Fluoride Toxicity

Fluoride Toxicity

Fluoride Toxicity Frank A. Smith U n i v e r s i t y of R o c h e s t e r S c h o o l of M e d i c i n e a n d D e n t i s t r y I. Toxicity in Human...

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Fluoride Toxicity Frank A. Smith U n i v e r s i t y of R o c h e s t e r S c h o o l of M e d i c i n e a n d D e n t i s t r y

I. Toxicity in Humans II. Acute Effects III. Chronic Effects

Glossary Carpopedal spasm Muscle spasms of the hands, fingers, feet, or toes. Chemosis Edema of the conjunctiva forming a swelling around the cornea. Hyperkalemia Elevated blood potassium level, re­ flected in an increased peak of Τ wave of the electrocardiogram. Hypocalcemia Reduced blood calcium level, re­ flected in prolonged QT interval of the electrocar­ diogram. Hypomagnesemia Reduced blood magnesium level. Hypovolemic Shock State of shock in which the blood volume has been reduced. Hypoxia Oxygen deficiency. Malaise General discomfort or uneasiness. + + N a - K A T P a s e Enzyme involved in the trans­ + + port of N a and K across cell membranes. Nephrotoxicity Injury to the kidney cells. Polyuria Excessive excretion of urine. Proteinuria Protein in the urine. Tachycardia Rapid beating of the heart. Tetany Intermittant muscular contraction. Ventricular fibrillation Rapid twitching of the ven­ tricular muscle of the heart.

FLUORIDES (viewed here as inorganic com­ pounds containing fluorine) are ubiquitous in na­ ture. This is not surprising, inasmuch as fluorine is the most electronegative and reactive of the ele­ ments. It occurs naturally in more than 50 minerals. The toxicology of fluoride as it pertains to humans has been a part of the medical literature since at

least 1873, when a fatality following the ingestion of a solution of hydrofluoric acid was reported. Our appreciation and understanding of the biological effects associated with fluorides have subsequently increased enormously, stimulated by their increas­ ing uses in industry, dentistry, and medicine. The fluoride-containing mineral cryolite (Na3 A I F 6 ) is an important raw material in the produc­ tion of aluminum by the Hall electrolytic process. Following exhaustion some years ago of the cryolite deposits in Greenland, the aluminum industry has turned to the use of synthetic cryolite. Rock phos­ phate (apatite) of which there are extensive deposits in Tennessee and Florida, is an important source of phosphoric acid and of phosphate fertilizers. Fluorsilicic acid recovered from the production of phos­ phoric acid is the principal source of fluoride added to domestic water supplies as a means of reducing the incidence of dental caries. More than half of the U.S. population lives in areas where the water sup­ ply is fluoridated up to levels recommended for opti­ mal dental benefit. The apatite also contains some fluorapatite [Caio(P0 4 )6F 2 ]. During processing, fluoride-containing dusts may be deposited on the surrounding territory, where it may become a hazard to vegetation and to grazing livestock. Conse­ quently, much research has been conducted into the effects of fluoride on these important economic assets. Domestic production of fluorspar or fluorite (CaF 2 ) is limited chiefly to Illinois. More than 20% of the fluorspar produced in this country in 1990 was used as a flux in steelmaking and in iron and steel foundries. Indeed, fluorite (from the Latin, "to flow") has been used by metallurgists for centuries. It is also used in the ceramic industry, in the manu­ facture of glass, enamels, and welding rod coatings. Over 60% of the fluorspar was used in the produc­ tion of hydrofluoric acid (HF). Major uses of HF include the manufacture of synthetic cryolite and aluminum fluoride required for the electrolytic pro-

Handbook of Hazardous Materials Copyright © 1993 by Academic Press, Inc. All rights of reproduction in any form reserved.

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Fluoride Toxicity

auction of aluminum, in petroleum alkylation, in the processing of uranium and of rare metals, etching of glass, manufacture of semiconductors, manufacture of herbicides, and a variety of fluoride salts. Hydro­ gen fluoride solutions and gels are readily available for home use as rust removers. The largest use of H F is in the manufacture of various fluorocarbons (e.g., fluoropolymers and chlorofluorocarbons). Produc­ tion of the latter compounds is expected to decrease over the next ten years, however, as efforts to protect the stratospheric ozone layer are imple­ mented. More than 100 occupations, encompassing over 350,000 workers, have been identified as having a potential exposure to fluoride and/or hydrogen fluoride. Moreover, fluorides are readily accessible in the form of fluoridated toothpastes, mouth­ washes, and vitamin preparation. From the foregoing, it is evident that there is a significant potential for exposure to fluorides. Moreover, exposures may be acute or chronic in nature, and routes of entry include absorption through the skin, inhalation, and ingestion, singly and in combination. However, when handled properly, and treated with caution, fluorides do not constitute an unusual or unique hazard and expo­ sures can be made to conform to acceptable limits. As was stated by Paracelsus more than 400 years ago, "All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy."

