Biological aspects of fluorine

Fluorine may interact with biological systems in the form of fluorine-containing compounds. Though elemental fluorine (F₂) is very rare in everyday life, fluorine-containing compounds such as fluorite occur naturally as minerals. Naturally occurring organofluorine compounds are extremely rare. Man-made fluoride compounds are common and are used in medicines, pesticides, and materials. Twenty percent of all commercialized pharmaceuticals contain fluorine, including Lipitor and Prozac.G. Siegemund, W. Schwertfeger, A. Feiring, B. Smart, F. Behr, H. Vogel, B. McKusick "Fluorine Compounds, Organic" in "Ullmann's Encyclopedia of Industrial Chemistry" 2005, Wiley-VCH, Weinheim. In many contexts, fluorine-containing compounds are harmless or even beneficial to living organisms; in others, they are toxic.

Aside from their use in medicine, man-made fluorinated compounds have also played a role in several noteworthy environmental concerns. Chlorofluorocarbons (CFCs), once major components of numerous commercial aerosol products, have proven damaging to Earth's ozone layer and resulted in the wide-reaching Montreal Protocol; though in truth the chlorine in CFCs is the destructive actor, fluorine is an important part of these molecules because it makes them very stable and long-lived. Similarly, the stability of many organofluorine compounds has raised the issue of biopersistence. Long-lived molecules from waterproofing sprays, for example PFOA and PFOS, are found worldwide in the tissues of wildlife and humans, including newborn children.

Fluorine biology is also relevant to a number of cutting-edge technologies. PFCs (perfluorocarbons) are capable of holding enough oxygen to support human liquid breathing. Organofluorine in the form of its radioisotope ¹⁸F is also at the heart of a modern medical imaging technique known as positron emission tomography (PET). A PET scan produces three-dimensional colored images of parts of the body that use a lot of sugar, particularly the brain or tumors.

Dental care

Since the mid-20th century, it has been discerned from population studies (though incompletely understood) that fluoride reduces tooth decay. 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) between teeth that were pre-fluoridated to different degrees. Current thinking is that fluoride prevents cavities primarily by helping teeth that are in the very early stages of tooth decay.

When teeth begin to decay from the acid produced by 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. 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.

Water fluoridation is the controlled addition of fluoride to a public water supply in an effort to reduce tooth decay in people who drink the water. Its use began in the 1940s, following studies of children in a region where water is naturally fluoridated. It is now used widely in public water systems in the United States and some other parts of the world, such that about two-thirds of the U.S. population is exposed to fluoridated water supplies and about 5.7% of people worldwide. 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, water fluoridation has been contentious for ethical, safety, and efficacy reasons, and opposition to water fluoridation exists despite its widespread support by public health organizations. 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. Systematic reviews in 2000 and 2007 showed significant reduction of cavities in children exposed to water fluoridation. Summary:

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. 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, which can be more quickly applied, exist and perform a similar function. Fluoride is also often present in prescription and non-prescription mouthwashes and is a trace component of foods manufactured using fluoridated water supplies.

Medical applications

Pharmaceuticals

Of all commercialized pharmaceutical drugs, twenty percent contain fluorine, including important drugs in many different pharmaceutical classes. Fluorine is often added to drug molecules during drug design, as even a single atom can greatly change the chemical properties of the molecule in desirable ways.

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.

Adding fluorine to biologically active organic compounds 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. Although the potential of fluorine being released in a fluoride leaving group depends on its position in the molecule, 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. Fluorine-containing fludrocortisone is one of the most common of these drugs. Dexamethasone and triamcinolone, which are among the most potent of the related synthetic corticosteroid class of drugs, contain fluorine as well.

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. Examples include sevoflurane, desflurane, enflurane, and isoflurane, all hydrofluorocarbon derivatives.

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

Scanning

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 usefully 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. 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. 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.

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 , 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. Fluorine-19 is commonly used in NMR study of metabolism, protein structures and conformational changes. In addition, inert fluorinated gases have the potential to be a cheap and efficient tool for imaging lung ventilation.

Oxygen transport research

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.

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) in order to be used as blood. One such product, Oxycyte, has been through initial clinical trials.

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

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

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

Agrichemicals

An estimated 30% of agrichemical compounds contain fluorine. Most of them are used as poisons, but a few stimulate growth instead.

Sodium fluoroacetate has been used as an insecticide, but it is especially effective against mammalian pests. The name "1080" refers to the catalogue number of the poison, which became its brand name. 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. Several other insecticides contain sodium fluoride, which is much less toxic than fluoroacetate. Insects fed 29-fluorostigmasterol use it to produce fluoroacetates. If a fluorine is transferred to a body cell, it blocks metabolism at the position occupied.

Trifluralin was widely used in the 20th century, for example, in over half of U.S. cotton field acreage in 1998. Because of its suspected carcinogenic properties some Northern European countries banned it in 1993. As of 2015, the European Union has banned it, although Dow made a case to cancel the decision in 2011.

Biochemistry

Biologically synthesized organofluorines are few in number, although some are widely produced. The most common example is fluoroacetate