When  abscisic acid  signals the guard cells, free Ca 2+  ions enter the cytosol from both outside the cell and internal stores, reversing the concentration gradient so the K+ ions begin exiting the cell. The loss of solutes makes the cell flaccid and closes the stomatal pores.


Calcium is a necessary ion in the formation of the  mitotic spindle . Without the mitotic spindle,  cellular division  cannot occur. Although young leaves have a higher need for calcium, older leaves contain higher amounts of calcium because calcium is relatively immobile through the plant. It is not transported through the  phloem  because it can bind with other nutrient ions and  precipitate  out of liquid solutions.


Ca 2+  ions are an essential component of plant  cell walls  and  cell membranes , and are used as  cations  to balance  organic   anions  in the plant  vacuole . [ 49 ]   The Ca 2+  concentration of the vacuole may reach millimolar levels.  The most striking use of Ca 2+  ions as a structural element in algae occurs in the marine  coccolithophores , which use Ca 2+  to form the  calcium carbonate  plates, with which they are covered.


Calcium is needed to form the  pectin  in the  middle lamella  of newly formed cells.


Calcium is needed to stabilize the permeability of cell membranes. Without calcium, the cell walls are unable to stabilize and hold their contents. This is particularly important in developing fruits. Without calcium, the cell walls are weak and unable to hold the contents of the fruit.


Some  plants  accumulate Ca in their tissues, thus making them more firm. Calcium is stored as Ca- oxalate  crystals in  plastids .


Ca 2+  ions are usually kept at nanomolar levels in the  cytosol  of  plant cells , and act in a number of signal transduction pathways as  second messengers .


Carbon  is a primary component of all known  life  on  Earth , and represents approximately 45–50% of all dry  biomass . [ 1 ]  Carbon compounds occur naturally in great abundance on Earth. Complex biological  molecules  consist of carbon atoms  bonded  with other  elements , especially  oxygen  and  hydrogen  and frequently also  nitrogen ,  phosphorus , and  sulfur  (collectively known as  CHNOPS ). [ 2 ] [ 3 ]


Because it is lightweight and relatively small in size, carbon molecules are easy for  enzymes  to manipulate.  Carbonic anhydrase  is part of this process. Carbon has an  atomic number  of 6 on the  periodic table .  The  carbon cycle  is a  biogeochemical cycle  that is important in maintaining life on Earth over a long time span. The cycle includes  carbon sequestration  and  carbon sinks . [ 4 ] [ 5 ]   Plate tectonics  are needed for life over a long time span, and carbon-based life is important in the plate tectonics process. [ 6 ]  Iron- and sulfur-based  Anoxygenic photosynthesis  life forms that lived from 3.80 to 3.85 billion years ago on Earth produced an abundance of  black shale  deposits. These shale deposits increase heat flow and crust buoyancy, especially on the sea floor, helping to increase plate tectonics.  Talc  is another organic mineral that helps drive plate tectonics. [ 7 ] [ 8 ]   Inorganic processes  also help drive plate tectonics. [ 9 ]  Carbon-based  photosynthesis  life caused a rise in  oxygen  on  Earth. This increase of oxygen helped plate tectonics form the first continents. [ 10 ]  It is frequently assumed in  astrobiology  that if life exists elsewhere in the  Universe , it will also be carbon-based. [ 11 ] [ 12 ]  Critics, like  Carl Sagan  in 1973, refer to this assumption as  carbon chauvinism . [ 13 ]


Carbon is capable of forming a vast number of  compounds , more than any other element, with almost ten million compounds described to date, [ 14 ]  and yet that is but a fraction of the number of compounds that are theoretically possible under standard conditions. The enormous diversity of carbon compounds, known as  organic compounds , has led to a distinction between them and the  inorganic compounds  that do not contain carbon. The branch of chemistry that studies organic compounds is known as  organic chemistry . [ 15 ]


Carbon is the 15th  most abundant element in the Earth's crust , and the  fourth most abundant element in the universe  by mass, after  hydrogen ,  helium , and  oxygen . Carbon's widespread abundance, its ability to form stable bonds with numerous other elements, and its unusual ability to form  polymers  at the temperatures commonly encountered on  Earth  enables it to serve as a common element of all known living organisms. In a 2018 study, carbon was found to compose approximately 550 billion tons of all life on Earth. [ 16 ] [ 17 ]  It is the second most abundant element in the  human body  by mass (about 18.5%) after oxygen. [ 18 ]


The most important characteristics of carbon as a basis for the  chemistry  of  cellular life  are that each carbon atom is capable of forming up to four  valence bonds  with other atoms simultaneously, and that the energy required to make or break a bond with a carbon atom is at an appropriate level for building large and complex molecules which may be both stable and reactive. [ 19 ]  Carbon atoms bond readily to other carbon atoms; this allows the building of arbitrarily long  macromolecules  and  polymers  in a process known as  catenation . [ 20 ] [ 21 ] [ 22 ]  "What we normally think of as 'life' is based on chains of carbon atoms, with a few other atoms, such as nitrogen or phosphorus", per  Stephen Hawking  in a 2008 lecture, "carbon [...] has the richest chemistry." [ 23 ]


Norman Horowitz  was the head of the  Jet Propulsion Laboratory 's bioscience section for the first U.S. mission,  Viking Lander of 1976 , to successfully land an unmanned probe on the surface of  Mars . He considered that the great versatility of the carbon atom makes it the element most likely to provide solutions, even exotic solutions, to the problems of survival on other planets. However, the  results of this mission  indicated that Mars was presently  extremely hostile  to carbon-based life. He also considered that, in general, there was only a remote possibility that non-carbon life forms would be able to evolve with genetic information systems capable of self-replication and adaptation. [ 24 ]


The most notable classes of biological  macromolecules  used in the fundamental processes of living organisms include: [ 25 ]


Liquid water  is essential for carbon-based life. Chemical bonding of carbon molecules requires liquid water. [ 30 ]  Water has the  chemical property  to make compound-solvent pairing. [ 31 ]  Water provides the reversible  hydration  of  carbon dioxide . Hydration of carbon dioxide is needed in carbon-based life. All life on Earth uses the same  biochemistry  of carbon.  Water is important in life's  carbonic anhydrase  the interaction of between carbon dioxide and water. Carbonic anhydrase needs a family of carbon base enzymes for the hydration of carbon dioxide and  acid–base homeostasis , that regulates  PH  levels in life.  [ 32 ] [ 33 ]  In  plant  life, liquid water  is needed for  photosynthesis , the  biological process  plants use to  convert   light energy  and carbon dioxide into  chemical energy . [ 34 ]  Water makes up 55% to 60% of the human body by weight. [ 35 ]


A few other elements have been proposed as candidates for supporting biological systems and processes as fundamentally as carbon does, for example, processes such as  metabolism . The most frequently suggested alternative is  silicon . [ 36 ]  Silicon, atomic number of 14, more than twice the size of carbon, shares a group in the  periodic table  with carbon, can also form four  valence bonds , and also bonds to itself readily, though generally in the form of  crystal lattices  rather than long chains. Despite these similarities, silicon is considerably more  electropositive  than carbon, and silicon compounds do not readily  recombine  into different permutations in a manner that would plausibly support lifelike processes. Silicon is abundant on Earth, but as it is more electropositive and in a water based environment it  forms Si–O bonds rather than Si–Si bonds. [ 37 ]   Boron  does not react with acids and does not form chains naturally. Thus boron is not a candidate for life. [ 38 ]   Arsenic  is  toxic  to life, and its possible candidacy has been rejected. [ 39 ] [ 40 ]  In the past (1960s-1970s) other candidates for life were plausible, but with time and more research, only carbon has the complexity and stability to make large molecules and polymers essential for life. [ 41 ] [ 42 ] [ 43 ]


Speculations about the chemical structure and properties of hypothetical non-carbon-based life have been a recurring theme in  science fiction . Silicon is often used as a substitute for carbon in fictional lifeforms because of its chemical similarities. In cinematic and literary science fiction, when man-made machines cross from non-living to living, this new form is often presented as an example of non-carbon-based life. Since the advent of the  microprocessor  in the late 1960s, such machines are often classed as "silicon-based life". Other examples of fictional "silicon-based life" can be seen in the 1967 episode " The Devil in the Dark " from  Star Trek: The Original Series , in which a living rock creature's biochemistry is based on silicon. [ 44 ]  In the 1994  The X-Files  episode " Firewalker ", in which a silicon-based organism is discovered in a volcano. [ 45 ] [ 46 ]


In the  1984 film adaptation  of  Arthur C. Clarke 's 1982 novel  2010: Odyssey Two , a character argues, "Whether we are based on carbon or on silicon makes no fundamental difference; we should each be treated with appropriate respect." [ 47 ]


In  JoJolion , the eighth part of the larger  JoJo's Bizarre Adventure  series, a mysterious race of silicon-based lifeforms "Rock Humans" serve as the primary antagonists. [ 48 ]


CHNOPS  and  CHON  are  mnemonic   acronyms  for the most common  elements  in living organisms. "CHON" stands for  c arbon ,  h ydrogen ,  o xygen , and  n itrogen , which together make up more than 95 percent of the mass of biological systems. [ 1 ]  "CHNOPS" adds  p hosphorus  and  s ulfur .