I. Toxicity

in

Humans

Acute poisoning with fluoride results from the inten­ tional or accidental ingestion of fluoride solutions or salts (the latter have been mistaken for confec­ tioner's sugar and for powdered eggs) and from ab­ sorption from the respiratory tract and/or skin fol­ lowing releases of gaseous hydrogen fluoride or splashes from hydrofluoric acid solution. Regardless of the route, the effects of the fluoride are the same and fatalities may occur. Exposures to hydrogen fluoride gas or solution may be further complicated by the chemical burn these agents can cause. During chronic exposures (e.g., occupational exposures to fluoride-containing dusts, gaseous hydrogen fluo­ ride, prolonged use of water supplies containing ex­ cessive levels of fluoride) osteosclerosis may de­ velop over a period of time. The severity of this problem will depend upon the magnitude and dura­ tion of the exposure.

A. Lethal Dose For the human subjects fatally poisoned by the in­ gestion of fluoride, we rarely have good information relating to the amount of fluoride taken. Based on a limited number of cases reported in the literature, it has been estimated that a dosage of 32-64 mg F/kg would be certainly lethal to a 70-kg person. The probably toxic dosage, defined as the threshold dos­ age for which the victim should receive immediate emergency treatment, has been estimated to be 5 mg F/kg. This observation should be useful from a prac­ tical viewpoint, albeit that it is based on limited data.

β.

Symptomatology

Upon ingestion, inhalation, or skin penetration, fluoride is absorbed into the blood. Approximately half of this fluoride is excreted into the urine over the next 24 hours. Most of the remainder is deposited in calcified tissue, chiefly the skeleton. These two processes, elimination in the urine and deposition in bone, constitute the body's means of detoxifying fluoride. Of the two, skeletal deposition is the faster. If the dose is sufficiently large to overwhelm these mechanisms, acute toxicity ensues. If death is to be the final outcome, it often occurs in the first 2-4 hours and usually within the first 12 hours. It may, however, be delayed as long as 24 hours. If the victim can be effectively supported through the first 24 hours, the prognosis is good. Following ingestion, gastrointestinal symptoms of nausea, vomiting, ab­ dominal pain, and diarrhea may be evident before signs of systemic poisoning are seen. Reported signs of acute systemic poisoning include General: malaise, weakness, pallor Cardiopulmonary: tachycardia, hypotension, prolonged QT interval on the electrocardiogram, ventricular fibrillation, pulmonary edema Neurologic/neuromuscular: central nervous system depression, respiratory depression and paralysis, seizures, carpopedal spasm, tetany Metabolic: hypocalcemia, hyperkalemia, hypomagnesemia Not all of these signs and symptoms are necessarily observed in every victim. Serum or plasma fluoride concentrations ranging between 2 and 30 /xg/ml have been reported in fatal cases of poisoning. The dose, however, is rarely known. Moreover, because fluo­ ride is rapidly absorbed into and removed from the

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Fluoride Toxicity

blood, concentrations may have been higher at some time prior to death. Normal plasma fluoride concen­ trations are generally less than 0.05 μg/ml.

C. Mechanism of Action Upon entry into the bloodstream, a series of events is initiated, which may well terminate fatally. These are shown in Figure 1, where it is assumed that a fluoride salt (e.g., sodium fluoride) has been in­ gested. Upon entering the acid milieu of the stom­ ach, the fluoride is converted to poorly dissociated hydrogen fluoride. This uncharged molecule readily passes across the gastric mucosa and the intestinal wall by passive diffusion. The irritation of these membranes, gastroenteritis, gives rise to nausea, vomiting, hemorrhage, and diarrhea. The attendant loss of fluid contributes to an electrolyte imbalance, a state of hypovolemic shock, and decreased blood pressure. Myocardial hypoxia ensues, accompanied by a state of acidosis, which in turn favors the

