Wikipedia

Biological aspects of fluorine

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Fluorine. Named the "savage beast" by the 1906 Nobel committee, perhaps no other element has occasioned as much controversy. Extremely hazardous as a gas, the element is also deadly in the more common industrial form: hydrogen fluoride. Over a 10 year period, at least 10 people in the United States alone, died from HF poisoning. And fluorine is a component of mammal killing 1080 poison, banned in much of the world, but still used to kill foxes in Australia and coyotes in America. Yet the element has a gentler, caring side. In dental products, it stops cavities. Although controversial, water fluoridation has shown consistent benefits especially for poor children.

A rotating, transparent image of a human figure with targeted organs highlighted
PET scan using fluorine-18

Because carbon-fluorine bonds are so difficult to form, very few organisms make them. But a few plants and bacteria in the tropics make fluorine containing poisons. And they do it to prevent being eaten. The same feature, the uncommon carbon-fluorine bond makes fluorination a powerful lever for rational drug design. It allows tweaking organic molecules in a way nature never did and has led to several blockbuster commercial successes such as Lipitor and Prozac.

However, fluorine has its impact on the environment as well. CFCs were proven to damage the ozone layer and led to the spectacular Montreal Protocol which changed an entire industry to save the ozone layer. The agreement served as a model for future global warming agreements (still not complete). Interestingly, fluorinated refrigerants are also global warming molecules. And then the hard to break carbon-fluorine bond also has a sneaky contamination of human body fluids. Waterproofing sprays with PFOA and PFOS are "biopersistent" and are found in polar bears and human breast milk.

Fluorine-biology also has its science fiction angle. PFCs (liquid fluorocarbons) are capable of holding so much oxygen as to support human liquid breathing...an aspect touched on in fiction and also prompting real world research in blood substites and burned lung care. Fluorine is also at the heart of a modern brain and cancern scanning tenchique: positron emission tomography (PET). Particles from a radioactive fluorine isotope allow scanning the brain and cancer cells.

Natural biochemistry

 
South Africa's gifblaar is one of the few organisms that makes fluorine compounds.

Biologically synthesized organofluorines have been found in microorganisms and plants,[1] but not in animals.[2] The most common example is fluoroacetate, with an active poison molecule identical to commercial "1080". It is used as a defense against herbivores by at least 40 green plants in Australia, Brazil, and Africa;[3] other biologically synthesized organofluorines include ω-fluoro fatty acids, fluoroacetone, and 2-fluorocitrate.[2] In bacteria, the enzyme adenosyl-fluoride synthase, which makes the carbon–fluorine bond, was isolated. The discovery was touted as possibly leading to biological routes for organofluorine synthesis.[4]

Fluoride is not considered an essential mineral element for mammals and humans.[5] Small amounts of fluoride may be beneficial for bone strength, but this is an issue only in the formulation of artificial diets.[6] See also "Fluoride deficiency".

Medicine

Dental care

Main articles: Fluoride therapy and Water fluoridation

Since the mid-20th century, it has been understood (from population studies) that fluoride reduces tooth decay, somehow. Initially, researchers hypothesized that fluoride helped by converting tooth enamel from the more-acid-soluble mineral hydroxyapatite to the less-acid-soluble mineral fluorapatite. However, more recent studies showed no difference in the frequency of caries (cavities) amongst teeth that were pre-fluoridated to different degrees. Current thinking is that fluoride prevent cavities primarily by helping teeth that are in the very early stages of tooth decay.[7]

When teeth begin to decay from the acid of sugar-consuming bacteria, calcium is lost (demineralization). However, teeth have a limited ability to recover calcium if decay is not too far advanced (remineralization). Fluoride appears to reduce demineralization and increase remineralization. Also, there is some evidence that fluoride interferes with the bacteria that consume sugars in the mouth and make tooth-destroying acids.[7] In any case, it is only the fluoride that is directly present in the mouth (topical treatment) that prevents cavities. Fluoride ions that are swallowed do not benefit the teeth.[7]