Carbon, hydrogen, nitrogen, oxygen, phosphorus, and sulfur are the six most important  chemical elements  whose  covalent  combinations make up most  biological   molecules  on Earth. [ 2 ]  All of these elements are  nonmetals .


In animals in general, the four elements—C, H, N, and O—compose about 96% of the weight, and major  minerals  (macrominerals) and minor minerals (also called  trace elements ) compose the remainder. [ 1 ]


Sulfur is contained in the  amino acids   cysteine  and  methionine . [ 3 ]
Phosphorus is contained in  phospholipids , a class of  lipids  that are a major component of all  cell membranes , as they can form  lipid bilayers , which keep  ions ,  proteins , and other molecules where they are needed for  cell  function, and prevent them from diffusing into areas where they should not be. Phosphate groups are also an essential component of the backbone of  nucleic acids  (general name for  DNA  &  RNA ) and are required to form  ATP  – the main molecule used as energy powering the cell in all living creatures. [ 4 ]


Carbonaceous asteroids  are rich in CHON elements. [ 5 ]
These asteroids are the most common type and frequently collide with Earth as  meteorites . Such collisions were especially common early in  Earth's history , and these impactors may have been crucial in the formation of the planet's oceans. [ 6 ]


The simplest compounds to contain all of the CHON elements are isomers  fulminic acid  (HCNO),  isofulminic acid  (HONC),  cyanic acid  (HOCN) and  isocyanic acid  (HNCO), having one of each atom. [ 7 ]


Cobalt  is essential to the metabolism of all  animals . It is a key constituent of  cobalamin , also known as vitamin B 12 , the primary biological reservoir of cobalt as an  ultratrace element . [ 1 ] [ 2 ]   Bacteria  in the stomachs of  ruminant  animals convert cobalt salts into vitamin B 12 , a compound which can only be produced by bacteria or  archaea . A minimal presence of cobalt in soils therefore markedly improves the health of  grazing  animals, and an uptake of 0.20 mg/kg a day is recommended because they have no other source of vitamin B 12 . [ 3 ]


Proteins based on cobalamin use  corrin  to hold the cobalt. Coenzyme B 12  features a reactive C-Co bond that participates in the reactions. [ 4 ]  In humans, B 12  has two types of  alkyl   ligand :  methyl  and adenosyl.  MeB 12  promotes methyl (−CH 3 ) group transfers. The adenosyl version of B 12  catalyzes rearrangements in which a hydrogen atom is directly transferred between two adjacent atoms with concomitant exchange of the second substituent, X, which may be a carbon atom with substituents, an oxygen atom of an alcohol, or an amine.  Methylmalonyl coenzyme A mutase  (MUT) converts  MMl-CoA  to  Su-CoA , an important step in the extraction of energy from proteins and fats. [ 5 ]


Although far less common than other  metalloproteins  (e.g. those of zinc and iron), other cobaltoproteins are known besides B 12 . These proteins include  methionine aminopeptidase 2 , an enzyme that occurs in humans and other mammals that does not use the corrin ring of B 12 , but binds cobalt directly. Another non-corrin cobalt enzyme is  nitrile hydratase , an enzyme in bacteria that metabolizes  nitriles . [ 6 ]


In humans, consumption of cobalt-containing vitamin B 12  meets all needs for cobalt. For cattle and sheep, which meet vitamin B 12  needs via synthesis by resident bacteria in the rumen, there is a function for inorganic cobalt. In the early 20th century, during the development of farming on the  North Island Volcanic Plateau  of New Zealand, cattle suffered from what was termed "bush sickness". It was discovered that the volcanic soils lacked the cobalt salts essential for the cattle food chain. [ 7 ] [ 8 ]  The "coast disease" of sheep in the  Ninety Mile Desert  of the  Southeast  of  South Australia  in the 1930s was found to originate in nutritional deficiencies of trace elements cobalt and copper. The cobalt deficiency was overcome by the development of "cobalt bullets", dense pellets of cobalt oxide mixed with clay given orally for lodging in the animal's  rumen . [ clarification needed ] [ 9 ] [ 8 ] [ 10 ]


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Fluoride  ( / ˈ f l ʊər aɪ d ,   ˈ f l ɔːr -/ ) [ 3 ]  is an  inorganic ,  monatomic   anion  of  fluorine , with the  chemical formula   F −  (also written  [F] − ), whose salts are typically white or colorless. Fluoride salts typically have distinctive bitter tastes, and are odorless. Its salts and minerals are important  chemical reagents  and industrial chemicals, mainly used in the production of  hydrogen fluoride  for  fluorocarbons . Fluoride is classified as a weak base since it only partially associates in solution, but concentrated fluoride is corrosive and can attack the skin.


Fluoride is the simplest fluorine  anion . In terms of charge and size, the fluoride  ion  resembles the  hydroxide  ion. Fluoride ions occur on  Earth  in several minerals, particularly  fluorite , but are present only in trace quantities in bodies of water in nature.


Fluorides include compounds that contain ionic fluoride and those in which fluoride does not dissociate. The nomenclature does not distinguish these situations. For example,  sulfur hexafluoride  and  carbon tetrafluoride  are not sources of fluoride ions under ordinary conditions.


The systematic name  fluoride , the valid  IUPAC  name, is determined according to the additive nomenclature. However, the name  fluoride  is also used in compositional IUPAC nomenclature which does not take the nature of bonding involved into account.
 Fluoride  is also used non-systematically, to describe compounds which release fluoride upon dissolving. Hydrogen fluoride is itself an example of a non-systematic name of this nature. However, it is also a  trivial name , and the  preferred IUPAC name  for  fluorane . [ citation needed ]


Fluorine  is estimated to be the 13th-most  abundant element  in Earth's crust and is widely dispersed in nature, entirely in the form of fluorides. The vast majority is held in  mineral deposits , the most commercially important of which is  fluorite  (CaF 2 ). [ 4 ]  Natural weathering of some kinds of rocks, [ 5 ] [ 6 ]  as well as human activities, releases fluorides into the  biosphere  through what is sometimes called the  fluorine cycle .


Fluoride is naturally present in groundwater,  fresh  and  saltwater  sources, as well as in rainwater, particularly in urban areas. [ 7 ]  Seawater fluoride levels are usually in the range of 0.86 to 1.4 mg/L, and average 1.1 mg/L [ 8 ]  (milligrams per  litre ). For comparison,  chloride  concentration in seawater is about 19 g/L. The low concentration of fluoride reflects the insolubility of the  alkaline earth  fluorides, e.g., CaF 2 .


Concentrations in fresh water vary more significantly.  Surface water  such as rivers or lakes generally contains between 0.01 and 0.3 mg/L. [ 9 ]   Groundwater  (well water) concentrations vary even more, depending on the presence of local fluoride-containing minerals. For example, natural levels of under 0.05 mg/L have been detected in parts of Canada but up to 8 mg/L in parts of China; in general levels rarely exceed 10 mg/litre [ 10 ]


Fluoride can be present in rain, with its concentration increasing significantly upon exposure to volcanic activity [ 14 ]  or atmospheric pollution derived from burning fossil fuels or other sorts of industry, [ 15 ] [ 16 ]  particularly  aluminium smelters . [ 17 ]


All vegetation contains some fluoride, which is absorbed from soil and water. [ 10 ]  Some plants concentrate fluoride from their environment more than others. All tea leaves contain fluoride; however, mature leaves contain as much as 10 to 20 times the fluoride levels of young leaves from the same plant. [ 18 ] [ 19 ] [ 20 ]


Fluoride can act as a  base . It can combine with a  proton  (   H + ):


This neutralization reaction forms  hydrogen fluoride  (HF), the  conjugate acid  of fluoride.


In aqueous solution, fluoride has a  p K b  value of 10.8. It is therefore a  weak base , and tends to remain as the fluoride ion rather than generating a substantial amount of hydrogen fluoride. That is, the following equilibrium favours the left-hand side in water:


However, upon prolonged contact with moisture, soluble fluoride salts will decompose to their respective hydroxides or oxides, as the hydrogen fluoride escapes. Fluoride is distinct in this regard among the halides. The identity of the solvent can have a dramatic effect on the equilibrium shifting it to the right-hand side, greatly increasing the rate of decomposition.


Salts containing fluoride are numerous and adopt myriad structures. Typically the fluoride anion is surrounded by four or six cations, as is typical for other halides.  Sodium fluoride  and  sodium chloride  adopt the same structure. For compounds containing more than one fluoride per cation, the structures often deviate from those of the chlorides, as illustrated by the main fluoride mineral  fluorite  (CaF 2 ) where the Ca 2+  ions are surrounded by eight F −  centers. In CaCl 2 , each Ca 2+  ion is surrounded by six Cl −  centers. The difluorides of the transition metals often adopt the  rutile  structure whereas the dichlorides have  cadmium chloride  structures.