presence of poorly dissociated hydrogen fluoride over ionic fluoride. At the cell surface, fluoride in­ + + hibits N a - K A T P a s e , leading to an increase in intracellular sodium, an increased sodium-calcium exchange, and increased intracellular calcium and a state of hypocalcemia. This latter state is also con­ tributed to by an increase in calcium uptake by bone as fluoride is deposited there as fluorapatite. Some calcium fluoride may be formed and precipitated in renal tubular fluid, urine, and possibly elsewhere. The hypocalcemia may induce painful involuntary muscle contractions (tetany) evidenced in carpopedal spasm, twitching of limb muscles, laryngospasm, and cardiospasm. These responses may be due to a fluoride-facilitated neuromuscular transmis­ sion by increasing the sensitivity of cholinergic re­ ceptors to acetylcholine. The increase in intracellu­ lar calcium results in a loss of intracellular potassium to blood and a state of hyperkalemia. The hyperkalemia and hypocalcemia are reflected in the electrocardiogram by a peaking of the Τ wave and a

NaF ingestion

in stomach

NaF + HCl ^ = " ^ NaCI + HF acid medium favors undissociated HF, more readily transported across membranes than F ion

irritation of mucous membranes hemorrhage gastroenteritis

abdominal pain cramp nausea vomiting ) diarrhea [ hemorrhage )

Ca

2+

binding

= loss of fluid electrolyte imbalance —» hypovolemic shock i blood pressure

erythrocytes, tissue cells X

N a + - K + ATPase

f intracellular Na +

acidosis

2+

hypocalcemia myocardial hypoxia

f in undissociated HF in plasma

f transport across membranes

I N a +I - intracellular Ca exchange Ca Loss intracellular Κ to plasma = hyperkalemia

interferes with neuromuscular function tetany carpopedal spasms muscle twitch (perhaps due to f neurotransmitter, not to 4 Ca)

Figure 1

cardiac effects

Acutely toxic actions of absorbed fluoride.

enzymes interference with oxidative metabolism glycolysis lipid metabolism

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Fluoride Toxicity

prolongation of the QT interval, respectively, though there may be hypocalcemia without a longer QT interval. Ventricular fibrillation can follow, sometimes preceded by ventricular trachycardia. The ventricular fibrillation eventually resists treat­ ment. Sinus tachycardia is the most common cardiac finding. Cardiovascular collapse is probably the most common proximal cause of death. Effects on the brain are commonly seen as lethargy, stupor, and coma, and as respiratory arrest just before ter­ minal cardiac arrest. Renal affects (e.g., proteinuria and polyuria) may be seen in some instances. The lungs may show congestion and hemorrhagic edema consistent with terminal congestive heart failure. In­ jury to the myocardium, thought to be due to fluo­ ride in the tissue with associated hypocalcemia, has been reported. Management of acute fluoride poisoning following ingestion is chiefly supportive in nature. As in any poisoning emergency, the physician must strive to maintain cardiac and respiratory function, prevent further absorption of the poison, and immobilize, remove, or otherwise inactivate that which has al­ ready been absorbed. Shock and the declining blood pressure are combated by infusion of glucose in sa­ line or of plasma or whole blood. This also helps correct the dehydration, alleviate thirst, and main­ tain a mild diuresis to aid in excreting fluoride. Gas­ tric lavage with calcium gluconate or with lime wa­ ter, or the ingestion of milk, retards further absorption of fluoride. Inclusion of calcium gluco­ nate in the infusion fluid also helps to offset hypocal­ cemia; considerable amounts of calcium may be re­ quired. Hypomagnesemia, if present, should be corrected. Acidosis should be corrected by infusion of sodium bicarbonate to reduce the presence of more readily absorbed undissociated hydrogen flu­ oride, and to improve the renal excretion of fluoride. Hemodialysis may be necessary to help remove fluoride and potassium from the blood. Cardiac monitoring by electrocardiogram should be insti­ tuted to warn of possible arrhythmias; monitoring should continue for up to 72 hours inasmuch as ap­ pearance of the hyperkalemia is sometimes delayed. The urine should be monitored for osmolality and volume to warn of possible polyuria.

II. Acute

Effects

Hydrofluoric acid burns may be caused by either gaseous H F or by aqueous solutions of HF.The so­ lutions encountered industrially range between 0.5

and 70% or higher. Concentrations commonly used are 10 and 70%. Rust remover preparations, readily available to anyone, contain up to 12% HF in a gel form or in solution. Most reported burns are to the fingers or other areas of the extremities and are gen­ erally due to dilute aqueous solutions. Accidents involving spills or splashes of more concentrated solutions may be more life threatening. In these ac­ cidents, the physician must be aware that there may be damage to the respiratory tract, and eyes from fumes and droplets on the victim. The physician may also be subject to injury from these sources.

