugs, or to patients with frank dental fluorosis [emphasis mine]
    • Sodium-free diets
    • Ingestion of fluorides may cause eczema, atopic dermatitis and urticaria
    • Reports include skin rash, gastrointestinal upsets and headache. These usually disappear when administration is discontinued
    • Chronic toxicity of fluoride is manifest in mottling of the dental enamel (dental fluorosis) and may result in increased density of bone

    Warnings [By the Editors of Consumer Guide Prescription Drugs, Beekman House, New York, 1988;

    • Poly-Vi-Flor {similar to Tri-Vi-Fluor} vitamin and fluoride supplement]: This drug should be used cautiously by those with heart disease, kidney disease, bone disease, or thyroid disease