Upon treatment with a standard acid, fluoride salts convert to  hydrogen fluoride  and metal  salts . With strong acids, it can be doubly protonated to give  H 2 F + . Oxidation of fluoride gives fluorine. Solutions of inorganic fluorides in water contain F −  and  bifluoride   HF − 2 . [ 21 ]  Few inorganic fluorides are soluble in water without undergoing significant hydrolysis. In terms of its reactivity, fluoride differs significantly from  chloride  and other halides, and is more strongly solvated in  protic solvents  due to its smaller radius/charge ratio. Its closest chemical relative is  hydroxide , since both have similar geometries.


Most fluoride salts dissolve to give the bifluoride ( HF − 2 ) anion. Sources of true F −  anions are rare because the highly basic fluoride anion abstracts protons from many, even adventitious, sources. Relative  unsolvated  fluoride, which does exist in aprotic solvents, is called "naked".  Naked fluoride  is a strong  Lewis base , [ 22 ]  and a powerful nucleophile. Some quaternary ammonium salts of naked fluoride include  tetramethylammonium fluoride   and  tetrabutylammonium fluoride . [ 23 ]   Cobaltocenium  fluoride is another example. [ 24 ]  However, they all lack structural characterization in aprotic solvents. Because of their high basicity, many so-called naked fluoride sources are in fact bifluoride salts. In late 2016  imidazolium  fluoride was synthesized that is the closest approximation of a thermodynamically stable and structurally characterized example of a "naked" fluoride source in an aprotic solvent (acetonitrile). [ 25 ]  The sterically demanding imidazolium cation stabilizes the discrete anions and protects them from polymerization. [ 26 ] [ 27 ]


At physiological pHs,  hydrogen fluoride  is usually fully ionised to fluoride. In  biochemistry , fluoride and hydrogen fluoride are equivalent. Fluorine, in the form of fluoride, is considered to be a  micronutrient  for human health, necessary to prevent dental cavities, and to promote healthy bone growth. [ 28 ]  The tea plant ( Camellia sinensis  L.) is a known accumulator of fluorine compounds, released upon forming infusions such as the common beverage. The fluorine compounds decompose into products including fluoride ions. Fluoride is the most bioavailable form of fluorine, and as such, tea is potentially a vehicle for fluoride dosing. [ 29 ]  Approximately, 50% of absorbed fluoride is excreted renally with a twenty-four-hour period. The remainder can be retained in the oral cavity, and lower digestive tract. Fasting dramatically increases the rate of fluoride absorption to near 100%, from a 60% to 80% when taken with food. [ 29 ]  Per a 2013 study, it was found that consumption of one litre of tea a day, can potentially supply the daily recommended intake of 4 mg per day. Some lower quality brands can supply up to a 120% of this amount. Fasting can increase this to 150%. The study indicates that tea drinking communities are at an increased risk of  dental  and  skeletal fluorosis , in the case where water fluoridation is in effect. [ 29 ]  Fluoride ion in low doses in the mouth reduces tooth decay. [ 30 ]  For this reason, it is used in toothpaste and water fluoridation. At much higher doses and frequent exposure, fluoride causes health complications and can be toxic.


Fluoride salts and hydrofluoric acid are the main fluorides of industrial value.


Organofluorine compounds are pervasive. Many drugs, many polymers, refrigerants, and many inorganic compounds are made from fluoride-containing reagents. Often fluorides are converted to hydrogen fluoride, which is a major reagent and precursor to reagents. Hydrofluoric acid and its anhydrous form,  hydrogen fluoride , are particularly important. [ 4 ]


The main uses of fluoride, in terms of volume, are in the production of cryolite, Na 3 AlF 6 . It is used in  aluminium smelting . Formerly, it was mined, but now it is derived from hydrogen fluoride. Fluorite is used on a large scale to separate slag in steel-making. Mined  fluorite  (CaF 2 ) is a commodity chemical used in steel-making.   Uranium hexafluoride  is employed in the purification of uranium isotopes.


Fluoride-containing compounds, such as  sodium fluoride  or  sodium monofluorophosphate  are used in topical and systemic  fluoride therapy  for preventing  tooth decay . They are used for  water fluoridation  and in many products associated with  oral hygiene . [ 31 ]  Originally, sodium fluoride was used to fluoridate water;  hexafluorosilicic acid  (H 2 SiF 6 ) and its salt  sodium hexafluorosilicate  (Na 2 SiF 6 ) are more commonly used additives, especially in the United States. The fluoridation of water is known to prevent tooth decay [ 32 ] [ 33 ]  and is considered by the U.S.  Centers for Disease Control and Prevention  to be "one of 10 great public health achievements of the 20th century". [ 34 ] [ 35 ]  In some countries where large, centralized water systems are uncommon, fluoride is delivered to the populace by fluoridating table salt. For the method of action for cavity prevention, see  Fluoride therapy . Fluoridation of water has its critics  (see  Water fluoridation controversy ) . [ 36 ]  Fluoridated  toothpaste  is in common use.  Meta-analysis  show the efficacy of 500 ppm fluoride in toothpastes. [ 37 ] [ 38 ]  However, no beneficial effect can be detected when more than one fluoride source is used for daily oral care. [ 39 ] [ need quotation to verify ]


Fluoride salts are commonly used in biological assay processing to  inhibit  the activity of  phosphatases , such as  serine / threonine  phosphatases. [ 40 ]  Fluoride mimics the  nucleophilic   hydroxide  ion in these enzymes' active sites. [ 41 ]   Beryllium fluoride  and  aluminium fluoride  are also used as phosphatase inhibitors, since these compounds are structural mimics of the  phosphate  group and can act as analogues of the  transition state  of the reaction. [ 42 ] [ 43 ]


The U.S. Institute of Medicine (IOM) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for some minerals in 1997. Where there was not sufficient information to establish EARs and RDAs, an estimate designated Adequate Intake (AI) was used instead. AIs are typically matched to actual average consumption, with the assumption that there appears to be a need, and that need is met by what people consume. The current AI for women 19 years and older is 3.0 mg/day (includes pregnancy and lactation). The AI for men is 4.0 mg/day. The AI for children ages 1–18 increases from 0.7 to 3.0 mg/day. The major known risk of  fluoride deficiency  appears to be an increased risk of bacteria-caused tooth cavities. As for safety, the IOM sets tolerable upper intake levels (ULs) for vitamins and minerals when evidence is sufficient. In the case of fluoride the UL is 10 mg/day. Collectively the EARs, RDAs, AIs and ULs are referred to as  Dietary Reference Intakes  (DRIs). [ 44 ]


The  European Food Safety Authority  (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL are defined the same as in the United States. For women ages 18 and older the AI is set at 2.9 mg/day (including pregnancy and lactation). For men, the value is 3.4 mg/day. For children ages 1–17 years, the AIs increase with age from 0.6 to 3.2 mg/day. These AIs are comparable to the U.S. AIs. [ 45 ]  The EFSA reviewed safety evidence and set an adult UL at 7.0 mg/day (lower for children). [ 46 ]


For U.S. food and dietary supplement labeling purposes, the amount of a vitamin or mineral in a serving is expressed as a percent of Daily Value (%DV). Although there is information to set Adequate Intake, fluoride does not have a Daily Value and is not required to be shown on food labels. [ 47 ]


Daily intakes of fluoride can vary significantly according to the various sources of exposure. Values ranging from 0.46 to 3.6–5.4 mg/day have been reported in several studies (IPCS, 1984). [ 28 ]  In areas where water is  fluoridated  this can be expected to be a significant source of fluoride, however fluoride is also naturally present in virtually all foods and beverages at a wide range of concentrations. [ 48 ]  The maximum safe daily consumption of fluoride is 10 mg/day for an adult (U.S.) or 7 mg/day (European Union). [ 44 ] [ 46 ]


The upper limit of fluoride intake from all sources (fluoridated water, food, beverages, fluoride dental products and dietary fluoride supplements) is set at 0.10 mg/kg/day for infants, toddlers, and children through to 8 years old. For older children and adults, who are no longer at risk for dental fluorosis, the upper limit of fluoride is set at 10 mg/day regardless of weight. [ 49 ]


According to the U.S. Department of Agriculture, the Dietary Reference Intakes, which is the "highest level of daily nutrient intake that is likely to pose no risk of adverse health effects" specify 10 mg/day for most people, corresponding to 10 L of fluoridated water with no risk. For young children the values are smaller, ranging from 0.7 mg/d to 2.2 mg/d for infants. [ 51 ]  Water and food sources of fluoride include community water fluoridation, seafood, tea, and gelatin. [ 52 ]