Λ. Skin Injuries may range from burns of the fingers from pinhole leaks in protective gloves to splashes on the torso, arms, neck, or face, to one instance of total immersion in a tank of 10-12% HF and anhydrous ammonia (the victim survived). Skin burns are the most common form of HF injury, and are rarely fatal. The injury proceeds in a characteristic twostep fashion. Initially, there is a corrosive skin burn similar to that caused by other mineral acids, but less severe because of the limited dissociation of HF. When the acid solution is dilute, the reaction may be delayed up to several hours, and the victim may not realize that he or she has indeed been in­ jured until a characteristic severe, throbbing pain sets in. In the second phase, a secondary chemical burn is produced as the acid penetrates into the deep subdermal layers, with associated severe destruc­ tion and liquefaction necrosis. The severe pain ac­ companying the burn is thought to be due to the release of potassium into the extracellular fluid and the intense stimulation of the nerve endings. Hydrofluoric acid burns have been classified with respect to acid concentration as follows: <20% HF: Pain; erythema may be delayed up to 24 hours 20-50%: Burn usually apparent in 1-8 hours >50%: Immediate, intense pain with tissue destruction Fatal systemic poisoning can occur from burns of the trunk, neck, face, or respiratory tract following absorption of lethal amounts of fluoride from the injured surface. The site of the burn is important. Absorption is more rapid from thin or highly vascu­ lar tissue than from, for example, the palms of the hand or soles of the feet. Death due to systemic fluoride poisoning has been reported following a fa-

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Fluoride Toxicity

cial burn involving only 2.5% of the body surface area. It has been recommended that persons with 2 burn areas greater than 50-100 cm be hospitalized 2 immediately; if the burn area exceeds 65 cm , the QT interval on the electrocardiogram should be monitored for indications of impending hypocalce­ 2 mia. For burn areas greater than 100-150 cm , the patient may need to be placed in an intensive care unit. Speed in treating H F burns is of the essence, be­ cause of the rapidity with which the acid penetrates deep into the underlying tissue. Essentially, treat­ ment consists first of stopping further exposure, and then inactivating that fluoride present in the tissue. The first objective is accomplished by copious la­ vage with water under a faucet or in a shower as appropriate. At this time, all contaminated clothing is removed. The current agent of choice for inac­ tivating fluoride is calcium gluconate. A 2.5% cal­ cium gluconate gel is applied liberally and frequently to the affected area. A 5 or 10% solution of calcium gluconate may be infiltrated into the burn area at the 2 rate of 0.5 ml/cm of surface; if injected into a finger, no more than 0.5 ml per digit should be adminis­ tered. Burns beneath the finger nail can be ex­ tremely painful; these can be treated with intraar­ terial injections, eliminating the possible need to remove the nail. The treatment does require hospi­ talization. A second frequently used treatment is the applica­ tion (as soaks or compresses) of iced aqueous solu­ tions of Zephiran (benzalkonium chloride, 0.13%) or Hyamine (benzethonium chloride, 0.2%). It is thought that the chloride atom in these quaternary amine compounds exchanges with the fluoride in the tissues. These solutions tend to irritate facial skin; therefore, calcium gluconate treatment is the better choice for head and neck burns. Following the initial treatment to minimize the specific fluoride effect, further treatment should fol­ low the usual guidelines for chemical or thermal burns.

B. Eyes The eye is highly susceptible to damage by H F gas or hydrofluoric acid solution. Damage by the latter is far more extensive than that caused by other acids in similar concentrations and is worse than that caused by the other halogen acids. The acidity per se of the HF solution is of less importance than is the ability of the undissociated H F to penetrate rapidly and deeply, thus carrying fluoride well into the tissue.

