Fluoride toxicity is a condition in which there are elevated levels of the fluoride

ion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...

in the body. Although fluoride is safe for dental health at low concentrations, sustained consumption of large amounts of soluble fluoride

salts In chemistry, a salt is a chemical compound consisting of an ionic assembly of positively charged cations and negatively charged anions, which results in a compound with no net electric charge. A common example is table salt, with positively c ...

is dangerous. Referring to a common salt of fluoride,

sodium fluoride Sodium fluoride (NaF) is an inorganic compound with the formula . It is used in trace amounts in the fluoridation of drinking water, in toothpaste, in metallurgy, and as a flux. It is a colorless or white solid that is readily soluble in water. I ...

(NaF), the lethal dose for most adult humans is estimated at 5 to 10 g (which is equivalent to 32 to 64 mg elemental fluoride/kg body weight). Ingestion of fluoride can produce

gastrointestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...

discomfort at doses at least 15 to 20 times lower (0.2–0.3 mg/kg or 10 to 15 mg for a 50 kg person) than lethal doses. Although it is helpful topically for dental health in low dosage, chronic ingestion of fluoride in large amounts interferes with bone formation. In this way, the most widespread examples of fluoride poisoning arise from consumption of ground water that is abnormally fluoride-rich.

Recommended levels

For optimal dental health, the

World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of ...

recommends a level of fluoride from 0.5 to 1.0 mg/L (milligrams per liter), depending on climate. Fluorosis becomes possible above this recommended dosage. As of 2015, the United States Health and Human Services Department recommends a maximum of 0.7 milligrams of fluoride per liter of water – updating and replacing the previous recommended range of 0.7 to 1.2 milligrams issued in 1962. The new recommended level is intended to reduce the occurrence of dental fluorosis while maintaining water fluoridation.

Toxicity

Chronic

In India an estimated 60 million people have been poisoned by well water contaminated by excessive fluoride, which is dissolved from the

granite Granite () is a coarse-grained ( phaneritic) intrusive igneous rock composed mostly of quartz, alkali feldspar, and plagioclase. It forms from magma with a high content of silica and alkali metal oxides that slowly cools and solidifies under ...

rocks. The effects are particularly evident in the bone deformities of children. Similar or larger problems are anticipated in other countries including China, Uzbekistan, and Ethiopia.

Acute

Historically, most cases of acute fluoride toxicity have followed accidental ingestion of sodium fluoride based

insecticides Insecticides are substances used to kill insects. They include ovicides and larvicides used against insect eggs and larvae, respectively. Insecticides are used in agriculture, medicine, industry and by consumers. Insecticides are claimed t ...

rodenticides Rodenticides are chemicals made and sold for the purpose of killing rodents. While commonly referred to as "rat poison", rodenticides are also used to kill mice, squirrels, woodchucks, chipmunks, porcupines, nutria, beavers, and voles. Despit ...

.Nochimson G. (2008)
Toxicity, Fluoride
. eMedicine. Retrieved 2008-12-28. Currently, in advanced countries, most cases of fluoride exposure are due to the ingestion of dental fluoride products. Other sources include glass-etching or chrome-cleaning agents like

ammonium bifluoride Ammonium hydrogen fluoride is the inorganic compound with the formula or . It is produced from ammonia and hydrogen fluoride. This colourless salt is a glass- etchant and an intermediate in a once-contemplated route to hydrofluoric acid. Structu ...

or hydrofluoric acid, industrial exposure to fluxes used to promote the flow of a molten metal on a solid surface,

volcanic A volcano is a rupture in the crust of a planetary-mass object, such as Earth, that allows hot lava, volcanic ash, and gases to escape from a magma chamber below the surface. On Earth, volcanoes are most often found where tectonic plates a ...

ejecta (for example, in cattle grazing after an 1845–1846 eruption of

Hekla Hekla (), or Hecla, is a stratovolcano in the south of Iceland with a height of . Hekla is one of Iceland's most active volcanoes; over 20 eruptions have occurred in and around the volcano since 874. During the Middle Ages, the Icelandic Nor ...

and the 1783–1784 flood basalt eruption of Laki), and metal cleaners. Malfunction of water fluoridation equipment has happened several times, including a notable incident in Alaska.