Soluble fluoride salts, of which  sodium fluoride  is the most common, are toxic, and have resulted in both accidental and self-inflicted deaths from  acute poisoning . [ 4 ]  The lethal dose for most adult humans is estimated at 5 to 10 g (which is equivalent to 32 to 64 mg elemental fluoride per kg body weight). [ 53 ] [ 54 ] [ 55 ]  A case of a fatal poisoning of an adult with 4 grams of sodium fluoride is documented, [ 56 ]  and a dose of 120 g sodium fluoride has been survived. [ 57 ]  For  sodium fluorosilicate  (Na 2 SiF 6 ), the  median lethal dose  (LD 50 ) orally in rats is 125 mg/kg, corresponding to 12.5 g for a 100 kg adult. [ 58 ]


Treatment may involve oral administration of dilute  calcium hydroxide  or  calcium chloride  to prevent further absorption, and injection of  calcium gluconate  to increase the calcium levels in the blood. [ 56 ]   Hydrogen fluoride  is more dangerous than salts such as NaF because it is corrosive and volatile, and can result in fatal exposure through inhalation or upon contact with the skin; calcium gluconate gel is the usual antidote. [ 59 ]


In the higher doses used to treat  osteoporosis , sodium fluoride can cause pain in the legs and incomplete stress fractures when the doses are too high; it also irritates the stomach, sometimes so severely as to cause ulcers. Slow-release and  enteric -coated versions of sodium fluoride do not have gastric side effects in any significant way, and have milder and less frequent complications in the bones. [ 60 ]  In the lower doses used for  water fluoridation , the only clear adverse effect is  dental fluorosis , which can alter the appearance of children's teeth during  tooth development ; this is mostly mild and is unlikely to represent any real effect on aesthetic appearance or on public health. [ 61 ]  Fluoride was known to enhance bone mineral density at the lumbar spine, but it was not effective for vertebral fractures and provoked more nonvertebral fractures. [ 62 ]  In areas that have naturally occurring high levels of fluoride in  groundwater  which is used for  drinking water , both  dental  and  skeletal fluorosis  can be prevalent and severe. [ 63 ]


Around one-third of the human population drinks water from groundwater resources. Of this, about 10%, approximately 300 million people, obtain water from groundwater resources that are heavily contaminated with arsenic or fluoride. [ 64 ]   These trace elements derive mainly from minerals. [ 65 ]  Maps locating potential problematic wells are available. [ 66 ]


Concentrated fluoride solutions are corrosive. [ 67 ]  Gloves made of  nitrile rubber  are worn when handling fluoride compounds. The hazards of solutions of fluoride salts depend on the concentration. In the presence of  strong acids , fluoride salts release  hydrogen fluoride , which is corrosive, especially toward glass. [ 4 ]


Organic and inorganic anions are produced from fluoride, including:


GFAJ-1  is a  strain  of  rod-shaped   bacteria  in the family  Halomonadaceae . It is an  extremophile  that was isolated from the  hypersaline  and  alkaline   Mono Lake  in eastern  California  by geobiologist  Felisa Wolfe-Simon , a NASA  research fellow  in residence at the  US Geological Survey . In a 2010  Science  journal publication, [ 1 ]  the authors claimed that the microbe, when starved of  phosphorus , is capable of substituting  arsenic  for a small percentage of its phosphorus to sustain its growth. [ 2 ] [ 3 ]  Immediately after publication, other microbiologists and biochemists expressed doubt about this claim, which was robustly criticized in the scientific community. Subsequent independent studies published in 2012 found no detectable arsenate in the DNA of GFAJ-1, refuted the claim, and demonstrated that GFAJ-1 is simply an arsenate-resistant, phosphate-dependent organism. [ 4 ] [ 5 ] [ 6 ] [ 7 ]


The GFAJ-1 bacterium was discovered by  geomicrobiologist   Felisa Wolfe-Simon , a  NASA   astrobiology  fellow in residence at the  US Geological Survey  in  Menlo Park, California . [ 8 ]  GFAJ stands for "Give Felisa a Job". [ 9 ]  The organism was isolated and  cultured  beginning in 2009 from samples she and her colleagues collected from sediments at the bottom of  Mono Lake , California, U.S.A. [ 10 ]  Mono Lake is  hypersaline  (about 90 grams/liter) and highly  alkaline  ( pH  9.8). [ 11 ]  It also has one of the highest natural concentrations of  arsenic  in the world (200 μ M ). [ 1 ]  The discovery was widely publicized on 2 December 2010. [ 2 ]


Escherichia coli  strain  O157:H7


Halomonas alkaliphila


Halomonas venusta  strain NBSL13


Halomonas  sp. GTW


Halomonas  sp. G27


Halomonas  sp. DH77


Halomonas  sp. mp3


Halomonas  sp. IB-O18


Halomonas  sp. ML-185


Molecular  analysis based on  16S rRNA  sequences shows GFAJ-1 to be closely related to other moderate  halophile  ("salt-loving") bacteria of the family  Halomonadaceae . Although the authors produced a  cladogram  in which the strain is nested among members of  Halomonas , including  H. alkaliphila  and  H. venusta , [ 12 ]  they did not explicitly assign the strain to that genus. [ 1 ] [ 10 ]  Many bacteria are known to be able to tolerate high levels of arsenic, and to have a proclivity to take it up into their cells. [ 1 ] [ 13 ]  However, GFAJ-1 was controversially proposed to go a step further; when starved of phosphorus, it was proposed to instead incorporate arsenic into its metabolites and macromolecules and continue growing. [ 10 ]


The sequence of the genome of the bacterium GFAJ-1 is now posted in  GenBank . [ 14 ]


In the  Science  journal article, GFAJ-1 is referred to as a  strain  of Halomonadaceae and not as a new  species . [ 1 ]  The  International Code of Nomenclature of Bacteria , the set of regulations which govern the  taxonomy  of bacteria, and certain articles in the  International Journal of Systematic and Evolutionary Microbiology  contain the guidelines and minimal standards to describe a new species, e.g. the minimal standards to describe a member of the  Halomonadaceae . [ 15 ]  Organisms are described as new species if they meet certain physiological and genetic conditions, such as generally less than 97%  16S rRNA  sequence identity to other known species [ 16 ]  and metabolic differences allowing them to be discerned apart. In addition to indicators to tell the novel species from other species, other analyses are required, such as  fatty acid composition , respiratory quinone used and tolerance ranges and deposition of the strain in at least two microbiological repositories. New proposed names are given in italics followed by  sp. nov.  (and  gen. nov.  if it is a novel genus according to the descriptions of that  clade ). [ 17 ] [ 18 ]


In the instance of the GFAJ-1 strain these criteria are not met, and the strain is not claimed to be a new species. [ 1 ]  When a strain is not assigned to a species (e.g. due to insufficient data or choice) it is often labeled as the genus name followed by "sp." (i.e., undetermined species of that genus) and the strain name. In the case of GFAJ-1 the authors chose to refer to the strain by strain designation only. Strains closely related to GFAJ-1 include  Halomonas  sp. GTW and  Halomonas  sp. G27, neither of which were described as valid species. [ 19 ] [ 20 ]  If the authors had formally assigned strain GFAJ-1 to the genus  Halomonas , [ 10 ]  the name would be given as  Halomonas  sp. GFAJ-1.


Until release R220, the  Genome Taxonomy Database  assigned GFAJ-1 its own tentative species,  Halomonas sp002966495 . This means that the strain falls into  Halomonas  phylogenetically, and its whole-genome similarity compared to other defined species of the genus is low enough. Neither strain GTW nor strain G27 has a genome available for the database to run its classification. In release R220, the databased moved the strain to  Vreelandella , a new genus published in 2023 (and validated in 2024). [ 21 ]


A phosphorus-free  growth medium  (which actually contained 3.1 ± 0.3 μM of residual phosphate, from impurities in reagents) was used to culture the bacteria in a regime of increasing exposure to  arsenate ; the initial level of 0.1 mM was eventually ramped up to 40 mM. Alternative media used for comparative experiments contained either high levels of  phosphate  (1.5 mM) with no arsenate, or had neither added phosphate nor added arsenate.  It was observed that GFAJ-1 could grow through many doublings in cell numbers when cultured in either phosphate or arsenate media, but could not grow when placed in a medium of a similar composition to which neither phosphate nor arsenate was added. [ 1 ]  The phosphorus content of the arsenic-fed, phosphorus-starved bacteria (as measured by  ICP-MS)  was only 0.019 (± 0.001) % by dry weight, one thirtieth of that when grown in phosphate-rich medium. This phosphorus content was also only about one tenth of the cells' average arsenic content (0.19 ± 0.25% by dry weight). [ 1 ]  The arsenic content of cells as measured by ICP-MS varies widely and can be lower than the phosphorus contents in some experiments, and up to fourteen times higher in others. [ 22 ]  Other data from the same study obtained with nano- SIMS  suggest a ~75-fold excess of phosphate (P) over arsenic (As) when expressed as P:C and As:C ratios, even in cells grown with arsenate and no added phosphate. [ 12 ]  When cultured in the arsenate solution, GFAJ-1 only grew 60% as fast as it did in phosphate solution. [ 2 ]  The phosphate-starved bacteria had an intracellular volume 1.5 times normal; the greater volume appeared to be associated with the appearance of large " vacuole -like regions". [ 1 ]


