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FLUORIDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Fluorides are ionic salts of fluorine, a halogen.

Specific Substances

    1) Fluoride, inorganic
    2) Inorganic fluoride
    3) Fluoride
    4) Fluoride ion
    5) Ammonium fluosilicate
    6) Ammonium hexafluorosilicate
    7) Ammonium silicofluoride, solid
    8) Barium fluorosilicate
    9) Barium fluosilicate
    10) Barium hexaflourosilicate
    11) Barium hexafluorosilicate
    12) Barium silicofluoride
    13) Barium silicon fluoride
    14) Cryptohalite
    15) Diammonium hexafluorosilicate
    16) Fluorosilicates
    17) Fluorosilicates, n.o.s.
    18) Fluosilicate de ammonium (french)
    19) Fluosilicate salts
    20) Fluosilicates
    21) Hexafluorosilicates
    22) Hexafluorosilicates(2-)
    23) Hexafluorosilicates(2-) ion
    24) Perfluoride
    25) Potassium hexafluorozirconate
    26) Silicates(2-), hexafluoro-
    27) Silicofluoride, solid, n.o.s.
    28) Silicofluorides
    29) Silicon fluoride barium salt
    30) Silicon hexafluoride ions
    31) Sodium fluoride solution
    32) Sodium fluoride, solid
    1.2.1) MOLECULAR FORMULA
    1) F

Available Forms Sources

    A) FORMS
    1) Dietary fluoride supplements come in both tablet and liquid form. The fluoride ion F is responsible for producing toxicity in poisonings.
    2) TOOTHPASTE
    a) The fluoride in toothpaste is usually sodium or stannous fluoride or sodium monofluorophosphate. Fluoride toothpaste commonly contains a maximum of 1 milligram of fluoride per gram of toothpaste.
    b) If an entire 6.4 oz tube of toothpaste containing 1 mg/g of fluoride were ingested and retained, this would represent over 200 mg of fluoride.
    c) The maximum allowable amount of fluoride in a tube of toothpaste is 260 mg. Serious symptoms might occur, if a large portion of the tube's contents were ingested by a child.
    d) Fluoride ion amounts should be calculated with all toothpaste ingestions. If the fluoride content is not available, an estimate using 1 mg/g is conservative.
    B) SOURCES
    1) SUMMARY - Fluoride is found in insecticides, rodenticides, the petroleum industry, glass etching, and timber preservation industries, dietary supplements, swine anthelmintics. Fluoride is often added to city water supplies.
    a) For information on HYDROFLUORIC ACID, please see that management.
    2) Manifestations of ammonium fluorosilicate toxicity are similar to sodium fluoride.
    a) Ammonium fluosilicate, silicofluoride, hexaflurosilicate, diammonium hexafluoro silicate and other fluosilicate salts are hydrolyzed by alkali to the fluoride ion.
    b) TABLE 1: FLUOROSILICATE CONVERSIONS
    FLUOROSILICATES
    COMPOUND% FLUORIDE
    Fluosilicic acid79.12%
    Sodium fluorosilicate60.62%
    Potassium fluorosilicate51.76%
    Barium fluorosilicate40.79%
    Magnesium fluorosilicate68.51%
    Zinc fluorosilicate54.95%
    Ammonium fluorosilicate63.99%
    Lead fluorosilicate32.64%

    3) TABLE 2: FLUORIDE PRODUCT CONVERSIONS
    FLUORIDE COMPOUNDSALT AMOUNTFLUORIDE ION EQUIVALENT
    Sodium fluoride (NaF) tablets2.2 mg1 mg
    Sodium fluoride (NaF) tablets1.1 mg0.5 mg
    Sodium fluoride (NaF) tablets0.55 mg0.25 mg
    Sodium fluoride toothpaste0.24%1.1 mg/g
    Sodium fluoride rinse2%9.1 mg/mL
    Stannous fluoride (SnF2)4.1 mg1 mg
    Stannous fluoride gel0.4%1 mg/mL
    Stannous fluoride rinse1.64%4 mg/mL
    Stannous fluoride rinse8%19.5 mg/mL
    Stannous fluoride rinse10%24.4 mg/mL
    Acidulated phosphate fluoride(APF)1.23%F12.3 mg/mL
    Sodium monofluorophosphate(MFP)7.6 mg1 mg
    MFP toothpaste0.76%1 mg/g

    4) PROFESSIONAL STRENGTH PRODUCTS
    a) Superdent(R) topical fluoride gel contains 1.23% fluoride (Fisher et al, 1991).
    b) Common professionally applied dental treatments include 2% NaF (equivalent to 0.91% F); 8% SnF2 (equivalent to 1.95% F); 10% SnF2 (equivalent to 2.4% F) or Acidulated Phosphate Fluoride Gel (equivalent to 1.23% F).
    5) FLUORIDE VARNISHES
    a) Fluoride varnishes are available in the United States and were created to prolong contact of the fluoride with tooth enamel. The USFDA has approved these products as medical devices to be used as cavity liners and for the treatment of hypersensitive teeth. Two commercially available fluoride varnishes in the US have concentrations of fluoride of 22,600 ppm F. These products are intended for application by dental professionals (Beltran-Aguilar et al, 2000).
    b) Plasma fluoride concentrations were analyzed in four children (ages 4, 5, 12 and 14 years) after application of a fluoride varnish (Duraphat(R)). The amount of varnish applied ranged from 2.3 to 5.0 milligrams. Peak plasma fluoride concentrations of 3.2 to 6.3 micromolar were observed within two hours of treatment, which was followed by a rapid two-hour decrease. Levels were comparable to brushing with a fluoridated toothpaste or after ingesting a 1 milligram fluoride tablet. The authors concluded that acute toxicity with these products is minimal, and the risk of dental fluorosis is low due to the infrequent application of these varnishes (Beltran-Aguilar et al, 2000).
    6) DENTAL FLUOROSIS SECONDARY TO INCREASED SOURCES OF FLUORIDE
    a) Sources of substantial amounts of ingested fluoride that may contribute to dental fluorosis in young children, other than drinking water, may include bottled water, fruit juices, ready-to- feed infant formulas, soft drinks processed in fluorinated areas, and tea (Levi & Zarei-M, 1991; (Nowak & Nowak, 1989; Flaitz et al, 1989; Stannard et al, 1990; Wiatrowski et al, 1975; Singer & Ophaug, 1979; Johnson & Bawden, 1987; McKnight-Hanes et al, 1988; Clovis & Hargreaves, 1988; Smid & Kruger, 1985).
    b) FOODS: One cup of tea contains 1 to 4 mg of fluoride (Richmond, 1986).
    c) WELL WATER: Fluorosis may occur in some areas as a result of the natural occurrence of fluoride in the groundwater (Felsenfeld & Roberts, 1991).
    d) MINERAL WATER: Some mineral waters contain 8.5 mg/L of fluoride, and have been associated with the development of skeletal fluorosis (Lantz et al, 1987).
    e) BOTTLED WATER: Some bottled water may be lacking in fluoride (McGire, 1989).
    f) META-ANALYSIS - In a review of 214 studies on water fluoridation, a dose-dependent increase in dental fluorosis was found. At a fluoride level of 1 ppm an estimated 12.5% of exposed individuals would develop fluorosis that would produce an aesthetic concern. Of note, the authors did report that the quality of the studies reviewed was low to moderate (McDonagh et al, 2000).
    g) MUNCIPAL WATER SUPPLIES
    1) Fluoride may be added to city or geographic water supplies at the recommended level of 1 ppm to promote the resistance to tooth decay in children (Baselt, 2000).
    C) USES
    1) Sodium fluoride, sodium duosilicate (NA2SiF6) and cryolite (Na3AIF6) are used as insecticides, rodenticides and delousing powders (Baselt, 2000).
    2) Fluoride promotes the resistance of tooth decay in children (Baselt, 2000).
    3) Fluoride can increase the density and calcification of bone, its use has been recommended for individuals with osteoporosis at a daily dose of 33-220 mg as the sodium salt (Baselt, 2000).
    a) In a multicenter prospective study, long term exposure (20 years) to fluoridated drinking water in older women did not increase the risk of fracture and may have had a protective effect (Phipps et al, 2000).
    4) EPIDEMIOLOGY
    a) Dermal exposures are common. Systemic fluoride poisoning is uncommon, but deaths are reported to poison centers each year, primarily from exposure to hydrofluoric acid. Toxicity is very rare following exposure to household dental products (toothpaste and dental rinses), but is theoretically possible following ingestion of fluoride supplements. Fluorosis is common in some areas of Asia due to high fluoride content of water (Hussain et al, 2010; Augenstein et al, 1991).