 
Topical fluoride treatment in Panama

Water fluoridation is the controlled addition of fluoride to a public water supply to reduce tooth decay.[8] Its use began in the 1940s, following studies of children in a region where water is naturally fluoridated. It is now used for about two-thirds of the U.S. population on public water systems[9] and for about 5.7% of people worldwide.[10] Although the best available evidence shows no association with adverse effects other than fluorosis (dental and, in worse cases, skeletal), most of which is mild,[11] water fluoridation has been contentious for ethical, safety, and efficacy reasons,[10] and opposition to water fluoridation exists despite its support by public health organizations.[12] The benefits of water fluoridation have lessened recently, presumably because of the availability of fluoride in other forms, but are still measurable, particularly for low income groups.[13] Systematic reviews in 2000 and 2007 showed significant reduction of cavities in children associated with water fluoridation.[14]

Sodium fluoride, tin difluoride, and, most commonly, sodium monofluorophosphate, are used in toothpaste. In 1955, the first fluoride toothpaste was introduced, in the United States. Now, almost all toothpaste in developed countries is fluoridated. For example, 95% of European toothpaste contains fluoride.[13] Gels and foams are often advised for special patient groups, particularly those undergoing radiation therapy to the head (cancer patients). The patient receives a four-minute application of a high amount of fluoride. Varnishes exist that perform a similar function, but are more quickly applied. Fluoride is also contained in prescription and non-prescription mouthwashes and is a trace component of foods manufactured from fluoridated water supplies.[15]

Pharmaceuticals

 
Prozac: one of several notable fluorine-containing drugs

Of all commercialized pharmaceutical drugs, 20% contain fluorine, including important drugs in many different pharmaceutical classes.[16] Fluorine is added to drug molecules as even a single atom of it can greatly change the chemical properties of the molecule in ways that are desirable.

Because of the considerable stability of the carbon-fluorine bond, many drugs are fluorinated to delay their metabolism, which is the chemical process in which the drugs are turned into compounds that allows them to be eliminated. This prolongs their half-lives and allows for longer times between dosing and activation. For example, an aromatic ring may prevent the metabolism of a drug, but this presents a safety problem, because some aromatic compounds are metabolized in the body into poisonous epoxides by the organism's native enzymes. Substituting a fluorine into a para position, however, protects the aromatic ring and prevents the epoxide from being produced.[citation needed]

Adding fluorine to biologically active organics increases their lipophilicity (ability to dissolve in fats), because the carbon–fluorine bond is even more hydrophobic than the carbon–hydrogen bond. This effect often increases a drug's bioavailability because of increased cell membrane penetration.[17] Although the potential of fluorine being released in a fluoride leaving group depends on its position in the molecule,[18] organofluorides are generally very stable, since the carbon–fluorine bond is strong.

Fluorines also find their uses in common mineralocorticoids, a class of drugs that increase the blood pressure. Adding a fluorine increases both its medical power and anti-inflammatory effects.[19] Fluorine-containing fludrocortisone is one of the most common of these drugs.[20] Dexamethasone and triamcinolone, which are among the most potent of the related synthetic corticosteroids class of drugs, contain fluorine as well.[20]

Several inhaled general anesthetic agents, including the most commonly used inhaled agents, also contain fluorine. The first fluorinated anesthetic agent, halothane, proved to be much safer (neither explosive nor flammable) and longer-lasting than those previously used. Modern fluorinated anesthetics are longer-lasting still and almost insoluble in blood, which accelerates the awakening.[21] Examples include sevoflurane, desflurane, enflurane, and isoflurane, all hydrofluorocarbon derivatives.[22]

Prior to 1980s, antidepressants altered not only the serotonin uptake (lack of serotonin is a reason for a depression), but also the altered norepinephrine uptake; this caused most antidepressants' side effects. The first drug to only alter the serotonin uptake was Prozac; it gave birth to the extensive selective serotonin reuptake inhibitor (SSRI) antidepressants class and is the best-selling antidepressant. Many other SSRI antidepressants are fluorinated organics, including Celexa, Luvox, and Lexapro.[23] Fluoroquinolones are a commonly used family of broad-spectrum antibiotics.[24]