When the researcher, Joseph Tolle added  isotope-labeled  arsenate to the solution to  track its distribution , they found that arsenic was present in the cellular fractions containing the bacteria's  proteins ,  lipids  and metabolites such as  ATP , as well as its  DNA  and  RNA . [ 2 ]  Nucleic acids from  stationary phase  cells starved of phosphorus were concentrated via five  extractions  (one with  phenol , three with  phenol-chloroform  and one with  chloroform  extraction solvent), followed by  ethanol precipitation . Although direct evidence of the incorporation of arsenic into biomolecules is still lacking,  radioactivity  measurements suggested that approximately one-tenth (11.0 ± 0.1%) of the arsenic absorbed by these bacteria ended up in the fraction that contained the  nucleic acids  (DNA and RNA) and all other co-precipitated compounds not extracted by the previous treatments. [ 1 ]  A comparable control experiment with isotope-labeled phosphate was not performed.
With the distribution of the strain in mid-2011, other labs began to independently test the validity of the discovery.  Rosemary Redfield  from the  University of British Columbia , following issues with the growth conditions, investigated the growth requirements of GFAJ-1, and found that the strain grows better on solid  agar  medium than in liquid culture. Redfield attributed this to low potassium levels and hypothesized that the potassium levels in basal ML60 medium may be too low to support growth. [ 23 ]  Redfield after finding and addressing further issues (ionic strength, pH and the use of glass tubes instead of polypropylene) found that arsenate marginally stimulated growth, but didn't affect the final densities of the cultures, unlike what was claimed. [ 24 ]  Subsequent studies using mass spectrometry by the same group found no evidence of arsenate being incorporated into the DNA of GFAJ-1. [ 25 ]


Arsenate  esters , such as those that would be  present in DNA , are generally expected to be  orders of magnitude  less stable to  hydrolysis  than corresponding  phosphate esters . [ 26 ]  dAMAs, the structural arsenic analog of the DNA building block  dAMP , has a  half-life  of 40 minutes in water at neutral pH. [ 27 ]  Estimates of the half-life in water of arsenodiester bonds, which would link the nucleotides together, are as short as 0.06 seconds—compared to 30 million years for the  phosphodiester bonds  in DNA. [ 28 ]  The authors speculate that the bacteria may stabilize arsenate esters to a degree by using  poly-β-hydroxybutyrate  (which has been found to be elevated in "vacuole-like regions" of related species of the genus  Halomonas [ 29 ]
) or other means to lower the  effective concentration  of water. [ 1 ] [ 10 ]  Polyhydroxybutyrates are used by many bacteria for energy and carbon storage under conditions when growth is limited by elements other than carbon, and typically appear as large waxy granules closely resembling the "vacuole-like regions" seen in GFAJ-1 cells. [ 30 ]  The authors present no mechanism by which insoluble polyhydroxybutyrate may lower the effective concentration of water in the cytoplasm sufficiently to stabilize arsenate esters. Although all halophiles must reduce the  water activity  of their cytoplasm by some means to avoid desiccation, [ 31 ]  the cytoplasm always remains an aqueous environment.


NASA's announcement of a news conference "that will impact the search for evidence of extraterrestrial life" was criticized as sensationalistic and misleading; an editorial in  New Scientist  commented "although the discovery of alien life, if it ever happens, would be one of the biggest stories imaginable, this was light-years from that". [ 32 ] [ 33 ]


In addition, many experts who have evaluated the paper have concluded that the reported studies do not provide enough evidence to support the claims made by the authors. [ 34 ]  In an online article on  Slate , science writer  Carl Zimmer  discussed the skepticism of several scientists: "I reached out to a dozen experts ... Almost unanimously, they think the NASA scientists have failed to make their case". [ 35 ] [ 36 ]  Chemist  Steven A. Benner  has expressed doubts that  arsenate  has replaced phosphate in the DNA of this organism. He suggested that the  trace contaminants  in the growth medium used by Wolfe-Simon in her laboratory cultures are sufficient to supply the phosphorus needed for the cells' DNA. He believes that it is more likely that arsenic is being sequestered elsewhere in the cells. [ 2 ] [ 10 ]   University of British Columbia   microbiologist  Rosemary Redfield said that the paper "doesn't present any convincing evidence that arsenic has been incorporated into DNA or any other biological molecule", and suggests that the experiments lacked the washing steps and  controls  necessary to properly validate their conclusions. [ 37 ] [ 38 ]  Harvard microbiologist Alex Bradley said that arsenic-containing DNA would be so unstable in water it could not have survived the analysis procedure. [ 35 ] [ 39 ]


On 8 December 2010,  Science  published a response by Wolfe-Simon, in which she stated that criticism of the research was expected. In response, a " Frequently Asked Questions " page to improve understanding of the work was posted on 16 December 2010. [ 40 ]  The team plans to deposit the GFAJ-1 strain in the  ATCC  and  DSMZ  culture collections to allow widespread distribution. [ 41 ]  In late May 2011 the strain was made available upon request directly from the laboratory of the authors. [ 42 ]   Science  has made the article freely available. [ 43 ]  The article was published in print six months after acceptance in the 3 June 2011 issue of  Science .  The publication was accompanied by eight technical comments addressing various concerns regarding the article's experimental procedure and conclusion, [ 44 ] [ 45 ] [ 46 ] [ 47 ] [ 48 ] [ 49 ] [ 50 ] [ 51 ] [ 52 ]  as well as a response by the authors to these concerns. [ 42 ] [ 53 ]  The editor in chief  Bruce Alberts  has indicated that some issues remain and that their resolution is likely to be a long process. [ 54 ]  A review by Rosen  et al. , [ 55 ]  in the March 2011 issue of the journal  BioEssays  discusses the technical issues with the  Science  paper, provides alternative explanations, and highlights known biochemistry of other arsenic resistant and arsenic utilizing microbes.


On 27 May 2011, Wolfe-Simon and her team responded to the criticism in a follow-up  Science  journal publication. [ 42 ]  Then in January 2012 a group of researchers led by Rosie Redfield at the  University of British Columbia  analyzed the DNA of GFAJ-1 using  liquid chromatography–mass spectrometry  and could not detect any arsenic, which Redfield calls a "clear refutation" of the original paper's findings. [ 56 ]  Following the publication of the analysis, Wolfe-Simon stated that she and her colleagues "expect to publish new information in the next few months", [ 57 ]  but as of 2024 has not submitted any new publications since 2011.


A simple explanation for the GFAJ-1 growth in medium supplied with arsenate instead of phosphate was provided by a team of researchers at the  University of Miami  in Florida.  After labeling the  ribosomes  of a laboratory strain of  Escherichia coli  with radioactive isotopes (forming a  radioactive tracer ), they followed bacterial growth in medium containing arsenate but no phosphate.  They found that arsenate induces massive  degradation  of ribosomes, thus providing sufficient phosphate for the slow growth of arsenate tolerant bacteria.  Similarly, they suggest, GFAJ-1 cells grow by recycling phosphate from degraded ribosomes, rather than by replacing it with arsenate. [ 58 ]


Following the publication of the articles challenging the conclusions of the original  Science  article first describing GFAJ-1, the website  Retraction Watch  argued that the original article should be retracted because of misrepresentation of critical data. [ 59 ] [ 60 ]  As of January 2024 [update] , the paper had not been retracted. [ 1 ]


Human iron metabolism  is the set of chemical reactions that maintain  human homeostasis  of  iron  at the systemic and cellular level.  Iron is both necessary to the body and potentially toxic. Controlling iron levels in the body is a critically important part of many aspects of human health and disease.  Hematologists  have been especially interested in systemic iron  metabolism , because iron is essential for  red blood cells , where most of the human body's iron is contained. Understanding iron metabolism is also important for understanding diseases of  iron overload , such as  hereditary hemochromatosis , and  iron deficiency , such as  iron-deficiency anemia .


Iron is an essential bioelement for most forms of life, from  bacteria  to  mammals . Its importance lies in its ability to mediate electron transfer. In the ferrous state (Fe 2+ ), iron acts as an  electron donor , while in the ferric state (Fe 3+ ) it acts as an  acceptor . Thus, iron plays a vital role in the  catalysis  of enzymatic reactions that involve electron transfer (reduction and oxidation,  redox ). Proteins can contain iron as part of different  cofactors , such as  iron–sulfur clusters  (Fe-S) and  heme  groups, both of which are assembled in  mitochondria .


