In a discussion of drug allergy it is necessary to distinguish between intolerance and allergy to drugs. One represents intoxication, the other is characterized by wheal formation, eosinophilia and other features of an allergic reaction. Gastric irritation, for instance, or acne from iodides or bromides represent intolerance to these drugs due to increased susceptibility of certain tissue; it cannot be associated with allergic reaction.
A discussion of allergy to halogens must establish characteristic allergic lesions with wheal formation or lesions of a contact dermatitis.
In 1934 Watson and Kibler (1) reported a case of bronchial asthma from chlorine in drinking water. In the discussion of this paper Eyermann reported two cases of urticaria from the same source. I related a case in which iodized salt had elicited asthmatic attacks. Tuft (2) noted rhinorrhea, conjunctivitis and a papular dermatitis from iodides. Allergic parotitis (3) is most commonly due to iodides. Allergic parotitis (3) is most commonly due to iodides. Small quantities of halogens are excreted through the parotid and other salivary glands; they may produce allergic edema in the parotid duct with eosinophilia of the kind demonstrated by Pearson (4). Contact dermatitis and allergic nasal disease from bromides and iodides are not uncommon.
Yet, such cases are rarely reported in the literature for two reasons:
1. Available laboratory methods for identifying allergy to drugs are inadequate. Such drugs as aspirin, for instance, may be extremely important sources of severe atopic symptoms, yet in a given case neither skin tests, conjunctival tests nor precipitin reactions will be conclusively positive.
2. It is often difficult to distinguish true allergy from manifestations of intoxication. Gastro-intestinal and lower urinary tract symptoms, for instance, may result from nonspecific irritation as well as from an atopic wheal reaction of the mucous membranes with which the drug has contact.
The most active halogen and indeed one of the most active chemicals in nature is fluoride. Because of its strong affinity to calcium, it is known to affect the calcium-phosphorus metabolism; because of its effects on certain enzymes it interferes with other viral functions, especially with oxidation (5).
During my studies on fluoride intoxication from drinking water (6) clinical data has been accumulated indicating that fluoride, like other inorganic chemicals may induce allergic reactions.
In reporting the following cases (table 1) it should be emphasized that in every single patient the condition has been reproduced by blindfold tests. Furthermore, cases 1, 4, 5 and 6 were not aware during their illness that fluoride was present in their drinking water; consequently, they could not have imagined that fluoride caused their disease. Each patient had thorough laboratory studies and consultation by other physicians.
Case no. 1 that of Mrs. W.E.A., age 61, has been described in detail in a previous publication (7).
This patient had had a tendency to allergic nasal disease, to gastro-intestinal and bladder disturbances due to food and other allergy. On five occasions when visiting fluoridated cities she developed the following symptoms: nasal congestion, rhinorrhea, conjunctival edema, general pruritus, severe spastic pains throughout the abdomen, diarrhea, flatulence, polyuria and dysuria. This was accompanied by extreme general malaise. After repeated episodes she began to suspect the drinking water in these towns, namely, Richmond, Va., Washington, D.C., and Charleston, W. Va. By refraining from drinking fluoridated water and avoiding food cooked with city water she was able to prevent recurrences.
A 1:10 dilution of 1% NaF in horse serum reproduced diarrhea, nasal obstruction, edema of both eyes and general pruritus within a few minutes, lasting for about 24 hours. Control tests with horse serum and with a weaker solution of NaF had no effect, whatsoever. The tests were made (2/23/56) in another allergist’s office (Dr. C.M.).
On July 14, 1956, I produced the same results within 10 minutes with a 0.1% aqueous solution of sodium fluoride (.1 mg).
Case no. 2. Mrs. L.C.H., 62-year-old white, developed an ulcer in the mouth within three days after she started to use stannous fluoride tooth paste. During the following 10 days, additional lesions developed throughout the oral mucosa accompanied by severe spastic pains throughout the whole abdomen, flatulence, diarrhea and dryness in mouth, nose and throat. These symptoms persisted for several weeks and were followed by a febrile colitis. Her dentist (Dr. W.H.P.) having observed a similar case suggested to her that the tooth paste might have induced this condition. Upon eliminating it, the condition gradually subsided. Diagnostic studies including gastro-intestinal X-rays by an internist (Dr. R.J.E.) were negative.
On 9/11/56 the patient was patch tested with several tooth pastes including one containing stannous fluoride and with a 1% aqueous solution of NaF. All tests were negative. Three days later she was given an intradermal test with 1/10 cc of a 1% aqueous solution of NaF. Within 15 minutes, an erythema developed at the site of injection extending along the lymph channels toward the axilla. It was associated with paresthesias in mouth and both arms. This was followed by severe pains in the lower abdomen and extreme general malaise.