Molecular structures of several fluorine-containing pharmaceuticals
       
Lipitor (atorvastatin) 5-FU (fluorouracil) Florinef (fludrocortisone) Isoflurane

Scanning

Main articles: Positron emission tomography and Fludeoxyglucose (18F)
 
PET scan for Alzheimer's diagnosis

Compounds containing fluorine-18, a radioactive isotope that emits positrons, are often used in positron emission tomography (PET) scanning, because the isotope's half-life of about 110 minutes is long by positron-emitter standards. One such radiopharmaceutical is 2-deoxy-2-(18F)fluoro-D-glucose (generically referred to as fludeoxyglucose), commonly abbreviated as 18F-FDG, or simply FDG.[25] In PET imaging, FDG can be used for assessing glucose metabolism in the brain and for imaging cancer tumors. After injection into the blood, FDG is taken up by "FDG-avid" tissues with a high need for glucose, such as the brain and most types of malignant tumors.[26] Tomography, often assisted by a computer to form a PET/CT (CT stands for "computer tomography") machine, can then be used to diagnose or monitor treatment of cancers; especially Hodgkin's lymphoma, lung cancer, and breast cancer.[27]

Natural fluorine is monoisotopic, consisting solely of fluorine-19. Fluorine compounds are highly amenable to nuclear magnetic resonance (NMR), because fluorine-19 has a nuclear spin of ½, a high nuclear magnetic moment, and a high magnetogyric ratio. Fluorine compounds typically have a fast NMR relaxation, which enables the use of fast averaging to obtain a signal-to-noise ratio similar to hydrogen-1 NMR spectra.[28] Fluorine-19 is commonly used in NMR study of metabolism, protein structures and conformational changes.[29] In addition, inert fluorinated gases have the potential to be a cheap and efficient tool for imaging lung ventilation.[30]

Oxygen transport research

See also: Blood substitute and Liquid breathing

Liquid fluorocarbons have a very high capacity for holding gas in solution. They can hold more oxygen or carbon dioxide than blood does. For that reason, they have attracted ongoing interest related to the possibility of artificial blood or of liquid breathing.[31]

 
Computer-generated model of nanocrystal of perflubron (red) and gentamicin (white, an antibiotic)

Blood substitutes are the subject of research because the demand for blood transfusions grows faster than donations. In some scenarios, artificial blood may be more convenient or safe. Because fluorocarbons do not normally mix with water, they must be mixed into emulsions (small droplets of perfluorocarbon suspended in water) to be used as blood.[32][33] One such product, Oxycyte, has been through initial clinical trials.[34][35]

Possible medical uses of liquid breathing (which uses pure perfluorocarbon liquid, not a water emulsion) involve assistance for premature babies or for burn victims (because the normal lung function is compromised). Both partial filling of the lungs and complete filling of the lungs have been considered, although only the former has any significant tests in humans. Several animal tests have been performed and some human partial liquid ventilation trials.[36] One effort, by Alliance Pharmaceuticals, reached clinical trials but was abandoned because of insufficient advantage compared to other therapies.[37]

Nanocrystals represent a possible method of delivering water or fat soluble drugs within a perfluorochemical fluid. The particles usage is being developed to help treat babies with damaged lungs.[38]

Perfuorocarbons are banned from sports, where they may be used to increase oxygen use for endurance athletes. One cyclist, Mauro Gianetti was investigated after a near fatality where PFC use was suspected.[39][40]

Other posited applications include deep sea diving and space travel, applications that would both require total liquid ventilation, not partial ventilation.[41][42] The 1989 film The Abyss showed a fictional use of perfluorocarbon for human diving but also filmed a real rat surviving while cooled and immersed in perfluorocarbon.[43] (See also list of fictional treatments of perfluorocarbon breathing.)