Overview

Laboratory Monitoring

    A) No testing is required for minor skin exposures.
    B) If there is concern for systemic poisoning, the serum electrolytes including calcium and magnesium, and renal function should be monitored.
    C) An ECG should be obtained and continuous cardiac monitoring instituted.
    D) If there is a potentially large exposure, the serum calcium should be monitored every 15 minutes for 4 to 6 hours.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Most patients with dermal exposure will do well if irrigated immediately. There is no evidence that any products are more effective than water. Patients with ophthalmic exposure should have each eye irrigated with 1 L of normal saline, LR or water.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Early administration of high doses of calcium salts and magnesium may be life-saving. Administer sufficient calcium to maintain serum concentrations in the high-normal range.
    C) DECONTAMINATION
    1) PREHOSPITAL: Decontamination generally is not required after inadvertent ingestion of a dental product. Administer a calcium-containing antacid. DILUTION: Administer milk (preferred) or water (1 or 2 glassfuls) to dilute the corrosive fluoride salt in the oropharynx, esophagus, and stomach. Milk provides calcium ions which may bind to fluoride ions and decrease their penetrability and systemic absorption.
    2) HOSPITAL: Administer a calcium-containing antacid. Consider gastric aspiration for large recent ingestion of a high concentration fluoride salt. Activated charcoal does not adsorb fluoride.
    D) ANTIDOTE
    1) DERMAL EXPOSURE: Patients should be treated in a stepwise manner based on their response to therapy. The initial treatment for pain from dermal exposure is topical calcium. One method for making a gel is to mix calcium gluconate with methylcellulose or water-soluble lubricant in a 1:2 ratio. Apply the gel to the affected areas as frequently as needed to relieve symptoms. If the patient has pain despite topical therapy, extremity burns can be treated with a regional infusion of 40 mL of 2.5% calcium gluconate solution using a Bier block. If this is not successful, an intra-arterial infusion of 40 mL of 2.5% calcium gluconate can be performed. If the area affected is not on an extremity, inject 0.3 to 0.5 mL/cm(2) of 2.5% calcium gluconate into the region.
    2) SYSTEMIC POISONING: Very high doses of calcium may be required. If there is a known large exposure, administer 1 to 2 g of calcium chloride (3 to 6 g of calcium gluconate) while awaiting the initial serum calcium determination. Administer additional calcium to maintain the serum calcium concentration in the high-normal range. Monitor the serum calcium every 15 minutes for several hours. If the patient develops dysrhythmias or hypotension, give an additional 1 to 2 g of calcium chloride (3 to 6 g of calcium gluconate). Hypomagnesemia should be treated with magnesium sulfate, 1 to 2 g given over 10 to 15 minutes (children: 25 to 50 mg/kg diluted to less than 10 mg/mL). Treat hyperkalemia with intravenous calcium and other usual measurements. Systemic alkalinization (to a pH of 7.45 to 7.5) improves survival in animal models of fluoride poisoning and should be considered in cases of life-threatening toxicity.
    E) ENHANCED ELIMINATION PROCEDURE
    1) Fluoride is removed by dialysis; however, patients with significant toxicity are usually too ill to tolerate dialysis.
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: Children with inadvertent ingestions of low fluoride concentration dental products can be managed at home if the ingestion is 8 mg/kg fluoride (17.7 mg/kg sodium fluoride) or less and the child does not have symptoms beyond minor gastrointestinal upset. To calculate the amount of fluoride ion ingested, use the following equations based on the type of fluoride in the product ingested: SODIUM FLUORIDE: (Concentration in %)(Amount ingested in oz)(Constant=128)/Patient weight in kg= mg/kg ingested; SODIUM MONOFLUOROPHOSPHATE: (Concentration in %)(Amount ingested in oz)(Constant=37)/Patient weight in kg= mg/kg ingested; FLUORIDE ION (w/v%): (Concentration in %)(Amount ingested in oz)(Constant=218)/Patient weight in kg= mg/kg ingested (Derivations of all constants are explained in the Range of Toxicity/Calculations section).
    2) OBSERVATION CRITERIA: All ingestion and inhalation exposures to higher concentration or industrial products, and all deliberate ingestions should be considered potentially fatal and should be referred to a healthcare facility and observed for a minimum of 6 hours. Patients with skin burn greater than 5% body surface area (BSA) from low concentration products or more than 1% BSA from high concentration products should be observed for systemic effects.
    3) ADMISSION CRITERIA: Patients with significant burns and those who require intra-arterial calcium require admission. Patients with systemic toxicity or ECG changes should be admitted to an ICU setting.
    G) PHARMACOKINETICS
    1) Fluoride is a weak acid (pKa 3.4) that is passively absorbed from the stomach and intestine. Fasting peak absorption occurs in 30 to 60 minutes. The volume of distribution is 0.5 to 0.7 L/kg and it is not protein bound. The elimination half-life is about 2.4 to 4.3 hours and prolonged in patients with renal failure.
    H) DIFFERENTIAL DIAGNOSIS
    1) Hyperkalemia, hyperphosphatemia, hypomagnesemia, or hypocalcemia from other causes.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) Patients with ophthalmic exposure should have each eye irrigated with 1 L of normal saline, LR or water.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Most patients with dermal exposure will do well if irrigated immediately. There is no evidence that any products are more effective than water.
    2) DERMAL EXPOSURE: Patients should be treated in a stepwise manner based on their response to therapy. The initial treatment for pain from dermal exposure is topical calcium. One method for making a gel is to mix calcium gluconate with methylcellulose or water-soluble lubricant in a 1:2 ratio. Apply the gel to the affected areas as frequently as needed to relieve symptoms. If the patient has pain despite topical therapy, extremity burns can be treated with a regional infusion of 40 mL of 2.5% calcium gluconate solution using a Bier block. If this is not successful, an intra-arterial infusion of 40 mL of 2.5% calcium gluconate can be performed. If the area affected is not on an extremity, inject 0.3 to 0.5 mL/cm(2) of 2.5% calcium gluconate into the region.

Range Of Toxicity

    A) TOXICITY: Vomiting and abdominal pain are common with ingestions of 3 to 5 mg/kg of elemental fluoride. Hypocalcemia and muscular symptoms may appear with 5 to 10 mg/kg. Thirty-two to 64 mg/kg of fluoride should be considered fatal if untreated. Intractable ventricular fibrillation has been reported in lethal cases.
    B) THERAPEUTIC DOSE: ADULTS: The average daily dietary fluoride intake ranges from 0.5 to 5 mg as the anion. CHILDREN: Fluoride supplementation may be recommended in children and infants, based on the amount of fluoride in the water supply: 0 to 6 months: None. 6 months to 3 yr: 0.25 mg/day if less than 0.3 ppm; 3 to 6 yr: 0.5 mg/day if less than 0.3 ppm and 0.25 mg/day if 0.3 to 0.6 ppm. 6 to 16 yr: 1 mg/day if less than 0.3 ppm and 0.5 mg/day if 0.3 to 0.6 ppm. Note: 2.2 mg of sodium fluoride contains 1 mg fluoride ion.
    C) CALCULATIONS: To calculate the amount of fluoride ion ingested from toothpaste, use the following equations based on the type of fluoride in the product (derivations of all constants and calculation conversions are explained in the Range of Toxicity/Calculations section):
    1) SODIUM FLUORIDE
    a) To calculate the amount of F ion ingested from sodium fluoride, use the following equation: (Concentration in %)(Amount ingested in oz)(Constant = 128)/Patient weight in kg = fluoride ion mg/kg ingested
    2) SODIUM MONOFLUOROPHOSPHATE
    a) To calculate the amount of F ion ingested from sodium monofluorophosphate, use the following equation: (Concentration in %)(Amount ingested in oz)(Constant = 37)/Patient weight in kg = fluoride ion mg/kg ingested
    3) STANNOUS FLUORIDE
    a) To calculate the amount of F ion ingested from stannous fluoride, use the following equation: (Concentration in %)(Amount ingested in oz)(Constant = 69)/Patient weight in kg = fluoride ion mg/kg ingested.
    4) FLUORIDE ION
    a) To calculate the amount of F ion ingested when only the w/v% of fluoride ion is given, use the following calculation (this assumes a specific gravity of 1.3): (Concentration in %)(Amount ingested in oz)(Constant = 218)/Patient weight in kg = fluoride ion mg/kg ingested
    5) QUICK CALCULATIONS FOR COMMON STRENGTHS
    a) 0.24% SODIUM FLUORIDE: Use the following equation: (Amount ingested in oz)(31 mg F ion/oz NaF)/Patient weight in kg = fluoride ion mg/kg ingested.
    b) 0.76% SODIUM MONOFLUOROPHOSPHATE: Use the following equation: (Amount ingested in oz)(28.35 mg F ion/oz NaMPF)/Patient weight of child in kg = fluoride ion mg/kg ingested