On 12/13/56, saline solution was applied with a cotton swab beneath her tongue without ill effect. Thirty minutes later a cotton swab soaked in 1% NaF was used similarly. Within 5 minutes hyperemia, edema and pruritus developed in the test area followed by more extensive irritation in a large portion of the oral mucosa. A smear of the mucus from the area showed marked eosinophilia. The patient refused further tests with the fluoride tooth paste.
Case no. 3. An 8-year-old girl gave a history since infancy, of abdominal pains associated with anorexia, frequent pyelitis and pruritus vulvae. Since early 1956 she had intermittently spastic pains and paresthesias in legs and arms. She consulted me because of seasonal upper respiratory allergy.
In February 1956 she had 3 local applications of a 2% solution of NaF by her dentist in the manner usually employed for caries prophylaxis. After the first and second treatments the oral mucosa became edematous and irritated for periods of about 4 days. Within an hour after the third application on 3/5/56, a cheilitis developed involving the entire anterior portion of the oral mucosa. This subsided gradually within a week.
Local application of this solution to the oral muccous membranes for about 30 seconds produced marked injection and edema of the test area. An intradermal test with a 1% aqueous solution of NaF produced an erythematous reaction of the size of a 25 cent piece; one for horse serum and horse serum combined with NaF were negative.
On 6/18/57 the patient was given as a placebo 300 cc. of distilled water without ill effect.
The following day a test dose of 6.8 mg. of fluoride (as NaF) elicited within 20 minutes moderately severe vomiting. Blood calcium levels ranged between 11.3 and 11.6 mg.%, blood phosphorus between 4.1 and 4.4 mg.%. Only 16% of the test dose of fluoride was recovered in the urine of a 137 mg. calcium diet; 17% on a daily calcium intake of 3.3 grams (7/1/57).
Case no. 4. Mrs. H.S., age 33, consulted me because or urticaria present intermittently for about 2 years; it had gradually become more severe in recent weeks. It was not related to food, season of the year, menses or ingestion of drugs. It was associated with pains in arms and legs, ulcers in the mouth, spastic abdominal pains, diarrhea and nausea, polyuria and dysuria, paresthesias in both arms and hands, bilateral frontal headaches radiating into the occipital region, loss of memory, ability to concentrate. In recent months, the patient had several episodes of syncope without apparent cause. She had had a mild sinus disease for about ten years.
On examination as an in-patient at Harper Hospital she exhibited a generalized papulous urticaria involving trunk and all extremities. Except for slight tenderness in the left lower quadrant and some muscular weakness in both hands, the examination was negative. Laboratory tests were unrevealing.
After having avoided fluoride water for 2 weeks, the patient was given, 2 days before the test, 6.8 mg. of F as NaF and another 6.8 mg. on the day of the test. The first dose caused no ill effect. However, within 30 minutes after she had taken the second dose she developed a severe outbreak of urticaria, cephalgia, paresthesias in legs and hands. She became lethargic and developed pain in the epigastric region followed by spastic pain in the lower abdomen. These symptoms began to clear in about one hour. Following the test, the 24 hour urine output was 3180 and 3445 cc. respectively. On a daily intake of a low calcium diet (137 mg.) for 3 days the urinary calcium excretion was 190.8, 9/6/57, and 192.3 mg. on 9/7/57.
Only 3.6 percent of the total test dose of 6.8 mg. of F was recovered in the urine within 24 hours.
The patient had a complete allergic survey, gastro-intestinal X-rays and thorough blood and biochemical studies which were unrevealing. Further studies in this case are in progress.
Case no. 5. Mrs. B.M., 50-year-old white female, consulted me because of generalized urticaria present since December, 1952, usually worse on arising. In addition, she complained of severe headaches, paresthesias in arms and hands, pains in legs and edema of both ankles, ulcers in the mouth, pain in the lower spine.
Typical urticarial lesions were present on trunk and extremities; there was limitation in motion in the lower spine. Laboratory and biochemical studies were entirely normal, except for a sedimentation rate of 67 mm per hour. There was X-ray evidence of sclerotic changes of the lower spine. An allergic survey including extensive intradermal tests failed to detect anything significant. On 6/10/57 the patient while being kept on a low (137 mg.) calcium diet was given a placebo test of 300 cc. of distilled water. It caused no ill effect. On June 12th 2 mg. NaF (.9 mg. F) in 300 cc. of distilled water was administered. The patient was not aware that the water contained fluoride. She had previously had similar tests (glucose tolerance and urea clearance). Within 20 minutes she developed a generalized urticaria associated with cough and pain in the gastric region followed by marked flatulence in the abdomen.
This test was repeated on June 18th, after placing the patient on a high calcium (2 gms.) diet to which 1.3 gms. of calcium lactate had been added. The patient experienced the same symptoms as had occurred subsequent to the above-described test. Urticaria dominated the picture.
Since eliminating fluoridated water for drinking and cooking foods all symptoms have subsided.