Poisons and agrichemicals

 
Sign warning of poisonous sodium fluoroacetate baits

Synthetic sodium fluoroacetate has been used as an insecticide but is especially effective against mammalian pests.[44] The name "1080" refers to the catalogue number of the poison, which became its brand name.[3] Fluoroacetate is similar to acetate, which has a pivotal role in the Krebs cycle (a key part of cell metabolism). Fluoroacetate halts the cycle and causes cells to be deprived of energy.[3] Several other insecticides contain sodium fluoride, which is much less toxic than fluoroacetate.[45]

An estimated 30% of agrichemical compounds contain fluorine.[46] Most of them are poisons, but a few stimulate the growth instead. It is expected that how often the fluorine agrichemicals will be used depends on two factors: if the synthesis reaction will be improved (to reduce the prices) and if green chemistry will be taken in account to a larger scale (fluorochemicals are more environment-friendly).[47]

An important agrichemcial is Trifluralin. It was once very important (for example, in 1998 over a half of U.S. cotton field area was coated with the chemical[48]); however, its suspected carcinogenic properties caused some Northern European countries to ban it in 1993.[49] Currently, the whole European Union has it banned, although there was a case intended to cancel the decision.[50]

The currently used agrichemicals utilize another tactic: instead of being poisonous themselves, e.g., by directly affecting metabolism, they transform the metabolism so the organism produces poisonous compounds. For example, insects fed 29-fluorostigmasterol produce the fluoroacetates from it. If a fluorine is transferred to a body cell, it blocks metabolism at the position occupied.[51]

Hazards

Fluorine gas

 
The U.S. hazard signs for commercially transported fluorine[52]

Elemental fluorine is highly toxic. Above a concentration of 25 ppm, it causes significant irritation while attacking the eyes, airways and lungs and affecting the liver and kidneys. At a concentration of 100 ppm, human eyes and noses are seriously damaged.[53]

Hydrofluoric acid

See also: Chemical burn

Hydrofluoric acid, the water solution of hydrogen fluoride, is a contact poison. Even though it is chemically only a weak acid, it is far more dangerous than the conventional strong mineral acids, such as nitric acid, sulfuric acid, or hydrochloric acid. Owing to its lesser chemical dissociation in water (remaining a neutral molecule), hydrogen fluoride penetrates tissue more quickly than typical acids. Poisoning can occur readily through the skin or eyes or when inhaled or swallowed. From 1984 to 1994, at least nine U.S. workers died from accidents with HF.[54]

Once in the blood, hydrogen fluoride reacts with calcium and magnesium, resulting in electrolyte imbalance (potentially hypocalcemia). The consequent effect on the heart (cardiac arrhythmia) may be fatal.[54] Formation of insoluble calcium fluoride also causes strong pain.[55] Burns with areas larger than 160 cm2, about the size of a man's hand, can cause serious systemic toxicity.[56]

 
Typical HF burns: the outward signs may not be evident for a day, at which point calcium treatments are less effective.[57]

Symptoms of exposure to hydrofluoric acid may not be immediately evident, with 8-hour delay for 50% HF and up to 24 hours for lower concentrations. Hydrogen fluoride interferes with nerve function, meaning that burns may not initially be painful.

If the burn has been initially noticed, then HF should be washed off with a forceful stream of water for ten to fifteen minutes to prevent its further penetration into the body. Clothing used by the person burned may also present a danger.[58] Hydrofluoric acid exposure is often treated with calcium gluconate, a source of Ca2+ that binds with the fluoride ions. Skin burns can be treated with a water wash and 2.5% calcium gluconate gel[59][60] or special rinsing solutions.[61] Because HF is absorbed, further medical treatment is necessary. Calcium gluconate may be injected or administered intravenously. Use of calcium chloride is contraindicated and may lead to severe complications. Sometimes surgical excision of tissue or amputation is required.[56][62]