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Several fluoride salts are used in dental products. Chronic fluoride poisoning (fluorosis) may occur in areas where the water has very high fluoride concentrations. Fluoride-liberating chemicals (such as ammonium fluoride, ammonium bifluoride, and sodium fluorosilicate) are used in some automobile wheel cleaners and rust removers. Sodium fluoride was used as a rodenticide. Hydrofluoric acid (HF) is used in etching glass and cleaning silicon chip products. Ammonium bifluoride and hydrofluoric acid are covered in separate managements.
    B) PHARMACOLOGY: Fluoride promotes remineralization of decalcified dental enamel and may interfere with the growth of bacteria in dental plaque.
    C) TOXICOLOGY: Sodium fluoride reacts with the gastric acid to form hydrofluoric acid. The major toxic effects of fluoride are due to the chelation of calcium and magnesium. In tissue, the local hypocalcemia causes pain and cellular death. Systemic hypocalcemia and hypomagnesemia may cause cardiac dysrhythmias and cardiovascular collapse. Fluoride opens the calcium-dependent potassium channels on erythrocytes resulting in hyperkalemia. Fluoride also impairs oxidative phosphorylation. Long-term ingestion of water with high fluoride concentrations results in weak and brittle bones (fluorosis).
    D) EPIDEMIOLOGY: Dermal exposures are common. Systemic fluoride poisoning is uncommon, but deaths are reported to poison centers each year, primarily from exposure to hydrofluoric acid. Toxicity is very rare following exposure to household dental products (toothpaste and dental rinses), but is theoretically possible following ingestion of fluoride supplements. Fluorosis is common in some areas of Asia due to high fluoride content of water.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Acute ingestion of dental products containing sodium fluoride generally causes minor gastrointestinal upset. Skin exposure to household products with higher concentrations of fluoride ion results in pain that develops slowly. The tissue may appear normal but the patient can have severe pain. Over time the skin may become hyperemic with subsequent blanching and cogitative necrosis. Eye exposure can cause irritation and corneal edema; if fluoride concentration is higher, conjunctival ischemia and chemosis may develop. Inhalation causes minor upper respiratory tract irritation. Nausea and vomiting frequently occurs within 30 to 60 minutes of ingestion.
    2) SEVERE TOXICITY: Severe toxicity generally only develops after exposure to industrial products containing fairly high concentrations of sodium fluoride or sodium bifluoride. Severe burns (ocular and dermal) may occur following exposure to higher concentration products. Burns involving more than 5% body surface area (BSA) from low concentration products or more than 1% BSA from high concentration products may produce systemic fluoride poisoning. Systemic toxicity most commonly occurs following ingestion, but may occur following dermal or inhalational exposure. Inhalation may cause acute lung injury from direct tissue injury. Symptoms of serious toxicity include skeletal muscle weakness and spasm, respiratory muscle weakness, and respiratory arrest. Ventricular dysrhythmias and fibrillation are thought to be the main cause of death. Patients may have severe toxicity without significant oral or gastrointestinal symptoms.
    0.2.5) CARDIOVASCULAR
    A) Cardiac dysrhythmias consistent with hyperkalemia may be noted. Fatal cardiac arrest occurred in several patients with renal failure exposed to fluoride during hemodialysis. QT prolongation secondary to hypocalcemia can occur following fluoride toxicity.
    0.2.6) RESPIRATORY
    A) Respirations are first stimulated then depressed. Death is usually from respiratory muscle paralysis. Following inhalation, coughing and choking may be noted.
    0.2.7) NEUROLOGIC
    A) Hyperactive reflexes, painful muscle spasms, weakness and tetanic contractures may be noted due to fluoride induced hypocalcemia.
    0.2.8) GASTROINTESTINAL
    A) Epigastric pain, nausea, dysphagia, salivation, hematemesis, and diarrhea can occur. These effects may be delayed for several hours following oral exposure. GI symptoms can develop following fluoride ingestions of 3 mg/kg or more.
    0.2.9) HEPATIC
    A) An increase of hepatic enzymes have been reported following sodium fluoride toxicity.
    0.2.12) FLUID-ELECTROLYTE
    A) Hyperkalemia and hypomagnesemia may occur following fluoride toxicity. Hypocalcemia is likely to develop with acute exposure.
    0.2.14) DERMATOLOGIC
    A) Urticaria and pruritus have been reported following dermal exposure to fluoride.
    0.2.20) REPRODUCTIVE
    A) Prenatal fluoride supplementation (2.2 mg NaF or 1 mg fluoride daily) during the last two trimesters of pregnancy has been reported to be safe.
    0.2.22) OTHER
    A) CHRONIC EXPOSURE: Prolonged exposure to fluorinated water may cause fluorosis. Signs and symptoms of fluorosis include brittle bones, calcified ligaments, and other crippling changes.

Clinical Effects

Summary Of Exposure

    A) USES: Several fluoride salts are used in dental products. Chronic fluoride poisoning (fluorosis) may occur in areas where the water has very high fluoride concentrations. Fluoride-liberating chemicals (such as ammonium fluoride, ammonium bifluoride, and sodium fluorosilicate) are used in some automobile wheel cleaners and rust removers. Sodium fluoride was used as a rodenticide. Hydrofluoric acid (HF) is used in etching glass and cleaning silicon chip products. Ammonium bifluoride and hydrofluoric acid are covered in separate managements.
    B) PHARMACOLOGY: Fluoride promotes remineralization of decalcified dental enamel and may interfere with the growth of bacteria in dental plaque.
    C) TOXICOLOGY: Sodium fluoride reacts with the gastric acid to form hydrofluoric acid. The major toxic effects of fluoride are due to the chelation of calcium and magnesium. In tissue, the local hypocalcemia causes pain and cellular death. Systemic hypocalcemia and hypomagnesemia may cause cardiac dysrhythmias and cardiovascular collapse. Fluoride opens the calcium-dependent potassium channels on erythrocytes resulting in hyperkalemia. Fluoride also impairs oxidative phosphorylation. Long-term ingestion of water with high fluoride concentrations results in weak and brittle bones (fluorosis).
    D) EPIDEMIOLOGY: Dermal exposures are common. Systemic fluoride poisoning is uncommon, but deaths are reported to poison centers each year, primarily from exposure to hydrofluoric acid. Toxicity is very rare following exposure to household dental products (toothpaste and dental rinses), but is theoretically possible following ingestion of fluoride supplements. Fluorosis is common in some areas of Asia due to high fluoride content of water.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Acute ingestion of dental products containing sodium fluoride generally causes minor gastrointestinal upset. Skin exposure to household products with higher concentrations of fluoride ion results in pain that develops slowly. The tissue may appear normal but the patient can have severe pain. Over time the skin may become hyperemic with subsequent blanching and cogitative necrosis. Eye exposure can cause irritation and corneal edema; if fluoride concentration is higher, conjunctival ischemia and chemosis may develop. Inhalation causes minor upper respiratory tract irritation. Nausea and vomiting frequently occurs within 30 to 60 minutes of ingestion.
    2) SEVERE TOXICITY: Severe toxicity generally only develops after exposure to industrial products containing fairly high concentrations of sodium fluoride or sodium bifluoride. Severe burns (ocular and dermal) may occur following exposure to higher concentration products. Burns involving more than 5% body surface area (BSA) from low concentration products or more than 1% BSA from high concentration products may produce systemic fluoride poisoning. Systemic toxicity most commonly occurs following ingestion, but may occur following dermal or inhalational exposure. Inhalation may cause acute lung injury from direct tissue injury. Symptoms of serious toxicity include skeletal muscle weakness and spasm, respiratory muscle weakness, and respiratory arrest. Ventricular dysrhythmias and fibrillation are thought to be the main cause of death. Patients may have severe toxicity without significant oral or gastrointestinal symptoms.

Vital Signs

    3.3.3) TEMPERATURE
    A) FEVER: Fever to 39.7 C developed in a 39-year-old man who ingested a roach powder containing 40% sodium fluoride (Harchelroad & Gowtz, 1993).

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) Eye exposure can cause irritation and corneal edema; if fluoride concentration is higher, conjunctival ischemia and chemosis may develop (McCulley et al, 1983).
    2) Eye irritation has been reported with the use of a potassium aluminum tetrafluoride flux (Hjortsberg et al, 1994).
    3.4.5) NOSE
    A) WITH POISONING/EXPOSURE
    1) RHINITIS: Rhinitis has been reported with the use of a potassium aluminum tetrafluoride flux (Hjortsberg et al, 1994).
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) DENTAL FLUOROSIS: Exposure of children to excessive fluoride results in defective dental enamel formation, causing pits to form in teeth (Ishu & Suckling, 1991).
    a) Patients with longstanding exposure to excessive fluoride level in water develop changes in pigmentation of teeth (yellow to brown or black) (Abdennebi et al, 1995).
    b) Young children may be at risk for dental fluorosis because they are receiving excess fluoride toothpaste, fluoridated water, and other sources (Levy & Zarei-M, 1991).
    c) CASE REPORT: An 8-year-old boy presented with severely mottled teeth, and a history revealed that he had consumed water from a fluoride-contaminated well for years in the past. He had a younger sibling with dental fluorosis, and 85 children from surrounding villages also presented with teeth problems. Despite not drinking the contaminated water at the time of presentation, the boy's urine fluoride level was 2.04 mg/L (reference level 0.1 mg/L), and the fluoride level of the well water was 15.74 mg/L (reference level 1.5 mg/L) (Nayak et al, 2009).