Case no. 6. Mrs. N.S., 29 years-old, consulted me on 10/7/57 because of a dermatitis in the suprapubic area and at the adjoining parts of both thighs. This had been present for 3 1/2 months during the past two weeks. She also complained of paresthesias in arms and legs, of severe frontal headaches associated with blurring of the eyes, dizziness and fainting spells, pain and stiffness in the lower spine, mild arthritic symptoms migratory in character, affecting practically every joint.
The skin eruption was characteristic of a dermatitis with papulo-pustular lesions, showing many scratch marks. There was tenderness and limitation in motion in the lower spine, hyper-reflexia in both extremities; otherwise the examination was negative.
X-rays showed minor hypertrophic changes in the lower spine. Blood and urine studies were normal except for an increase in cholesterol esters (130.5 mg.%). Intradermal skin tests were inconclusive.
During the stay at Women’s Hospital the lesions improved spontaneously without treatment.
On 10/10/57, the patient was given a placebo test dose of 300 cc. of distilled water. It had no ill effect. The following day she received 6.8 mg. of fluoride as NaF in the same amount of water. Within one hour the skin lesions which had practically subsided returned with marked vesiculation, oozing and severe pruritus. In addition she developed frontal headache, lethargy and minor episodes of syncope. The headaches began to subside after 5 to 6 hours; the skin started to improve during the following days.
This patient has been well without treatment following elimination of fluoride water.
Allergy to fluorides has been described by Feltman (9) who observed three cases of atopic eczema following daily ingestion of a dose of 1 mg., the amount recommended by public health authorities for prevention of tooth decay. In two of his patients the eczema was reproduced by resumption of fluoride tablets and subsided upon their elimination. Additional instances of allergy to fluorides have come to my attention but could not be included here because confirmatory studies could not be carried out.
In every case reported here the symptoms were reproduced with adequate controls by the blindfold method. This was accomplished by different means namely, by ingestion of a test dose of NaF, by the injection of a diluted aqueous solution of sodium fluoride, by local application of fluoride to the oral mucous membranes.
The characteristic allergic appearance of the nasal mucosa in case no. 1, the occurrence of urticaria in 3 cases, the reproduction of dermatitis leaves no doubt that we are dealing with true allergic phenomena. Eosinophilia and pruritus further point in this direction.
Whether or not any of the other symptoms noted are allergic in nature cannot be decided at this time. Such manifestations as paresthesias and arthritic changes in the lower spine, gastrointestinal and urinary disturbances can be linked with fluoride intoxication.
The purpose of this paper is to draw attention to the development of allergic reactions from fluorides. It should also be emphasized that in allergic patients intoxication appears to be more prevalent than in normal individuals. Evidence presented elsewhere (10) indicates that allergic patients are likely to be less tolerant to the toxic action of drugs than normal individuals. In another study (7) on fluoride intoxication among 52 cases of chronic incipient intoxication from fluoridated water, 18 gave a history of allergy. With widespread exposures to fluorides in drinking water, through contamination of the air and of foods processed with fluoridated water, diagnostic problems bearing on this subject are bound to arise in our daily practice.
Six cases are described with allergic manifestations from fluorides. The symptoms were reproduced by administering an aqueous fluoride solution either by ingestion, injection or local application. Control tests had no such effect. The patients had no way of knowing which solution contained fluoride.
1. Watson, S.H., and Kibler, C.S.: Drinking Water as a Cause of Asthma. J. Allergy 5: 197-198 (1934).
2. Tuft, L.: Clinical Allergy, p. 122 (Lea and Febiger, Philadelphia 1949).
3. Waldbott, G.L., and Shea, J.J.: Allergic Parotitis, J. Allergy 18: 51 (1947).
4. Pearson, R.S.B.: Two Cases of Recurrent Swelling of the Parotids, Guy’s Hosp. Rep., 86: 333-342 (1936).
5. Waldbott, G.L.: Incipient Chronic Fluoride Intoxication from Drinking Water, Int. Arch. Allergy 7: 70-74 (1955).
6. Borei, H.: Inhibition of Cellular Oxidation by Fluoride (H.K. Lewis, London 1945).
7. Waldbott, G.L.: Incipient Chronic Fluoride Intoxication from Drinking Water. I. Report on 52 cases. Acta med. scand. 156: 157-168 (1956).
8. Waldbott, G.L.: Incipient Chronic Fluoride Intoxication from Drinking Water. II. Distinction between Allergy 9: 241-249 (1956).
9. Feltman R.: Prenatal and Postnatal Ingestion of Fluorides. A Progress Report. Dental Digest 8: 354-356 (1956).
10. Waldbott, G.L., Blair, N.E. and McKeever, R.: Drug Tolerance in Asthma. Ann. Allergy 11: 199-203 (1953).