Fluoride ion

See also: Fluoride toxicity

Soluble fluorides are moderately toxic. For sodium fluoride, the lethal dose for adults is 5–10 g, which is equivalent to 32–64 mg of elemental fluoride per kilogram of body weight.[63] The dose that may lead to adverse health effects is about one fifth the lethal dose.[64] Chronic excess fluoride consumption can lead to skeletal fluorosis, a disease of the bones that affects millions in Asia and Africa.[64][65]

The fluoride ion is readily absorbed by the stomach and intestines. Ingested fluoride forms hydrofluoric acid in the stomach. In this form, fluoride crosses cell membranes and then binds with calcium and interferes with various enzymes. Fluoride is excreted through urine. Fluoride exposure limits are based on urine testing, which has determined the human body's capacity for ridding itself of fluoride.[64][66]

Historically, most cases of fluoride poisoning have been caused by accidental ingestion of insecticides containing inorganic fluoride.[67] Most calls to poison control centers for possible fluoride poisoning come from the ingestion of fluoride-containing toothpaste.[64] Malfunction of water fluoridation equipment has occurred several times, including an Alaskan incident that sickened nearly 300 people and killed one.[68]

Environmental concerns

Atmosphere

See also: Ozone depletion and global warming

Because they deplete the ozone layer, chlorofluorocarbons (CFCs) and bromofluorocarbons (BFCs) have been strictly regulated via a series of international agreements called the Montreal Protocol. It is the chlorine and bromine from these molecules that cause harm, not the fluorine. Because of the inherent stability of these fully halogenated molecules (which makes them so nonflammable and useful), they are able to attain the upper reaches of the atmosphere before decomposing. At high altitudes, they release chlorine and bromine atoms which attack ozone molecules.[69] Predictions are that generations will be required, even after the CFC ban, for these molecules to leave the atmosphere and for the ozone layer to fully recover. Early indications are that the CFC ban is working: ozone depletion has stopped, and recovery has started.[70][71]

 
NASA projection of stratospheric ozone levels over North America if CFCs had not been banned[72]

Hydrochlorofluorocarbons (HCFCs) are current replacements for CFCs, with about one tenth the ozone damaging potential (ODP).[73] They were originally scheduled for elimination by 2030 in developed nations and 2040 in undeveloped. In 2003, the U.S. Environmental Protection Agency prohibited production of one HCFC and capped the production of the two others.[74] In 2007, a new treaty was signed by almost all nations to move HCFC phaseout up to 2020 because HFCs, which have no chlorine and thus zero ODP, are available.[75]

Fluorocarbon gases of all sorts (CFCs, HFCs, etc.) are greenhouse gases about 4,000 to 10,000 times as potent as carbon dioxide. Sulfur hexafluoride exhibits an even stronger effect, about 20,000 times the global warming potential of carbon dioxide.[76]

Biopersistance

Because of the strength of the carbon–fluorine bond, organofluorines endure in the environment. Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), used in waterproofing sprays, are persistent global contaminants. Trace quantities of these substances have been detected worldwide, from polar bears in the Arctic to the global human population. PFOA has been detected in breast milk and the blood of newborns. One study indicates that PFOS levels in wildlife are starting to decrease because of reducing production.[77][78]

In the body, PFOA binds to a protein, serum albumin. PFOA's tissue distribution in humans is unknown, but studies in rats suggest it is present mostly in the liver, kidney, and blood. PFOA is not metabolized by the body but is excreted by the kidneys.[77][78]

The potential health effects of PFOA are unclear. Unlike chlorinated hydrocarbons, PFOA is not lipophilic (stored in fat), nor is it genotoxic (damaging genes). While both PFOA and PFOS cause cancer in high quantities in animals, studies on exposed humans have not been able to prove an impact at current exposures. Bottlenose dolphins have some of the highest PFOS concentrations of any wildlife studied; one study suggests an impact on their immune systems.[77][78]

Because biological systems do not metabolize fluorinated molecules easily, fluorinated pharmaceuticals (often antibiotics and antidepressants) are among the major fluorinated organics found in treated city sewage and wastewater.[79] Fluorine-containing agrichemicals are measurable in farmland runoff and nearby rivers.[80]

See also

Citations

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