Occurrence

Organofluorine compounds

Twenty percent of modern pharmaceuticals contain fluorine. These organofluorine compounds are not sources of fluoride poisoning. The

carbon–fluorine bond The carbon–fluorine bond is a polar covalent bond between carbon and fluorine that is a component of all organofluorine compounds. It is one of the strongest single bonds in chemistry (after the B–F single bond, Si–F single bond, and H–F ...

is too strong to release fluoride.

Fluoride in toothpaste

Children may experience gastrointestinal distress upon ingesting excessive amounts of flavored toothpaste. Between 1990 and 1994, over 628 people, mostly children, were treated after ingesting too much fluoride-containing toothpaste. "While the outcomes were generally not serious," gastrointestinal symptoms appear to be the most common problem reported. However given the low concentration of fluoride present in dental products, this is potentially due to consumption of other major components.

Fluoride in drinking water

Around one-third of the world's population drinks water from groundwater resources. Of this, about 10 percent, approximately 300 million people, obtains water from groundwater resources that are heavily contaminated with arsenic or fluoride. These trace elements derive mainly from leaching of minerals. Maps are available of locations of potential problematic wells via the Groundwater Assessment Platform (GAP).

Effects

Excess fluoride consumption has been studied as a factor in the following:

Brain

Some research has suggested that high levels of fluoride exposure may adversely affect neurodevelopment in children, but the evidence is of insufficient quality to allow any firm conclusions to be drawn.

Bones

Whilst fluoridated water is associated with decreased levels of fractures in a population, toxic levels of fluoride have been associated with a weakening of

bone A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...

s and an increase in hip and wrist fractures. The U.S. National Research Council concludes that fractures with fluoride levels 1–4 mg/L, suggesting a dose-response relationship, but states that there is "suggestive but inadequate for drawing firm conclusions about the risk or safety of exposures at mg/L.. See als
CDC's statement on this report
. Consumption of fluoride at levels beyond those used in fluoridated water for a long period of time causes

skeletal fluorosis Skeletal fluorosis is a bone disease caused by excessive accumulation of fluoride leading to weakened bones. In advanced cases, skeletal fluorosis causes painful damage to bones and joints. Symptoms Symptoms are mainly promoted in the bone structu ...

. In some areas, particularly the Asian subcontinent, skeletal fluorosis is endemic. It is known to cause irritable-bowel symptoms and joint pain. Early stages are not clinically obvious, and may be misdiagnosed as (seronegative)

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are invol ...

ankylosing spondylitis Ankylosing spondylitis (AS) is a type of arthritis characterized by long-term inflammation of the joints of the spine typically where the spine joins the pelvis. Occasionally areas affected may include other joints such as the shoulders or hi ...

Kidney

Fluoride induced nephrotoxicity is

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...

injury due to toxic levels of serum fluoride, commonly due to release of fluoride from fluorine-containing drugs, such as methoxyflurane. Within the recommended dose, no effects are expected, but chronic ingestion in excess of 12 mg/day are expected to cause adverse effects, and an intake that high is possible when fluoride levels are around 4 mg/L. Those with impaired kidney function are more susceptible to adverse effects. The kidney injury is characterised by failure to concentrate

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra. Cellular ...

, leading to

polyuria Polyuria () is excessive or an abnormally large production or passage of urine (greater than 2.5 L or 3 L over 24 hours in adults). Increased production and passage of urine may also be termed diuresis. Polyuria often appears in conjunction wit ...

, and subsequent

dehydration In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mil ...

with

hypernatremia Hypernatremia, also spelled hypernatraemia, is a high concentration of sodium in the blood. Early symptoms may include a strong feeling of thirst, weakness, nausea, and loss of appetite. Severe symptoms include confusion, muscle twitching, and b ...

and hyperosmolarity. Inorganic fluoride inhibits

adenylate cyclase Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...

activity required for antidiuretic hormone effect on the

distal convoluted tubule The distal convoluted tubule (DCT) is a portion of kidney nephron between the loop of Henle and the collecting tubule. Physiology It is partly responsible for the regulation of potassium, sodium, calcium, and pH. On its apical surface (lumen ...

of the kidney. Fluoride also stimulates intrarenal

vasodilation Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstrictio ...

, leading to increased medullary

blood flow Hemodynamics or haemodynamics are the dynamics of blood flow. The circulatory system is controlled by homeostatic mechanisms of autoregulation, just as hydraulic circuits are controlled by control systems. The hemodynamic response continuously m ...