Human cells require iron in order to obtain energy as  ATP  from a multi-step process known as cellular respiration, more specifically from  oxidative phosphorylation  at the mitochondrial  cristae . Iron is present in the iron–sulfur cluster and heme groups of the  electron transport chain  proteins that generate a  proton gradient  that allows  ATP synthase  to synthesize ATP ( chemiosmosis ).


Heme groups are part of  hemoglobin , a protein found in red blood cells that serves to transport oxygen from the  lungs  to other tissues. Heme groups are also present in  myoglobin  to store and diffuse oxygen in muscle cells.


The human body needs iron for oxygen transport. Oxygen (O 2 ) is required for the functioning and survival of nearly all cell types. Oxygen is transported from the lungs to the rest of the body bound to the  heme  group of  hemoglobin  in red blood cells. In muscles cells, iron binds oxygen to  myoglobin , which regulates its release.


Iron is also potentially toxic. Its ability to donate and accept electrons means that it can catalyze the conversion of  hydrogen peroxide  into  free radicals . Free radicals can cause damage to a wide variety of cellular structures, and ultimately kill the cell. [ 1 ]


Iron bound to proteins or  cofactors  such as  heme  is safe. Also,  there are virtually no truly free iron ions in the cell, since they readily form complexes with organic molecules. However, some of the intracellular iron is bound to low-affinity complexes, and is termed labile iron or "free" iron. Iron in such complexes can cause damage as described above. [ 2 ]


To prevent that kind of damage, all life forms that use iron bind the iron atoms to  proteins . This binding allows cells to benefit from iron while also limiting its ability to do harm. [ 1 ] [ 3 ]  Typical intracellular labile iron concentrations in bacteria are 10-20 micromolar, [ 4 ]  though they can be 10-fold higher in anaerobic environment, [ 5 ]  where free radicals and  reactive oxygen species  are scarcer. In mammalian cells, intracellular labile iron concentrations are typically smaller than 1 micromolar, less than 5 percent of total cellular iron. [ 2 ]


In response to a systemic bacterial infection, the immune system initiates a process known as " iron withholding ". If bacteria are to survive, then they must obtain iron from their environment. Disease-causing bacteria do this in many ways, including releasing iron-binding molecules called  siderophores  and then reabsorbing them to recover iron, or scavenging iron from hemoglobin and  transferrin . The harder the bacteria have to work to get iron, the greater a  metabolic price  they must pay. That means that iron-deprived bacteria reproduce more slowly. So, control of iron levels appears to be an important defense against many bacterial infections. Certain bacteria species have developed strategies to circumvent that defense,  TB  causing bacteria can reside within  macrophages , which present an iron rich environment and  Borrelia burgdorferi  uses  manganese  in place of iron. People with increased amounts of iron, as, for example, in hemochromatosis, are more susceptible to some bacterial infections. [ 6 ]


Although this mechanism is an elegant response to short-term bacterial infection, it can cause problems when it goes on so long that the body is deprived of needed iron for red cell production. Inflammatory  cytokines  stimulate the liver to produce the iron metabolism regulator protein  hepcidin , that reduces available iron. If hepcidin levels increase because of non-bacterial sources of inflammation, like viral infection, cancer, auto-immune diseases or other chronic diseases, then the  anemia of chronic disease  may result. In this case, iron withholding actually impairs health by preventing the manufacture of enough hemoglobin-containing red blood cells. [ 3 ]


Most well-nourished people in industrialized countries have 4 to 5 grams of iron in their bodies (~38 mg iron/kg body weight for women and ~50 mg iron/kg body for men). [ 7 ]  Of this, about  2.5 g  is contained in the hemoglobin needed to carry oxygen through the blood (around 0.5 mg of iron per mL of blood), [ 8 ]  and most of the rest (approximately 2 grams in adult men, and somewhat less in women of childbearing age) is contained in  ferritin  complexes that are present in all cells, but most common in bone marrow,  liver , and  spleen . The liver stores of ferritin are the primary physiologic source of reserve iron in the body. The reserves of iron in industrialized countries tend to be lower in children and women of child-bearing age than in men and in the elderly. Women who must use their stores to compensate for iron lost through  menstruation ,  pregnancy  or  lactation  have lower non-hemoglobin body stores, which may consist of  500 mg , or even less.


Of the body's total iron content, about  400 mg  is devoted to cellular proteins that use iron for important cellular processes like storing oxygen (myoglobin) or performing energy-producing redox reactions ( cytochromes ). A relatively small amount (3–4 mg) circulates through the  plasma , bound to transferrin. [ 9 ]  Because of its toxicity, free soluble iron is kept in low concentration in the body.


Iron deficiency  first affects the storage of iron in the body, and depletion of these stores is thought to be relatively asymptomatic, although some vague and  non-specific symptoms  have been associated with it. Since iron is primarily required for hemoglobin,  iron deficiency anemia  is the primary clinical manifestation of iron deficiency. Iron-deficient people will suffer or die from organ damage well before their cells run out of the iron needed for intracellular processes like electron transport.


Macrophages  of the  reticuloendothelial system  store iron as part of the process of breaking down and processing hemoglobin from engulfed red blood cells. Iron is also stored as a pigment called  hemosiderin , which is an ill-defined deposit of protein and iron, created by macrophages where excess iron is present, either locally or systemically, e.g., among people with iron overload due to frequent blood cell destruction and the necessary transfusions their condition calls for. If systemic iron overload is corrected, over time the hemosiderin is slowly resorbed by the macrophages.


Human iron homeostasis is regulated at two different levels. Systemic iron levels are balanced by the controlled absorption of dietary iron by  enterocytes , the cells that line the interior of the  intestines , and the uncontrolled loss of iron from epithelial sloughing, sweat, injuries and blood loss. In addition, systemic iron is continuously recycled. Cellular iron levels are controlled differently by different cell types due to the expression of particular iron regulatory and transport proteins.


The absorption of dietary iron is a variable and dynamic process. The amount of iron absorbed compared to the amount ingested is typically low, but may range from 5% to as much as 35% depending on circumstances and type of iron. The efficiency with which iron is absorbed varies depending on the source. Generally, the best-absorbed forms of iron come from animal products. Absorption of dietary iron in iron salt form (as in most supplements) varies somewhat according to the body's need for iron, and is usually between 10% and 20% of iron intake. Absorption of iron from animal products, and some plant products, is in the form of heme iron, and is more efficient, allowing absorption of from 15% to 35% of intake. Heme iron in animals is from blood and heme-containing proteins in meat and mitochondria, whereas in plants, heme iron is present in mitochondria in all cells that use oxygen for respiration.


Like most mineral nutrients, the majority of the iron absorbed from digested food or supplements is absorbed in the  duodenum  by  enterocytes  of the duodenal lining. These cells have special molecules that allow them to move iron into the body. To be absorbed, dietary iron can be absorbed as part of a protein such as heme protein or iron must be in its ferrous Fe 2+  form. A ferric reductase enzyme on the enterocytes'  brush border , duodenal cytochrome B ( Dcytb ), reduces ferric Fe 3+  to Fe 2+ . [ 10 ]  A protein called divalent metal transporter 1 ( DMT1 ), which can transport several  divalent  metals across the plasma membrane, then transports iron across the enterocyte's  cell membrane  into the cell. If the iron is bound to heme, it is instead transported across the apical membrane by  heme carrier protein 1  (HCP1). [ 11 ]  Heme is then  catabolized  by microsomal  heme oxygenase  into  biliverdin , releasing Fe 2+ . [ 12 ]


These intestinal lining cells can then either store the iron as  ferritin , which is accomplished by Fe 2+  binding to apoferritin (in which case the iron will leave the body when the cell dies and is sloughed off into  feces ), or the cell can release it into the body via the only known iron exporter in mammals,  ferroportin .  Hephaestin , a  ferroxidase  that can oxidize Fe 2+  to Fe 3+  and is found mainly in the small intestine, helps ferroportin transfer iron across the basolateral end of the intestine cells. Upon release into the bloodstream, Fe 3+  binds transferrin and circulates to tissues. In contrast, ferroportin is post-translationally repressed by  hepcidin , a 25-amino acid peptide hormone. The body regulates iron levels by regulating each of these steps. For instance, enterocytes synthesize more Dcytb, DMT1 and ferroportin in response to iron deficiency anemia. [ 13 ]  Iron absorption from diet is enhanced in the presence of vitamin C and diminished by excess calcium, zinc, or manganese. [ 14 ]


The human body's rate of iron absorption appears to respond to a variety of interdependent factors, including total iron stores, the extent to which the bone marrow is producing new red blood cells, the concentration of hemoglobin in the blood, and the oxygen content of the blood. The body also absorbs less iron during times of  inflammation , in order to deprive bacteria of iron. Recent discoveries demonstrate that hepcidin regulation of ferroportin is responsible for the syndrome of anemia of chronic disease.