Cardiovascular

    3.5.1) SUMMARY
    A) Cardiac dysrhythmias consistent with hyperkalemia may be noted. Fatal cardiac arrest occurred in several patients with renal failure exposed to fluoride during hemodialysis. QT prolongation secondary to hypocalcemia can occur following fluoride toxicity.
    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH POISONING/EXPOSURE
    a) SUMMARY: Cardiac dysrhythmias secondary to hypocalcemia or hyperkalemia can occur following fluoride toxicity (Clancy, 2002).
    b) In patients with serious toxicity, ventricular dysrhythmias and fibrillation are thought to be the main cause of death (Klasner et al, 1996).
    c) CASE REPORTS
    1) A 38-year-old man inadvertently ingested approximately 100 mL of liquid containing 70% zinc hexafluorosilicate and was taken to the emergency department immediately. Cyanosis, hypotension, and a serum calcium level near 0 were noted on exam. He was treated with gastric lavage, ranitidine, hydrocortisone, and dopamine. Approximately 3 hours after ingestion, he developed ventricular fibrillation. CPR was started and the patient was intubated. He was defibrillated 15 times but died approximately 35 minutes after the onset of ventricular fibrillation (Lech, 2011).
    2) Dysrhythmias consistent with hyperkalemia (ie, marked peaking of T-waves) were reported in a fatal fluoride overdose. The patient developed refractory ventricular fibrillation (Baltazar et al, 1980).
    3) A 56-year-old man who ingested a spoonful of etching cream containing 20% ammonium bifluoride and 13% sodium bifluoride developed ST depression followed by ventricular fibrillation associated with hypomagnesemia and hypocalcemia (Swanson et al, 1993).
    B) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 38-year-old man inadvertently ingested approximately 100 mL of liquid containing 70% zinc hexafluorosilicate and was taken to the emergency department immediately. Cyanosis, hypotension (80/50 mmHg), and a serum calcium level near 0 were noted on exam. He was treated with gastric lavage, ranitidine, hydrocortisone, and dopamine. Approximately 3 hours after ingestion, he developed ventricular fibrillation. CPR was started and the patient was intubated. He was defibrillated 15 times but died approximately 35 minutes after the onset of ventricular fibrillation (Lech, 2011).
    b) CASE REPORT: Hypotension (blood pressure 80/40) developed in a 56-year-old man who ingested a spoonful of etching cream containing 20% ammonium bifluoride and 13% sodium bifluoride (Swanson et al, 1993).
    C) CARDIAC ARREST
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 38-year-old man inadvertently ingested approximately 100 mL of liquid containing 70% zinc hexafluorosilicate and was taken to the emergency department immediately. Cyanosis, hypotension (80/50 mmHg), and a serum calcium level near 0 were noted on exam. He was treated with gastric lavage, ranitidine, hydrocortisone, and dopamine. Approximately 3 hours after ingestion, he developed ventricular fibrillation. CPR was started and the patient was intubated. He was defibrillated 15 times but died approximately 35 minutes after the onset of ventricular fibrillation (Lech, 2011).
    b) CASE REPORTS: Cardiac arrest occurred in three patients following exposure to fluoride (used in water purification) during hemodialysis. Symptoms developed 4 to 6.5 hours after treatment began. Pruritus, nausea, vomiting, diarrhea, and chest or leg pain were described prior to arrest. Each patient had fatal ventricular fibrillation, which was unresponsive to cardioversion. Older age and longer hemodialysis treatment were found to be associated with an increased likelihood of fatal dysrhythmias compared with other patients who did not die following dialysis using the same system. The authors found that the dialysis system was releasing high concentrations of fluoride (increased serum concentrations were found in all patients) because of continued use after the ion exchange resin was exhausted (Arnow et al, 1994).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ECG ABNORMAL
    a) DOGS: ECG changes noted in dogs receiving intravenous sodium fluoride include peaked T waves, decreased QRS voltage and increased T wave voltage, QRS widening, ST changes, loss of P wave amplitude and ventricular fibrillation. Increased pulmonary artery and wedge pressures and a decreased central venous pressure also occurred in this model (Gaugl & Wooldridge, 1983; McIvor et al, 1987; Cummings & McIvor, 1988).

Respiratory

    3.6.1) SUMMARY
    A) Respirations are first stimulated then depressed. Death is usually from respiratory muscle paralysis. Following inhalation, coughing and choking may be noted.
    3.6.2) CLINICAL EFFECTS
    A) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Inhalation may cause acute lung injury from direct tissue injury (Kono et al, 2000).
    B) APNEA
    1) WITH POISONING/EXPOSURE
    a) RESPIRATORY PARALYSIS: Respirations are first stimulated, then depressed. Death usually is from muscle respiratory paralysis (Heifetz & Horowitz, 1986).
    C) PNEUMONIA
    1) WITH POISONING/EXPOSURE
    a) On inhalation of fluoride, coughing and choking will occur for 1 to 2 hours after exposure, followed by an asymptomatic period 1 to 2 days. Fever, cough, chest tightness, rales, and cyanosis may then occur 2 to 4 days after exposure and then slowly regress over the following 10 to 30 days.
    D) DYSPNEA
    1) WITH POISONING/EXPOSURE
    a) Shortness of breath developed in 4 of 91 patients (4%) who drank water contaminated with sodium fluoride (150 mg/L) (Gessner et al, 1994).
    E) DISORDER OF RESPIRATORY SYSTEM
    1) WITH POISONING/EXPOSURE
    a) Symptoms of serious toxicity include respiratory muscle weakness and respiratory arrest (Klasner et al, 1996).
    b) REACTIVE AIRWAYS: Cough, chest tightness and a decrease in FEV1 after methacholine challenge were reported in workers exposed to potassium aluminum tetrafluoride via inhalation during the soldering of aluminum (Hjortsberg et al, 1994).

Neurologic

    3.7.1) SUMMARY
    A) Hyperactive reflexes, painful muscle spasms, weakness and tetanic contractures may be noted due to fluoride induced hypocalcemia.
    3.7.2) CLINICAL EFFECTS
    A) HYPERREFLEXIA
    1) WITH POISONING/EXPOSURE
    a) Hypocalcemia secondary to fluoride toxicity can result in an increase in skeletal muscle excitability, hyperactive reflexes, painful muscular spasms (particularly in the extremities), weakness, and tetanic contractures approximately 3 to 5 hours after exposure (Arena, 1979).
    b) CARPOPEDAL SPASM may develop in patients with severe hypocalcemia (Harchelroad & Gowtz, 1993).
    B) FATIGUE
    1) WITH POISONING/EXPOSURE
    a) Weakness developed in 10 of 91 patients (10%) who drank water contaminated with sodium fluoride (150 mg/L) (Gessner et al, 1994).
    C) PARESTHESIA
    1) WITH POISONING/EXPOSURE
    a) Numbness or tingling of an extremity developed in 4 of 91 patients (4%) who drank water contaminated with sodium fluoride (150 mg/L) (Gessner et al, 1994).
    D) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Headache developed in 11 of 91 patients (11%) who drank water contaminated with sodium fluoride (150 mg/L) (Gessner et al, 1994).

Gastrointestinal

    3.8.1) SUMMARY
    A) Epigastric pain, nausea, dysphagia, salivation, hematemesis, and diarrhea can occur. These effects may be delayed for several hours following oral exposure. GI symptoms can develop following fluoride ingestions of 3 mg/kg or more.
    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH POISONING/EXPOSURE
    a) SYMPTOMS: Acute ingestion can result in the following: epigastric pain, dysphagia, salivation, nausea, vomiting, and hematemesis (Monsour et al, 1984; Eichler et al, 1982; Augenstein et al, 1991; Gessner et al, 1994; Swanson et al, 1993).
    b) ONSET: Acute fluoride poisoning occurred in two villages in Alaska following excessive levels of fluoride found in one of two public water systems. Clinical effects may develop within minutes or be delayed for several hours after acute oral exposure (Gessner et al, 1994).
    c) Patients may have severe toxicity without significant oral or gastrointestinal symptoms (Kao et al, 1999).
    B) INJURY OF STOMACH
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 56-year-old man who ingested a spoonful of etching cream containing 20% ammonium bifluoride and 13% sodium bifluoride developed significant burns of the distal esophagus, antrum and gastric body (Swanson et al, 1993).
    C) EPIGASTRIC PAIN
    1) WITH THERAPEUTIC USE
    a) Epigastric pain, anorexia and nausea are common complaints in patients taking therapeutic doses (30 mg/day) of sodium fluoride (Das et al, 1994).
    2) WITH POISONING/EXPOSURE
    a) A 23-year-old male complained of severe epigastric pain after accidentally ingesting magnesium fluorosilicate (Brookes et al, 1984). The patient recovered completely following dilution with milk and 300 mL of 1% calcium hydroxide. Laboratory analyses remained normal.
    D) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea has been reported with therapeutic use of sodium fluoride (Das et al, 1994).
    2) WITH POISONING/EXPOSURE
    a) Diarrhea occurred after acute oral exposure from a water supply with excessive levels of fluoride (Gessner et al, 1994).
    E) GASTRITIS
    1) WITH THERAPEUTIC USE
    a) MUCOSAL INJURY: Fairly low concentrations of fluoride (1 mg/mL) can cause superficial damage to the gastric mucosa (Spak et al, 1989; Pashley et al, 1984).
    b) In one study all 10 patients taking 30 mg/day of sodium fluoride for at least 3 months demonstrated petechiae, erosions and erythema on upper gastrointestinal endoscopy, compared with 0 of 10 control subjects (Das et al, 1994).
    F) DYSPHAGIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 50-year-old man, who developed compromised salivary function following post-surgical radiation for treatment of squamous cell carcinoma of the tongue, was prescribed a fluoride treatment regimen, 1 to 2 mL of a topical fluoride gel applied once daily via maxillary and mandibular thermoplastic trays. The patient modified his treatment regimen by applying the fluoride gel twice daily instead of once daily, and subsequently developed gastric distress and dysphagia, as well as myalgia and arthralgia of the leg muscles and knee joints. A CT scan showed esophageal thickening and an endoscopy revealed abnormal motility with normal mucosa. Urine samples showed elevated fluoride levels ranging from 1.73 to 7.26 parts per million (ppm). Discontinuing the tray treatments and switching the patient to brushing once daily with 1.1% sodium fluoride dentrifice resolved his symptoms. Ten days after beginning dentrifice treatment, urine samples, collected at 8.5 hours and 24 hours after brushing, showed urinary fluoride concentrations of 1.71 and 0.87 ppm, respectively (Eichmiller et al, 2005).