The cornea and conjunctiva can be extensively dam­ aged by exposure to H F vapor alone. The signs and symptoms of ocular injury by H F include the fol­ lowing: Rapid onset of pain Edema of the eyelid Tearing Conjunctival inflammation, Chemosis, corneal opacification, and decrease in visual acuity Conjunctival hemorrhage may be evident. Chronic conjunctival and corneal inflammation, scarring, and perforation may develop later. The corneal epi­ thelium may be severely denuded, with reepithelialization taking place over a period of several weeks. There may be recurrent breakdown and erosion of the corneal epithelium. Generally, the ocular effects of hydrogen fluoride exposure are noted within the first day. The prognosis is not good if treatment is delayed or inadequate; permanent eye injury can occur associated with permanent loss of vision. Hydrofluoric acid burns of the eye are to be con­ sidered as ophthalmic emergencies, and the atten­ tion of an ophthalmologist should be sought promptly. Immediately upon injury, the eye should be irrigated with water or saline until lavage is possi­ ble with at least two liters of 1% calcium gluconate in saline. Isotonic magnesium chloride solution has also been used, though the former solution is preferable. Following washing, drops of 1% calcium gluconate may be used every 2-3 hours for 48-72 hours. Quaternary amine compounds or 10% cal­ cium gluconate can cause extreme irritation and damage and should not be used.

C. Respiratory

System

Patients with hydrofluoric acid burns of the face and neck (indeed all patients with extensive burns) should be closely monitored for signs of pulmonary edema on the assumption that burns of the respira­ tory tract may have occurred. Airborne concentra­ 3 tions of 5 ppm (4.1 mg/m ) are irritating to the nose and eye. Heavily contaminated clothing, especially in the chest area, may produce concentrations of 4 5 10 -10 ppm in the victim's breathing zone [the limit 3 for occupational exposures is 3 ppm (2.5 mg/m )]. Effects of exposure may range from mild upper air­ way and eye irritation to airway obstruction to pul­ monary edema to death. The edema may be rapid or delayed in onset. The swelling of the oral or pharyn­ geal mucosa may obstruct the airway and require

282

Fluoride Toxicity

tracheostomy or endotracheal intubation for relief. Pulmonary reactions may persist for several weeks. Immediate first aid consists of administering 100% oxygen, followed by a 2.5% solution of calcium glu­ conate given by a nebulizer. The edema is treated by the usual standard methods.

D. Kidney Acute fluoride poisoning may induce in some indi­ viduals a polyuria resembling diabetes insipidus, which may persist for days to months. In a few instances, the acute polyuric renal failure has termi­ nated fatally. Interest was sharply focused on the problem when it was realized that an unexpected polyuria was being encountered in some surgical patients who has been anesthetized with methoxyflurane (2,2-dichloro-l,l-difluorethyl methyl ether). It was shown that fluoride ion is released when the parent compound is metabolized in vivo, and that the nephrotoxicity is directly related to the level of serum fluoride. Clinical experience has shown this relationship to be as follows: Peak serum F associated with No nephrotoxicity: <0.76 ^ g F/ml) Subclinical toxicity: 0.95-1.5 Mild clinical toxicity: 1.7-2.3 Clinical toxicity: 1.5-3.3 It is believed that fluoride brings about the diuresis by inhibiting the resorption of salt (NaCl) and there­ fore water in the ascending limb of the loop of Henle and by interfering with the action of the antidiuretic hormone in regulating water absorption in the col­ lecting ducts of the kidney. Means should be instituted to reduce the blood levels of fluoride, (e.g., by establishing a state of alkalosis and by increasing fluid intake). Hemodialy­ sis may be necessary.

III. Chronic

Effects

A. Bone As stated earlier, the deposition of fluoride in the skeleton is one of the two major mechanisms by which the body detoxifies absorbed fluoride. Fluo­ ride brought into contact with the bone mineral sur­