Most of the iron in the body is hoarded and recycled by the reticuloendothelial system, which breaks down aged red blood cells. In contrast to iron uptake and recycling, there is no physiologic regulatory mechanism for  excreting  iron. People lose a small but steady amount by gastrointestinal blood loss, sweating and by shedding cells of the skin and the  mucosal  lining of the  gastrointestinal tract . The total amount of loss for healthy people in the developed world amounts to an estimated average of  1 mg  a day for men, and 1.5–2 mg a day for women with regular menstrual periods. [ 15 ]  People with gastrointestinal parasitic infections, more commonly found in developing countries, often lose more. [ 1 ]  Those who cannot regulate absorption well enough get disorders of iron overload. In these diseases, the toxicity of iron starts overwhelming the body's ability to bind and store it. [ 16 ]


Most cell types take up iron primarily through  receptor-mediated endocytosis  via  transferrin receptor 1  (TFR1),  transferrin receptor 2  (TFR2) and  GAPDH . TFR1 has a 30-fold higher affinity for transferrin-bound iron than TFR2 and thus is the main player in this process. [ 17 ] [ 18 ]  The higher order multifunctional glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) also acts as a transferrin receptor. [ 19 ] [ 20 ]  Transferrin-bound ferric iron is recognized by these transferrin receptors, triggering a conformational change that causes endocytosis. Iron then enters the cytoplasm from the endosome via importer DMT1 after being reduced to its ferrous state by a STEAP family reductase. [ 21 ]


Alternatively, iron can enter the cell directly via plasma membrane divalent cation importers such as DMT1 and ZIP14 (Zrt-Irt-like protein 14). [ 22 ]  Again, iron enters the cytoplasm in the ferrous state after being reduced in the extracellular space by a reductase such as STEAP2, STEAP3 (in red blood cells), Dcytb (in enterocytes) and SDR2. [ 21 ]


Iron can also enter cells via  CD44  in complexes bound to  hyaluronic acid  during  epithelial–mesenchymal transition  (EMT). In this process,  epithelial cells  transform into  mesenchymal cells  with detachment from the  basement membrane , to which they’re normally anchored, paving the way for the newly differentiated motile mesenchymal cells to begin migration away from the epithelial layer. [ 23 ] [ 24 ]


While EMT plays a crucial role in physiological processes like  implantation , where it enables the  embryo  to invade the  endometrium  to facilitate  placental  attachment, its dysregulation can also fuel the  malignant  spread of  tumors  empowering them to invade surrounding tissues and establish distant colonies ( metastasis ). [ 24 ]


Malignant cells often exhibit a heightened demand for iron, fueling their transition towards a more invasive mesenchymal state. This iron is necessary for the expression of mesenchymal genes, like those encoding  transforming growth factor beta  (TGF-β), crucial for EMT. Notably, iron’s unique ability to catalyze  protein  and  DNA   demethylation  plays a vital role in this gene expression process. [ 23 ]


Conventional iron uptake pathways, such as those using the transferrin receptor 1 (TfR1), often prove insufficient to meet these elevated iron demands in cancer cells. As a result, various  cytokines  and  growth factors  trigger the upregulation of CD44, a surface molecule capable of internalizing iron bound to the hyaluronan complex. This alternative pathway, relying on CD44-mediated endocytosis, becomes the dominant iron uptake mechanism compared to the traditional TfR1-dependent route. [ 23 ] [ 24 ]


In the cytoplasm, ferrous iron is found in a soluble, chelatable state which constitutes the labile iron pool (~0.001 mM). [ 25 ]  In this pool, iron is thought to be bound to low-mass compounds such as peptides, carboxylates and phosphates, although some might be in a free, hydrated form ( aqua ions ). [ 25 ]  Alternatively, iron ions might be bound to specialized proteins known as  metallochaperones . [ 26 ]  Specifically, poly-r(C)-binding proteins  PCBP1  and  PCBP2  appear to mediate transfer of free iron to ferritin (for storage) and  non-heme iron enzymes  (for use in catalysis). [ 22 ] [ 27 ]  The labile iron pool is potentially toxic due to iron's ability to generate reactive oxygen species. Iron from this pool can be taken up by mitochondria via  mitoferrin  to synthesize Fe-S clusters and heme groups. [ 21 ]


Iron can be stored in ferritin as ferric iron due to the  ferroxidase  activity of the ferritin heavy chain. [ 28 ]  Dysfunctional ferritin may accumulate as  hemosiderin , which can be problematic in cases of iron overload. [ 29 ]  The ferritin storage iron pool is much larger than the labile iron pool, ranging in concentration from 0.7 mM to 3.6 mM. [ 25 ]


Iron export occurs in a variety of cell types, including  neurons , red blood cells, hepatocytes, macrophages and enterocytes. The latter two are especially important since systemic iron levels depend upon them. There is only one known iron exporter,  ferroportin . [ 30 ]  It transports ferrous iron out of the cell, generally aided by  ceruloplasmin  and/or  hephaestin  (mostly in enterocytes), which oxidize iron to its ferric state so it can bind ferritin in the extracellular medium. [ 21 ]   Hepcidin  causes the internalization of ferroportin, decreasing iron export. Besides, hepcidin seems to downregulate both TFR1 and DMT1 through an unknown mechanism. [ 31 ]  Another player assisting ferroportin in effecting cellular iron export is GAPDH. [ 32 ]  A specific post translationally modified isoform of GAPDH is recruited to the surface of iron loaded cells where it recruits apo-transferrin in close proximity to ferroportin so as to rapidly chelate the iron extruded. [ 33 ]


The expression of hepcidin, which only occurs in certain cell types such as  hepatocytes , is tightly controlled at the transcriptional level and it represents the link between cellular and systemic iron homeostasis due to hepcidin's role as "gatekeeper" of iron release from enterocytes into the rest of the body. [ 21 ]   Erythroblasts  produce  erythroferrone , a hormone which inhibits hepcidin and so increases the availability of iron needed for hemoglobin synthesis. [ 35 ]


Although some control exists at the transcriptional level, the regulation of cellular iron levels is ultimately controlled at the translational level by  iron-responsive element-binding proteins  IRP1 and especially IRP2. [ 36 ]  When iron levels are low, these proteins are able to bind to  iron-responsive elements  (IREs). IREs are stem loop structures in the untranslated regions (UTRs) of mRNA. [ 21 ]


Both ferritin and ferroportin contain an IRE in their 5' UTRs, so that under iron deficiency their translation is repressed by IRP2, preventing the unnecessary synthesis of storage protein and the detrimental export of iron. In contrast, TFR1 and some DMT1 variants contain 3' UTR IREs, which bind IRP2 under iron deficiency, stabilizing the mRNA, which guarantees the synthesis of iron importers. [ 21 ]


Functional or actual iron deficiency can result from a variety of causes. These causes can be grouped into several categories:


The body is able to substantially reduce the amount of iron it absorbs across the mucosa. It does not seem to be able to entirely shut down the iron transport process. Also, in situations where excess iron damages the intestinal lining itself (for instance, when children eat a large quantity of iron tablets produced for adult consumption), even more iron can enter the bloodstream and cause a potentially deadly syndrome of iron overload. Large amounts of free iron in the circulation will cause damage to critical cells in the liver, the  heart  and other metabolically active organs.


Iron toxicity results when the amount of circulating iron exceeds the amount of transferrin available to bind it, but the body is able to vigorously regulate its iron uptake. Thus, iron toxicity from ingestion is usually the result of extraordinary circumstances like iron tablet over-consumption [1] [ 42 ]  rather than variations in  diet . The type of acute toxicity from iron ingestion causes severe mucosal damage in the gastrointestinal tract, among other problems.


Excess iron has been linked to higher rates of disease and mortality. For example, breast cancer patients with low  ferroportin  expression (leading to higher concentrations of intracellular iron) survive for a shorter period of time on average, while high ferroportin expression predicts 90% 10-year survival in breast cancer patients. [ 43 ]  Similarly, genetic variations in iron transporter genes known to increase serum iron levels also reduce  lifespan  and the average number of years spent in good health. [ 44 ]  It has been suggested that mutations that increase iron absorption, such as the ones responsible for hemochromatosis (see below), were selected for during  Neolithic  times as they provided a  selective advantage  against iron-deficiency anemia. [ 45 ]  The increase in systemic iron levels becomes pathological in old age, which supports the notion that  antagonistic pleiotropy  or "hyperfunction" drives human aging. [ 44 ]


Chronic iron toxicity is usually the result of more chronic iron overload syndromes associated with genetic diseases, repeated transfusions or other causes. In such cases the iron stores of an adult may reach 50 grams (10 times normal total body iron) or more. The most common diseases of iron overload are  hereditary hemochromatosis  (HH), caused by mutations in the  HFE  gene, and the more severe disease  juvenile hemochromatosis  (JH), caused by mutations in either  hemojuvelin  ( HJV ) [ 46 ]  or hepcidin ( HAMP ). The exact mechanisms of most of the various forms of adult hemochromatosis, which make up most of the genetic iron overload disorders, remain unsolved. So, while researchers have been able to identify genetic mutations causing several adult variants of hemochromatosis, they now must turn their attention to the normal function of these mutated genes.