Hepatic

    3.9.1) SUMMARY
    A) An increase of hepatic enzymes have been reported following sodium fluoride toxicity.
    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) Of 14 patients who drank water contaminated with sodium fluoride, all had mild elevations of lactate dehydrogenase (median 152 Units/L) and 11 had elevated aspartate aminotransferase levels (Gessner et al, 1994).
    b) CASE REPORT: A 39-year-old man who ingested a roach powder containing 40% sodium fluoride developed a transiently elevated LDH level (390 International Units/Liter) (Harchelroad & Gowtz, 1993).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL RENAL FUNCTION
    1) WITH POISONING/EXPOSURE
    a) Renal damage may occur after chronic fluoride intoxication (Maes et al, 1960; Manigand et al, 1970; Lantz et al, 1987).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) BLOOD COAGULATION PATHWAY FINDING
    1) Reduction of serum calcium, secondary to fluoride toxicity can interfere with blood coagulation.
    B) LEUKOCYTOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 39-year-old man who ingested a roach powder containing 40% sodium fluoride developed a transient leukocytosis (Harchelroad & Gowtz, 1993).

Dermatologic

    3.14.1) SUMMARY
    A) Urticaria and pruritus have been reported following dermal exposure to fluoride.
    3.14.2) CLINICAL EFFECTS
    A) PAIN
    1) WITH POISONING/EXPOSURE
    a) Skin exposure to household products with higher concentrations of fluoride ion results in pain that develops slowly. The tissue may appear normal but the patient can have severe pain. Over time the skin may become hyperemic with subsequent blanching and cogitative necrosis (Hojer et al, 2002).
    B) DERMATITIS
    1) WITH POISONING/EXPOSURE
    a) Skin eruptions may occur. Sodium fluoride, ammonium fluoride, and sodium hexafluorosilicate have all been reported to produce contact pustular reactions on previously damaged or inflamed skin (Fisher et al, 1959; Becker & O'Brien, 1959; Dooms-Goossens et al, 1985).
    C) URTICARIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: An 8-year-old girl with a history of allergies developed disseminated urticaria and angioedema after the third application of a sodium fluoride product to her teeth. The authors could not determine whether this represented immunological or non-immunological contact urticaria (Camarasa et al, 1993).
    D) ITCHING OF SKIN
    1) WITH POISONING/EXPOSURE
    a) CASE REPORTS: Pruritus was reported in 10 of 12 patients on chronic hemodialysis secondary to acute fluoride intoxication from a temporary deionization water purification system. Unexposed (did not receive dialysis in the same room) patients in the same dialysis center did not complain of any symptoms. Pruritic symptoms were described as severe and did not improve with diphenhydramine use (Arnow et al, 1994).
    E) BURN
    1) WITH POISONING/EXPOSURE
    a) Severe burns (ocular and dermal) may occur following exposure to higher concentration products. Burns involving more than 5% body surface area (BSA) from low concentration products or more than 1% BSA from high concentration products may produce systemic fluoride poisoning (Greco et al, 1988).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) OSTEOSCLEROSIS
    1) WITH POISONING/EXPOSURE
    a) SKELETAL FLUOROSIS: In a survey of aluminum workers exposed to fluoride, 20% had possible or definite fluorosis after 1 to 32 years. Symptoms included joint pain, limited joint mobility, ossifications on x-ray, osteosclerosis, and thickening of long bone cortices (Czerwinski et al, 1988).
    1) Prolonged exposure to water contaminated with high levels of fluoride (0.86 to 1.33 mcg/mL) and fluoride contaminated soil may cause fluorosis. Effects of fluorosis may include brittle bones, calcification of ligaments, and joint pain (Abdennebi et al, 1995). Histological changes such as osteomalacia may occur.
    2) Treatment of osteoporosis with sodium fluoride has also been associated with severe extremity pain and skeletal fluorosis demonstrated by bone scan (Weingrad et al, 1991).
    b) CASE REPORT: A 48-year old woman developed crippling (phase 3) skeletal fluorosis after a 36 year history of drinking 1 to 2 gallons daily of brewed black tea containing an estimated 14.6 mg of fluoride ion/gallon. She presented with pain in her elbows, wrists, hips, knees, and ankles and was experiencing increased difficulties with mobility. Physical exam revealed severe bone and joint pain (without swelling or warmth), kyphosis, and osteosclerosis. Initial lab analysis revealed serum 25-hydroxyvitamin D (25OHD) less than 10 nanograms (ng)/mL (normal range 30 to 80 ng/mL); parathyroid hormone (PTH), 169 and 196 picograms (pg)/mL (normal range 10 to 65 pg/mL); TSH, 5.1 micro international units/mL (normal range 0.3 to 4.2 micro international units/mL). Bone scintigraphy showed active bone remodeling and findings consistent with metabolic bone disease. However, bone mineral density (BMD) T-scores were normal with a low fracture risk. After 5 months of treatment with oral ergocalciferol 50,000 units once weekly, lab analysis showed a normal 25OHD level of 62 ng/mL; PTH remained elevated at 196 pg/mL; total calcium, 9.2 mg/dL; serum osteocalcin, 266 ng/mL (normal range 10 to 50 ng/mL); urine N-telopeptide of type I collagen, 495 nM bone collage equivalents/mM creatinine (normal 21 to 83). After 6 months of ergocalciferol therapy and cessation from drinking tea, she reported nearly complete resolution of pain(Izuora et al, 2011).
    B) MUSCLE PAIN
    1) WITH POISONING/EXPOSURE
    a) Myalgia and arthralgia of the leg muscles and knee joints were reported in a 50-year-old man who topically applied 1 to 2 mL of a fluoride gel twice daily via maxillary and mandibular thermoplastic trays instead of once daily as prescribed. His urinary fluoride levels ranged from 1.73 to 7.26 parts per million (ppm). Discontinuing the tray treatments and switching to brushing once daily with 1.1% sodium fluoride dentrifice resolved the patient's symptoms. Ten days after beginning dentrifice treatment, urine samples, collected at 8.5 hours and 24 hours after brushing, showed urinary fluoride concentrations of 1.71 and 0.87 ppm, respectively (Eichmiller et al, 2005).
    C) SPASM
    1) WITH POISONING/EXPOSURE
    a) Skeletal muscle weakness and spasm may occur with serious toxicity (Klasner et al, 1996).