face by the extracellular fluid penetrates the hydra­ tion shell of the bone crystal. These crystals are essentially hydroxyapatite and upon reaching the mineral surface, the fluoride exchanges with the hydroxyl group to form fluorapatite. By this means, the level of fluoride in the circulating plasma can be rapidly lowered. The deposited fluoride is released gradually to the plasma over a prolonged period of time and the plasma concentrations do not rise to dangerous levels. There are no significant deleterious effects on the bone of such brief encounters as might occur in an acute fluoride poisoning. However, ongoing cycles of rapid deposition and slow release, as occur for example in occupational exposure to fluoride or in the use of water supplies containing dangerously high concentrations of fluoride, can lead to a pro­ gressive building of bone fluoride concentrations with attendant hypermineralization, and potentially harmful consequences. An awareness of this prob­ lem came about when it was realized that long-term Danish cryolite workers were afflicted with a condi­ tion characterized by excessive bone formation, fu­ sion of vertebrae of the spinal column, and calcifi­ cation of ligaments of the pelvic floor, leading to a crippling loss of skeletal mobility. Bending over to pick up a tool from the floor became impossible, and the condition was referred to as "poker back." Ex­ tensive studies of these workers established that the causative agent was the fluoride in cryolite. Crip­ pling fluorosis has not been seen in American workers. An osteosclerosis, defined as an increased density of bones to x-rays (radiopacity) has been seen in some employees in various industries associ­ ated with fluoride exposure. The increased density is attributable to increased bone formation brought about by fluoride. Osteosclerosis is detectable in bone with fluoride concentrations as low as 40005000 ppm in bone ash. Severe osteosclerosis is asso­ ciated with concentrations greater than 10,000 ppm. Normal concentrations for persons of comparable age are approximately 1000 ppm. As yet, the only practical way to achieve a lower­ ing of skeletal fluoride is to reduce fluoride intake. It has been estimated that 8-9 years are required to reduce bone fluoride levels by one-half. Lower flu­ oride intake by the worker can be achieved by ensur­ ing that airborne concentrations in the work place do not exceed the mandated standard of 2.5 mg F as 3 dust/m or 3 ppm F as HF. Community water sup­ plies containing more than the concentrations rec­ ommended for optimal dental benefits should be

Fluoride Toxicity

replaced if possible or the water treated to reduce the fluoride concentration.

β.

Cancer

The ubiquitous distribution of fluoride in nature makes it virtually impossible to avoid exposure to this element, and it is not surprising, therefore, that concern surfaces again and again about its possible carcinogenicity. It suffices to say that the bulk of the published literature supports the view that fluoride is not associated with an increase in cancer risk in humans. Recent studies in New York, the Midwest (Iowa and Nebraska), and in Alberta, Canada have led to the conclusion that there is no link between fluoridation of public water supplies and osteosar­ coma. A recent rodent study in which rats were fed diets containing 1.8, 4.5, or 11.3 mg F (as NaF/kg of body weight for up to 99 weeks) found no evidence that fluoride altered the natural incidence of preneo­ plastic and neoplastic lesions at any site (including bone) in animals of either sex.

Bibliography Caravati, Ε. M. (1988). Acute hydrofluoric acid exposure. Am. J. Emerg. Med. 6, 143-150. Gosselin, R. E., Smith, R. P., Hodge, H. C., and Braddock,

283 J. D. (1984). "Clinical Toxicology of Commercial Prod­ ucts," 5th ed. pp. III-185-III-193, Williams and Wilkins, Bal­ timore, MD. Hrudey, S. E., Soskolne, C. L., Berkel, J., and Fincham, S. (1990). Drinking water fluoridation and osteosarcoma. Canad. J. Publ. Hlth. 81, 415-416. McCulley, J. P., Whiting, D. W., Petitt, M. G., and Lauber, S. E. (1983). Hydrofluoric acid burns of the eye. J. Occup. Med. 25, 447-450. McGuire, S. M., Vanable, E. D., McGuire, M. H., Buckwalter, J. Α., and Douglass, C. W. (1991). Is there a link between fluoridated water and osteosarcoma? J. Am. Dent. Assoc. 122, 39-45. Mclvor, Μ. E. (1990). Acute fluoride toxicity: Pathophysiology and management. Drug Safety 5, 79-85. MacKinnon, M. A. (1988). Hydrofluoric acid burns. Dermatol. Clinics 6, 67-74. Mahoney, M. C , Nasca, P. C , Burnett, W. S., and Melius, J. M. (1991). Bone cancer incidence rates in New York State: Time trends and fluoridated drinking water. Am. J. Publ. Hlth. 81, 475-479. Maurer, J. K., Cheng, M. C , Boysen, B. G., and Anderson, R. L. (1990). Two-year carcinogenicity study of sodium fluoride in rats. J. Natl. Cancer Inst. 82, 1118-1126. Mayer, T. G. (1985). Fatal systemic fluorosis due to hydrofluoric acid burns. Annals. Emerg. Med. 14, 149-153. Shupe, J. L., Peterson, Η. B., and Leone, N. C. eds. (1983). "Fluorides: Effects on Vegetation, Animals, and Humans." Paragon Press, Salt Lake City. Smith, F. Α., and Hodge, H. C. (1979). Airborne fluorides and man. Part I. CRC Critical Reviews in Environmental Control 8, 293-371. Part II, 9, 1-25. Upfal, M., and Doyle, C. (1990). Medical management of hydro­ fluoric acid exposure. / . Occup. Med. 32, 726-731.