, which interferes with the counter current mechanism in the

required for concentration of

. Fluoride induced nephrotoxicity is dose dependent, typically requiring serum fluoride levels exceeding 50 micromoles per liter (about 1 ppm) to cause clinically significant

renal The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; bloo ...

dysfunction, which is likely when the dose of methoxyflurane exceeds 2.5 MAC hours. (Note: "MAC hour" is the multiple of the minimum alveolar concentration (MAC) of the anesthetic used times the number of hours the drug is administered, a measure of the dosage of inhaled anesthetics.) Elimination of fluoride depends on

glomerular filtration rate Renal functions include maintaining an acid–base balance; regulating fluid balance; regulating sodium, potassium, and other electrolytes; clearing toxins; absorption of glucose, amino acids, and other small molecules; regulation of blood pre ...

. Thus, patients with chronic kidney disease will maintain serum fluoride for longer period of time, leading to increased risk of fluoride induced nephrotoxicity.

Teeth

The only generally accepted adverse effect of fluoride at levels used for

water fluoridation Water fluoridation is the controlled adjustment of fluoride to a public water supply solely to reduce tooth decay. Fluoridated water contains fluoride at a level that is effective for preventing cavities; this can occur naturally or by adding ...

dental fluorosis Dental fluorosis is a common disorder, characterized by hypomineralization of tooth enamel caused by ingestion of excessive fluoride during enamel formation. It appears as a range of visual changes in enamel causing degrees of intrinsic tooth d ...

, which can alter the appearance of children's teeth during

tooth development Tooth development or odontogenesis is the complex process by which teeth form from embryonic cells, grow, and erupt into the mouth. For human teeth to have a healthy oral environment, all parts of the tooth must develop during appropriate st ...

; this is mostly mild and usually only an aesthetic concern. Compared to unfluoridated water, fluoridation to 1 mg/L is estimated to cause fluorosis in one of every 6 people (range 4–21), and to cause fluorosis of aesthetic concern in one of every 22 people (range 13.6–∞).

Thyroid

Fluoride's suppressive effect on the

thyroid The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...

is more severe when iodine is deficient, and fluoride is associated with lower levels of iodine. Thyroid effects in humans were associated with fluoride levels 0.05–0.13 mg/kg/day when iodine intake was adequate and 0.01–0.03 mg/kg/day when iodine intake was inadequate. Its mechanisms and effects on the

endocrine system The endocrine system is a messenger system comprising feedback loops of the hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neu ...

remain unclear. Testing on mice shows that the medication gamma-Aminobutyric acid (GABA) can be used to treat fluoride toxicity of the thyroid and return normal function.

Effects on aquatic organisms

Fluoride accumulates in the bone tissues of fish and in the

exoskeleton An exoskeleton (from Greek ''éxō'' "outer" and ''skeletós'' "skeleton") is an external skeleton that supports and protects an animal's body, in contrast to an internal skeleton (endoskeleton) in for example, a human. In usage, some of the ...

of aquatic invertebrates. The mechanism of fluoride toxicity in aquatic organisms is believed to involve the action of fluoride ions as enzymatic poisons. In soft waters with low ionic content, invertebrates and fishes may develop adverse effects from fluoride concentration as low as 0.5 mg/L. Negative effects are less in hard waters and seawaters, as the bioavailability of fluoride ions is reduced with increasing water hardness Seawater contains fluoride at a concentration of 1.3 mg/L.

Mechanism

Like most soluble materials, fluoride compounds are readily absorbed by the stomach and intestines, and

excreted Excretion is a process in which metabolic waste is eliminated from an organism. In vertebrates this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific tasks after lea ...

through the urine.

Urine tests A urine test is any medical test performed on a urine specimen. The analysis of urine is a valuable diagnostic tool because its composition reflects the functioning of many body systems, particularly the kidneys and urinary system, and specimens a ...

have been used to ascertain rates of excretion in order to set upper limits in exposure to fluoride compounds and associated detrimental health effects. Ingested fluoride initially acts locally on the intestinal mucosa, where it forms hydrofluoric acid in the stomach.

References

External links

{{Elements in biology Element toxicology Toxic effects of substances chiefly nonmedicinal as to source Fluorides