Reproductive

    3.20.1) SUMMARY
    A) Prenatal fluoride supplementation (2.2 mg NaF or 1 mg fluoride daily) during the last two trimesters of pregnancy has been reported to be safe.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) Several epidemiological studies have found no correlation between the level of fluoride in drinking water (typically between 1 and 10 ppm) and birth defects (Knox, 1980; Erickson, 1976). In general, there is no danger of osteosclerosis in the unborn even with high-level maternal fluoride exposure, because this condition requires many years to develop (Hodge & Macgregor, 1982).
    2) Fluoride at a concentration of 8 ppm in the drinking water has been shown to have no effect on human reproduction (Hodge & Macgregor, 1982), while levels in the range of 12 to 18 ppm have rarely produced mottled deciduous teeth (Hodge & Macgregor, 1982). In another study, fluoride at a concentration of 8 ppm or greater in the drinking water is known to cause mottled deciduous teeth if exposure occurs during the period of synthesis of the dental enamel (from before birth to approximately age 8 years) (Gedalia, 1964).
    3) The effect of prenatal exposure to fluoride on permanent teeth is debatable. One study found no difference in caries incidence in children born before versus at least 9 months after community drinking water fluoridation (Anon, 1967).
    B) ANIMAL STUDIES
    1) Sodium fluoride at doses of 30 or 60 mg was embryotoxic to rats, doses of 10 to 66 mg/kg for 2 months resulted in no conceptions in mice, and a dose of 30 mg/kg for 1 year affected fertility and was embryotoxic in rabbits (Mandrik & Yakubovskaya, 1984).
    2) Fewer corpora lutea and implants were seen in pregnant rats exposed to 250 ppm sodium fluoride in the drinking water throughout gestation, but there were no treatment related external malformations or developmental bone defects. Nonsignificant increases in skeletal variations were seen, but these are not considered defects (Collins et al, 1995).
    3.20.3) EFFECTS IN PREGNANCY
    A) PLACENTAL BARRIER
    1) Fluoride metabolism is not affected by pregnancy (Maheshwari, 1981). The maternal plasma fluoride level decreases during pregnancy, presumably because the fetus extracts fluoride for normal development of bone and teeth (Hahijarvi, 1981). With low maternal fluoride intake, the fetus concentrates fluoride (Gedalia, 1964), such that fetal plasma fluoride levels can exceed those of the mother by ten times (Louw & Van WYK, 1984). Another study found similar levels of plasma fluoride in maternal and cord blood (Teotia, 1979).
    2) Transplacental transfer of fluoride occurs, primarily to the fetal skeleton (Gedalia, 1964). Fluoride is thought to be required for normal fetal development.
    B) PREGNANCY DISORDER
    1) Gynecological disorders, miscarriages, and pathological pregnancies were reported following occupational exposure of fluoride (Danilov, 1975).
    C) ANIMAL STUDIES
    1) Sodium fluoride at levels as high as 300 ppm in the drinking water of pregnant rats on days 6 through 15 of gestation did not affect postimplantation loss, fetal weight, or malformations. Similar results were seen in rabbits exposed to levels as high as 400 ppm (Heindel et al, 1996).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Up to 25% of absorbed fluoride can be excreted in breast milk, sweat, tears, and feces (McIvor, 1990).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS16984-48-8 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) IARC Classification
    a) Listed as: Fluorides (inorganic, used in drinking-water)
    b) Carcinogen Rating: 3
    1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    3.21.3) HUMAN STUDIES
    A) LACK OF EFFECT
    1) Excess incidences of lung and bladder cancer were seen in a follow-up study of men exposed to cryolite. The highest rates were seen 10 to 19 years after employment (Grandjean et al, 1992). While it is possible that there may have been a smoking effect, the bladder cancers could not be explained by smoking alone.
    2) In a case-control study on 130 children with osteosarcoma in New York State, lifetime fluoride exposure was not associated with this cancer, and there was a protective effect in males (Gelberg et al, 1995).
    3) None of the epidemiologic studies relating fluoride levels in drinking water with cancer has shown a positive association. Fluoride (in drinking water) is in IARC Group 3 (not classifiable as to its carcinogenicity to humans) (ACGIH, 1992).
    4) The preponderance of human epidemiology has concluded that fluoride is not a human carcinogen (DHHS, 1985).
    5) In one epidemiological study, 431 male cryolite workers exposed to fluoride between 1924 and 1961 had excess deaths from violence and cancers, especially respiratory cancers, with the latter thought NOT to be due to fluoride (Grandjean, 1985). A study of 948 employees in fertilizer manufacturing from 1959-1963 found mortality similar to that of unexposed persons (Machle & Barnes, 1966).
    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) Chronic exposure studies with sodium fluoride in experimental animals have shown a possible increase in cancer. Mammary carcinomas were increased in mice given sodium fluoride at doses of 900 mg/kg in the diet or 0.4, 1.0, 4.0 mg/L in the water (HSDB). However, these types of tumors occurred spontaneously at high frequencies in the mice; therefore the IARC regards sodium fluoride as an animal indefinite carcinogen (IARC, 1982).
    2) Sodium fluoride has been further studied for its ability to cause cancer in experimental animals in the National Toxicology Program (NTP). In this latter study, a modest number of osteosarcomas were seen in male rats, but the results have been called equivocal (Bucher et al, 1991). No increases in neoplasms were seen in mice or in female rats.
    B) LACK OF EFFECT
    1) Studies have failed to establish an association between fluoride and cancer (CDC, 1991).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No testing is required for minor skin exposures.
    B) If there is concern for systemic poisoning, the serum electrolytes including calcium and magnesium, and renal function should be monitored.
    C) An ECG should be obtained and continuous cardiac monitoring instituted.
    D) If there is a potentially large exposure, the serum calcium should be monitored every 15 minutes for 4 to 6 hours.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Determine serum calcium if ingestion is suspected.
    2) The normal serum concentration is 0.4 to 2 mcg% (mcg/dL) for ionic fluorides. However, fluoride levels are rarely helpful in the acute management of patients.
    4.1.3) URINE
    A) URINARY LEVELS
    1) In an occupational setting where workers are exposed to fluoride, urine fluoride measurements should be monitored every 6 months.
    2) Several sources have suggested maximum urinary excretion values of 4 (preshift) and 7 (postshift) mg/L in occupational exposures (Levi et al, 1986).
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Monitor ECG. The presence of peaked T waves may indicate hyperkalemia; prolonged Q-T interval may indicate hypocalcemia and may place the individual at risk to develop cardiac dysrhythmias.

Radiographic Studies

    A) RADIOGRAPHIC-OTHER
    1) Chronic fluorosis is diagnosed based on clinical manifestations and x-rays showing increased bone density, mineral deposits in ligaments, tendons, and muscles, and periosteal outgrowths.
    2) A bone scan may demonstrate increased uptake along the shaft of the long bones and joints (Weingrad et al, 1991).

Methods

    A) OTHER
    1) Fluoride content may be analyzed in serum, saliva, and urine with an ion-specific electrode analyzer (Kiss, 1987; Drummond et al, 1990).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with significant burns and those who require intra-arterial calcium require admission. Patients with systemic toxicity or ECG changes should be admitted to an ICU setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Children with inadvertent ingestions of low fluoride concentration dental products can be managed at home if the ingestion is 8 mg/kg fluoride (17.7 mg/kg sodium fluoride) or less and the child does not have symptoms beyond minor gastrointestinal upset (Augenstein et al, 1991). To calculate the amount of fluoride ion ingested, use the following equations based on the type of fluoride in the product ingested:
    1) SODIUM FLUORIDE: (Concentration in %)(Amount ingested in oz)(Constant=128)/Patient weight in kg= mg/kg ingested
    2) SODIUM MONOFLUOROPHOSPHATE: (Concentration in %)(Amount ingested in oz)(Constant=37)/Patient weight in kg= mg/kg ingested
    3) FLUORIDE ION (w/v%): (Concentration in %)(Amount ingested in oz)(Constant=218)/Patient weight in kg= mg/kg ingested
    4) Derivations of all constants are explained in the Range of Toxicity/Calculations section.
    B) In a prospective study of 475 patients who had ingested dental fluoride preparations, 392 patients who ingested less than 8 mg/kg were treated at home with milk and observation, and no adverse outcomes resulted (Phillips et al, 1992).
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All ingestion and inhalation exposures to higher concentration or industrial products, and all deliberate ingestions should be considered potentially fatal and should be referred to a healthcare facility and observed for a minimum of 6 hours. Patients with skin burn greater than 5% body surface area (BSA) from low concentration products or more than 1% BSA from high concentration products should be observed for systemic effects.

Monitoring

    A) No testing is required for minor skin exposures.
    B) If there is concern for systemic poisoning, the serum electrolytes including calcium and magnesium, and renal function should be monitored.
    C) An ECG should be obtained and continuous cardiac monitoring instituted.
    D) If there is a potentially large exposure, the serum calcium should be monitored every 15 minutes for 4 to 6 hours.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) PREHOSPITAL: Decontamination generally is not required after inadvertent ingestion of a dental product. Administer a calcium-containing antacid.
    B) DILUTION
    1) Administer milk (preferred) or water (1 or 2 glassfuls) to dilute the corrosive fluoride salt in the oropharynx, esophagus, and stomach.
    2) Milk provides calcium ions which may bind to fluoride ions and decrease their penetrability and systemic absorption.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY: Administer a calcium-containing antacid. Consider gastric aspiration for large recent ingestion of a high concentration fluoride salt. Activated charcoal does not adsorb fluoride.
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) No testing is required for minor skin exposures.
    2) If there is concern for systemic poisoning, the serum electrolytes including calcium and magnesium, and renal function should be monitored.
    3) An ECG should be obtained and continuous cardiac monitoring instituted.
    4) If there is a potentially large exposure, the serum calcium should be monitored every 15 minutes for 4 to 6 hours.
    B) ANTIDOTE
    1) SYSTEMIC POISONING: Very high doses of calcium may be required. If there is a known large exposure, administer 1 to 2 g of calcium chloride (3 to 6 g of calcium gluconate) while awaiting the initial serum calcium determination. Administer additional calcium to maintain the serum calcium concentration in the high-normal range. Monitor the serum calcium every 15 minutes for several hours. If the patient develops dysrhythmias or hypotension, give an additional 1 to 2 g of calcium chloride (3 to 6 g of calcium gluconate). Hypomagnesemia should be treated with magnesium sulfate, 1 to 2 g given over 10 to 15 minutes (children: 25 to 50 mg/kg diluted to less than 10 mg/mL). Treat hyperkalemia with intravenous calcium and other usual measurements. Systemic alkalinization (to a pH of 7.45 to 7.5) improves survival in animal models of fluoride poisoning and should be considered in cases of life-threatening toxicity.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.
    6.7.2) TREATMENT
    A) SUPPORT
    1) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.
    B) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) Patients with ophthalmic exposure should have each eye irrigated with 1 L of normal saline, LR or water.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) Most patients with dermal exposure will do well if irrigated immediately. There is no evidence that any products are more effective than water.
    6.9.2) TREATMENT
    A) SUPPORT
    1) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.
    2) DERMAL EXPOSURE: Patients should be treated in a stepwise manner based on their response to therapy. The initial treatment for pain from dermal exposure is topical calcium. One method for making a gel is to mix calcium gluconate with methylcellulose or water-soluble lubricant in a 1:2 ratio. Apply the gel to the affected areas as frequently as needed to relieve symptoms. If the patient has pain despite topical therapy, extremity burns can be treated with a regional infusion of 40 mL of 2.5% calcium gluconate solution using a Bier block. If this is not successful, an intra-arterial infusion of 40 mL of 2.5% calcium gluconate can be performed. If the area affected is not on an extremity, inject 0.3 to 0.5 mL/cm(2) of 2.5% calcium gluconate into the region.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) SUMMARY
    1) Fluoride is removed by dialysis; however, patients with significant toxicity are usually too ill to tolerate dialysis.
    B) PERITONEAL DIALYSIS
    1) Peritoneal dialysis was not of value in a patient with normal renal function (Yolken et al, 1976).
    C) HEMODIALYSIS
    1) Hemodialysis, in patients with significant toxicity, may be beneficial (Berman et al, 1973); however, patients with significant toxicity are usually too ill to tolerate dialysis.

Abstracts

Case Reports

    A) ADULT
    1) ROUTE OF EXPOSURE
    a) ORAL
    1) LETHAL INADVERTENT INGESTION: A 38-year-old man inadvertently ingested approximately 100 mL of liquid containing 70% zinc hexafluorosilicate and was taken to the emergency department immediately. Cyanosis, hypotension, and a serum calcium level near 0 were noted on exam. He was treated with gastric lavage, ranitidine, hydrocortisone, and dopamine. Approximately 3 hours after ingestion, he developed ventricular fibrillation. CPR was started and the patient was intubated. He was defibrillated 15 times but died approximately 35 minutes after the onset of ventricular fibrillation (Lech, 2011).
    2) ACUTE EFFECTS OF PROFESSIONAL STRENGTH DENTAL FLUORIDE: Serious toxicity including GI hemorrhage, hypocalcemia, hypomagnesemia, ventricular tachycardia, and ventricular fibrillation occurred in a 43-year-old man following an ingestion of up to 25 ounces of Superdent(R) topical fluoride gel (1.23% fluoride). The patient survived with treatment consisting of cardioversion and aggressive calcium and magnesium replacement (Fisher et al, 1991).

Range Of Toxicity

Summary

    A) TOXICITY: Vomiting and abdominal pain are common with ingestions of 3 to 5 mg/kg of elemental fluoride. Hypocalcemia and muscular symptoms may appear with 5 to 10 mg/kg. Thirty-two to 64 mg/kg of fluoride should be considered fatal if untreated. Intractable ventricular fibrillation has been reported in lethal cases.
    B) THERAPEUTIC DOSE: ADULTS: The average daily dietary fluoride intake ranges from 0.5 to 5 mg as the anion. CHILDREN: Fluoride supplementation may be recommended in children and infants, based on the amount of fluoride in the water supply: 0 to 6 months: None. 6 months to 3 yr: 0.25 mg/day if less than 0.3 ppm; 3 to 6 yr: 0.5 mg/day if less than 0.3 ppm and 0.25 mg/day if 0.3 to 0.6 ppm. 6 to 16 yr: 1 mg/day if less than 0.3 ppm and 0.5 mg/day if 0.3 to 0.6 ppm. Note: 2.2 mg of sodium fluoride contains 1 mg fluoride ion.
    C) CALCULATIONS: To calculate the amount of fluoride ion ingested from toothpaste, use the following equations based on the type of fluoride in the product (derivations of all constants and calculation conversions are explained in the Range of Toxicity/Calculations section):
    1) SODIUM FLUORIDE
    a) To calculate the amount of F ion ingested from sodium fluoride, use the following equation: (Concentration in %)(Amount ingested in oz)(Constant = 128)/Patient weight in kg = fluoride ion mg/kg ingested
    2) SODIUM MONOFLUOROPHOSPHATE
    a) To calculate the amount of F ion ingested from sodium monofluorophosphate, use the following equation: (Concentration in %)(Amount ingested in oz)(Constant = 37)/Patient weight in kg = fluoride ion mg/kg ingested
    3) STANNOUS FLUORIDE
    a) To calculate the amount of F ion ingested from stannous fluoride, use the following equation: (Concentration in %)(Amount ingested in oz)(Constant = 69)/Patient weight in kg = fluoride ion mg/kg ingested.
    4) FLUORIDE ION
    a) To calculate the amount of F ion ingested when only the w/v% of fluoride ion is given, use the following calculation (this assumes a specific gravity of 1.3): (Concentration in %)(Amount ingested in oz)(Constant = 218)/Patient weight in kg = fluoride ion mg/kg ingested
    5) QUICK CALCULATIONS FOR COMMON STRENGTHS
    a) 0.24% SODIUM FLUORIDE: Use the following equation: (Amount ingested in oz)(31 mg F ion/oz NaF)/Patient weight in kg = fluoride ion mg/kg ingested.
    b) 0.76% SODIUM MONOFLUOROPHOSPHATE: Use the following equation: (Amount ingested in oz)(28.35 mg F ion/oz NaMPF)/Patient weight of child in kg = fluoride ion mg/kg ingested

Therapeutic Dose

    7.2.1) ADULT
    A) AVERAGE DAILY INTAKE: The average daily dietary fluoride intake for an adult ranges from 0.5 to 5 mg as the anion (Baselt, 2000).
    B) OSTEOPOROSIS: High dose fluoride therapy has been used in conjunction with calcium salts for the treatment of osteoporosis. Doses of 30 to 60 mg/day are usually recommended (Richmond, 1985).
    7.2.2) PEDIATRIC
    A) RECOMMENDED FLUORIDE SCHEDULE
    1) Fluoride supplementation may be recommended in children and infants, based on the amount of fluoride in the water supply (Centers for Disease Control and Prevention, 2001).
    Fluoride concentration in drinking water 1 ppm = 1 mg/L
    AGELESS THAN 0.3 ppm0.3-0.6 ppmGREATER THAN 0.6 ppm
    0-6 monthsNoneNoneNone
    6 months to 3 years0.25 mg/dayNoneNone
    3 to 6 years0.5 mg/day0.25 mg/dayNone
    6 to 16 years1 mg/day0.5 mg/dayNone

    2) 2.2 mg of sodium fluoride contains 1 mg fluoride ion (Centers for Disease Control and Prevention, 2001).

Minimum Lethal Exposure

    A) ACUTE
    1) GENERAL/SUMMARY
    a) Industrial exposure to fluoride is generally due to inhalation of dust that is produced during the processing of fluoride-containing minerals in various industries. The threshold limit value for fluoride in air is 2.5 mg/m(3) (expressed as F) (Baselt, 2004).
    b) Thirty-two to 64 mg/kg of fluoride should be considered fatal if untreated (Heifetz & Horowitz, 1986).
    2) CASE REPORTS
    a) PEDIATRICS
    1) Death has been reported following ingestion of 200 mg (16 mg/kg) of fluoride in a 3-year-old boy (Eichler et al, 1982).
    2) Lethargy and vomiting was described in a 13-month-old 30 minutes after ingesting an unknown amount of insecticide powder (65% sodium fluoride/35% talc); within 1 hour the patient was limp, comatose, and in respiratory failure. The patient went into cardiac arrest and died 5 hours after ingestion (Augenstein et al, 1991).
    b) ADULTS
    1) A 38-year-old man died of intractable ventricular fibrillation associated with severe hypocalcemia (serum level near 0) approximately 3 hours after inadvertently ingesting approximately 100 mL of liquid containing 70% zinc hexafluorosilicate (Lech, 2011).
    2) A 56-year-old man died of intractable ventricular fibrillation associated with hypomagnesemia and hypocalcemia after ingesting a spoonful of etching cream containing 20% ammonium bifluoride and 13% sodium bifluoride (Swanson et al, 1993).
    3) Fatal cardiac arrest was reported in three patients on chronic hemodialysis after exposure to fluoride used in the water purification system during dialysis (Arnow et al, 1994).

Maximum Tolerated Exposure

    A) ROUTE OF EXPOSURE
    1) INGESTION
    a) Mild fluorosis has been seen after 0.1 mg/kg/day, indicating a narrow therapeutic range (AAP, 1986).
    1) Accidental ingestion of sodium fluoride by children usually does not present serious risk if the amount of fluoride ingested is less than 5 mg/kg (Spoerke et al, 1980).
    2) Most gastrointestinal symptoms occur within the first hour following ingestion (Spoerke et al, 1980). The recommended limit of sodium fluoride stored in the home is 264 mg.
    b) Though some radiological evidence of fluoride effects on bone can be detected at intake of 5 to 8 parts per million fluoride, these are said not to be clinically significant. Pathological skeletal fluorosis requires intake of 10 to 25 mg F-/day for 10 to 20 years (Heifetz & Horowitz, 1986).
    c) As the fluoride supplementation is removed, the symptoms, except for mottling, will disappear (Grandjean & Thomsen, 1983).
    2) DENTAL ENAMEL FLUOROSIS
    a) It has been estimated, based on studies in rats, that single ingestions of 3 grams of a 0.1% fluoride-containing dentifrice may produce fluoride levels capable of causing tooth mottling. This amount is 2 to 3 times greater than that used for normal tooth brushing. Dental fluorosis is a potential concern in very small children who brush several times a day with these products, and who do not expectorate (Trautner & Einwag, 1988).
    b) Enamel fluorosis was reported in a 12-year-old girl who received daily tooth brushing from the age of 5 months with a fluoridated product. Mottling was evident at 6 years of age (Stephen, 1984).
    c) Teeth are only susceptible to dental fluorosis during the period of mineralization, until about 5 to 6 years of age (Heifetz & Horowitz, 1986).
    B) ACUTE
    1) The toxic range is approximately 5 to 10 mg/kg of fluoride (11 to 22 mg/kg of NaF) with GI symptoms usually developing at 3 to 5 mg/kg of fluoride or more (6.6 to 11 mg/kg of NaF) (Spoerke et al, 1980).
    2) The amount of sodium fluoride ingested by children has been correlated with the risk of developing symptoms (Augenstein et al, 1991). Ingested doses of ELEMENTAL FLUORIDE were associated with clinical signs in children in this study (ingested dose of elemental fluoride was calculated using the ratio of 1 mg fluoride per 2.2 mg sodium fluoride) -
    INGESTEDDOSE F ION (mg/kg)TOTAL NNUMBER WITH SYMPTOMS% WITH SYMPTOMS
    Less than 13638%
    1 to less than 26117%
    2 to less than 315427%
    3 to less than 4 10550%
    4-8.433100%
    TOTAL7016 

    3) Nausea alone was associated with ingestion of 47 to 94 mg in contaminated drinking water (Vogt et al, 1982).
    4) Vomiting was associated with ingestion of 94 to 188 mg in drinking water in individuals aged 9 to 70 years (Vogt et al, 1982).
    5) Serious toxicity including GI hemorrhage, hypocalcemia, hypomagnesemia, ventricular tachycardia and ventricular fibrillation occurred in a 43-year-old following an ingestion of up to 25 ounces of Superdent(R) topical fluoride gel (1.23% fluoride) (Fisher et al, 1991). The patient survived with treatment consisting of cardioversion and aggressive calcium and magnesium replacement.
    C) CHRONIC
    1) Low level exposure to airborne fluoride initially results in mucous membrane irritation of the eyes, nose and throat. Ongoing exposure may produce symptoms of early fluoride toxicity that can include respiratory distress, neurological abnormalities, gastrointestinal pain and muscular fibrillation(Baselt, 2004) .
    2) Daily absorption of 10 to 80 mg of fluoride over years can result in crippling skeletal fluorosis due to excessive calcification of bone resulting in stiffening of ligaments and fusion of joints (Baselt, 2004).
    3) CASE REPORT: A 48-year old woman who chronically ingested 1 to 2 gallons of brewed black tea containing an estimated 14.6 mg of fluoride ion/gallon daily from the age of 12 years developed symptoms consistent with phase 3 (crippling) skeletal fluorosis. After 6 months of ergocalciferol therapy and cessation from drinking tea, she reported nearly complete resolution of pain. She was lost to follow up after 6 months (Izuora et al, 2011).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) NORMAL CONCENTRATIONS: Plasma fluoride concentrations in normal subjects ranges from 0.01 to 0.2 mg/L (Kiss, 1987).
    b) CASE REPORT: Survival has been reported after serum fluoride levels of 3.4 mg/L in an untreated adult (Saady & Rose, 1988), and 14.7 mg/L in a treated adult (Baselt, 1982).
    c) CASE REPORT: Following exposure of fluoro silicate in an adult, the urinary fluoride level was 92 micromoles/L 17 hours after ingestion with a urine pH of 5.6. The patient had an uneventful recovery (Brookes et al, 1984).
    d) CASE REPORT: A 48-year old woman who chronically ingested 1 to 2 gallons of brewed black tea containing an estimated 14.6 mg of fluoride ion/gallon daily from the age of 12 years presented with symptoms consistent with phase 3 (crippling) skeletal fluorosis. Her serum fluoride ion level was 220 microg/L (normal 20 to 80 microg/L) and a 24-hour urine collection of 3.5 liters contained 3.5 mg/L of fluoride ion (normal 0.2 to 3.2 mg/L). After 6 months of oral ergocalciferol therapy and cessation from drinking tea, she reported nearly complete resolution of pain(Izuora et al, 2011).
    e) CASE REPORT: An 8-year-old boy with a history of ingesting water from a fluoride-contaminated well presented with dental fluorosis. Although he was not at present drinking the contaminated water, his urine fluoride level was 2.04 mg/L (reference level 0.1 mg/L), and the fluoride level of the well water was 15.74 mg/L (reference level 1.5 mg/L) (Nayak et al, 2009).
    f) POSTMORTEM: Fluoride was detected in the blood and internal organ tissue of a 38-year-old man who died about 3 hours after inadvertently ingesting approximately 100 mL of liquid containing 70% zinc hexafluorosilicate (Lech, 2011):
    1) Stomach content: 293 mcg/mL (reference level: 2.1 mcg/mL)
    2) Intestine content: 24.1 mcg/g (reference level: 0 mcg/g)
    3) Liver: 9.49 mcg/g (reference level: 0.8 mcg/g)
    4) Kidney: 29.6 mcg/g (reference level: 1.3mcg/g)
    5) Brain: 1.39 mcg/g (reference level: 0.8 mcg/g)
    6) Blood: 6.03 mcg/mL (reference level: less than 0.5 mcg/mL)
    g) POSTMORTEM: Fluoride was not detectable in the blood of a 33-year-old woman who died after ingesting a sodium fluoride roach powder (Poklis & Mackell, 1989).
    1) Fluoride was detectable in bile (3.4 mg/L), gastric content (225 mg/L), kidney (16 mg/kg), liver (8.6 mg/kg), and urine (295 mg/L).

Workplace Standards

    A) ACGIH TLV Values for CAS16984-48-8 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.
    a) Adopted Value
    1) Fluorides, as F
    a) TLV:
    1) TLV-TWA: 2.5 mg/m(3)
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A4
    2) Codes: BEI
    3) Definitions:
    a) A4: Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
    b) BEI: The BEI notation is listed when a BEI is also recommended for the substance listed. Biological monitoring should be instituted for such substances to evaluate the total exposure from all sources, including dermal, ingestion, or non-occupational.
    c) TLV Basis - Critical Effect(s): Bone dam; fluorosis
    d) Molecular Weight: Varies
    1) For gases and vapors, to convert the TLV from ppm to mg/m(3):
    a) [(TLV in ppm)(gram molecular weight of substance)]/24.45
    2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:
    a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance
    e) Additional information:

    B) NIOSH REL and IDLH Values for CAS16984-48-8 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS16984-48-8 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A4 ; Listed as: Fluorides, as F
    a) A4 :Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 3 ; Listed as: Fluorides (inorganic, used in drinking-water)
    a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS16984-48-8 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: Fluorides (as F)
    2) Table Z-1 for Fluorides (as F):
    a) 8-hour TWA:
    1) ppm:
    a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.
    2) mg/m3: 2.5
    a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.
    3) Ceiling Value:
    4) Skin Designation: No
    5) Notation(s): Not Listed
    3) Table Z-2 for Fluoride as dust (Z37.28-1969):
    a) 8-hour TWA:25 mg/m(3)
    b) Acceptable Ceiling Concentration:
    c) Acceptable Maximum Peak above the Ceiling Concentration for an 8-hour Shift:
    1) Concentration:
    2) Maximum Duration:
    d) Notation(s): Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Fluoride promotes remineralization of decalcified dental enamel and may interfere with the growth of bacteria in dental plaque (Brown et al, 1983; Winter, 1983).

Toxicologic Mechanism

    A) Sodium fluoride reacts with the gastric acid to form hydrofluoric acid. The major toxic effects of fluoride are due to the chelation of calcium and magnesium. In tissue, the local hypocalcemia causes pain and cellular death. Systemic hypocalcemia and hypomagnesemia may cause cardiac dysrhythmias and cardiovascular collapse. Fluoride opens the calcium-dependent potassium channels on erythrocytes resulting in hyperkalemia. Fluoride also impairs oxidative phosphorylation. Long-term ingestion of water with high fluoride concentrations results in weak and brittle bones (fluorosis) (Wittinghofer, 1997; McIvor et al, 1985).

Physicochemical

Molecular Weight

    A) 18.99

Animal Toxicology

Clinical Effects

    11.1.2) BOVINE/CATTLE
    A) OSTEODYSTROPHY: Fluorosis in cattle has been associated with lameness and spontaneous fractures (Anand & Roberts, 1990).
    11.1.9) OVINE/SHEEP
    A) OSTEODYSTROPHY: Fluorosis in sheep has been associated with lameness and spontaneous fractures (Anand & Roberts, 1990).
    11.1.13) OTHER
    A) OTHER
    1) ACUTE TOXICOSIS: Clinical signs of acute fluoride toxicosis may include rapid onset of restlessness, stiffness, anorexia, excessive salivation, nausea, vomiting, incontinence of urine and feces, reduced milk production in lactating animals, clonic seizures, weakness, severe depression, and cardiac failure (Shupe et al, 1986).
    2) CHRONIC TOXICOSIS: Clinical signs develop gradually and insidiously over months or years. Signs may include mottling and abrasion of permanent teeth, osteofluorosis, fluoride in urine, and intermittent lameness (Shupe et al, 1986).

Treatment

    11.2.1) SUMMARY
    A) GENERAL TREATMENT
    1) Treatment of chronic fluoride toxicosis in animals is symptomatic and supportive (Shupe et al, 1986).

Continuing Care

    11.4.1) SUMMARY
    11.4.1.2) DECONTAMINATION/TREATMENT
    A) GENERAL TREATMENT
    1) Treatment of chronic fluoride toxicosis in animals is symptomatic and supportive (Shupe et al, 1986).

Sources

    A) GENERAL
    1) Forage crops, drinking water, and improperly defluorinated inorganic dietary phosphates may be sources of excess fluoride ingested by livestock (Shupe et al, 1986).

References

General Bibliography

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