Iodine  is an essential  trace element  in  biological  systems. It has the distinction of being the heaviest  element  commonly needed by living organisms as well as the second-heaviest known to be used by any form of life (only  tungsten , a component of a few bacterial enzymes, has a higher  atomic number  and  atomic weight ). It is a component of biochemical pathways in organisms from all biological kingdoms, suggesting its fundamental significance throughout the evolutionary history of life. [ 1 ]


Iodine is critical to the proper functioning of the vertebrate  endocrine  system, and plays smaller roles in numerous other organs, including those of the digestive and reproductive systems. An adequate intake of iodine-containing compounds is important at all stages of development, especially during the fetal and neonatal periods, and diets  deficient in iodine  can present serious consequences for growth and metabolism.


In  vertebrate  biology, iodine's primary function is as a constituent of the  thyroid   hormones ,  thyroxine  (T4) and  triiodothyronine  (T3). These  molecules  are made from addition-condensation products of the  amino acid   tyrosine , and are stored prior to release in an iodine-containing  protein  called  thyroglobulin . T4 and T3 contain four and three  atoms  of iodine per molecule, respectively; iodine accounts for 65% of the molecular weight of T4 and 59% of T3. The  thyroid gland  actively absorbs iodine from the  blood  to produce and release these hormones into the blood, actions which are regulated by a second hormone, called  thyroid-stimulating hormone  (TSH), which is produced by the  pituitary gland . Thyroid hormones are  phylogenetically  very old molecules which are synthesized by most  multicellular   organisms , and which even have some effect on  unicellular  organisms.
Thyroid hormones play a fundamental role in biology, acting upon gene  transcription  mechanisms to regulate the  basal metabolic rate . T3 acts on  small intestine  cells and  adipocytes  to increase  carbohydrate  absorption and  fatty acid  release, respectively. [ 2 ]  A deficiency of thyroid hormones can reduce basal metabolic rate up to 50%, while an excessive production of thyroid hormones can increase the basal metabolic rate by 100%. [ 3 ]  T4 acts largely as a  precursor  to T3, which is (with minor exceptions) the biologically active hormone.
Via the thyroid hormones, iodine has a nutritional relationship with  selenium . A family of selenium-dependent  enzymes  called  deiodinases  converts T4 to T3 (the active hormone) by removing an iodine atom from the outer tyrosine ring. These enzymes also convert T4 to  reverse T3  (rT3) by removing an inner ring iodine atom, and also convert T3 to  3,3'-Diiodothyronine  (T2) by removing an inner ring atom. Both of the latter products are inactivated hormones which have essentially no biological effects and are quickly prepared for disposal. A family of non-selenium-dependent enzymes then further deiodinates the products of these reactions.


The total amount of iodine in the human body is still controversial, and in 2001,  M.T. Hays published in  Thyroid  that "it is surprising that the total iodine content of the human body remains uncertain after many years of interest in iodine metabolism. Only the iodine content of the thyroid gland has been measured accurately by fluorescent scanning, and it is now well estimate of 5–15 mg in the normal human thyroid. But similar methods are not available for other tissues and for the extrathyroidal organs. Many researchers reported different numbers of 10–50 mg of the total iodine content in human body". [ 4 ] [ 5 ]
Selenium also plays a very important role in the production of  glutathione , the body's most powerful  antioxidant . During the production of the thyroid hormones,  hydrogen peroxide  is produced in large quantities, and therefore high iodine in the absence of selenium can destroy the thyroid gland (often described as a  sore throat  feeling); the peroxides are neutralized through the production of glutathione from selenium. In turn, an excess of selenium increases demand for iodine, and deficiency will result when a diet is high in selenium and low in iodine. [ citation needed ]


Extra-thyroidal iodine exists in several other organs, including the  mammary glands , eyes,  gastric mucosa ,  cervix ,  cerebrospinal fluid , arterial walls,  ovary  and  salivary glands . [ 6 ]  In the cells of these tissues the  iodide  ion (I − ) enters directly by the  sodium-iodide symporter  (NIS). Different tissue responses for iodine and iodide occur in the mammary glands and the thyroid gland of rats. [ 7 ]  The role of iodine in mammary tissue is related to fetal and neonatal development, but its role in the other tissues is not well known. [ 8 ]  It has been shown to act as an antioxidant [ 8 ]  and antiproliferant [ 9 ]  in various tissues that can uptake iodine. Molecular iodine (I 2 ) has been shown to have a suppressive effect on benign and cancerous  neoplasias . [ 9 ]


The U.S. Food and Nutrition Board and Institute of Medicine recommended daily allowance of iodine ranges from 150 micrograms per day for adult humans to 290 micrograms per day for lactating mothers. However, the thyroid gland needs no more than 70 micrograms per day to synthesize the requisite daily amounts of T4 and T3. The higher recommended daily allowance levels of iodine seem necessary for optimal function of a number of other body systems, including lactating breasts, gastric mucosa, salivary glands, oral mucosa, arterial walls,  thymus , epidermis,  choroid plexus  and  cerebrospinal fluid , among others. [ 10 ] [ 11 ] [ 12 ]


Iodine and thyroxine have also been shown to stimulate the spectacular  apoptosis  of the cells of the larval gills, tail and fins during  metamorphosis  in  amphibians , as well as the transformation of their nervous system from that of the aquatic, herbivorous  tadpole  into that of the terrestrial, carnivorous adult. The  frog  species  Xenopus laevis  has proven to be an ideal  model organism  for experimental study of the mechanisms of apoptosis and the role of iodine in developmental biology. [ 13 ] [ 1 ] [ 14 ] [ 15 ]


It is believed that  thyroid hormones  evolved in the  Urbilaterian  well before the development of the  thyroid  itself and molluscs, echinoderms, cephalochordates and ascidians all use such hormones. [ 16 ]  Cnidarians also respond to Thyroid hormone despite being  parahoxozoans  rather than  bilaterians . [ 16 ] [ 17 ]


Insects use hormones similar to thyroid hormone using iodine. [ 18 ] [ 19 ] [ 20 ]


Phosphorylated tyrosines  created with  tyrosine kinases  are fundamental signalling molecules in all animals and in  choanoflagellates . [ 21 ] [ 22 ]


Iodine is known to be crucial for life in many unicellular organisms [ 23 ]   Phosphorylated tyrosines  created with  tyrosine kinases  are fundamental signalling molecules in all animals and in  Choanoflagellates [ 21 ] [ 22 ]  and may be linked to the usage of tyrosine iodine compounds for similar roles. [ 23 ]   Crockford  proposes that iodine was originally used in protecting cell membranes from oxidative damage in  photosynthesis  and later moved into cytoplasm and became involved with balancing cytoplasmic composition of ions, and later the non enzymatic synthesis of tyrosine in early life. [ 23 ]


It is common across all domains of life and uses  tyrosine  bonded to iodine. [ 23 ]


Plants, insects, zooplankton and algae store iodine as mono-iodotyrosine (MIT), di-iodotyrosine (DIT), iodocarbons, or iodoproteins. [ 24 ] [ 25 ] [ 26 ]


Many plants use thyroid like hormones for regulating growth. [ 24 ] [ 27 ]


Gut-inhabiting bacteria use iodine from host thyroid hormone. [ 28 ]


Thyroid-like hormones may be linked to the development of multicellularity. [ 29 ] [ 30 ]  Iodotyrosines are highly reactive with other molecules [ 31 ]  which may have made them important cell signalling molecules early in evolutionary history. [ 23 ]  They form spontaneously without need for enzymatic catalysts which may have contributed to their early adoption by organisms, [ 32 ] [ 33 ]  although enzymes make the yields significantly higher. [ 34 ]


The ease of reaction with water may explain why iodine is so common across cell signalling in all domains of life. [ 35 ]


Many photosynthetic microbes are able to reduce inorganic  iodate  to  iodide  in their cell walls [ 36 ] [ 37 ] [ 38 ] [ 39 ] [ 40 ]  but much of it gets released into the environment rather than cytoplasm in compounds such as  methyl iodide . [ 41 ] [ 36 ] [ 42 ]  Many  sulfate-reducing microorganisms  and  Iron-oxidizing bacteria  also reduce iodate to iodide [ 43 ] [ 40 ]  as well as many  facultative anaerobic organisms [ 44 ]  suggesting this may be ancestral among anaerobic organisms. [ 23 ]


Kelp  store large quantities of iodide primarily as iodotyrosines for unknown reasons. [ 45 ] [ 46 ]


Molecular iodine (I 2 ) is toxic to most single-celled organisms by disrupting the cell membrane [ 47 ]  however  Alphaproteobacteria  and  Choanoflagellates  are resistant. [ 48 ]  Organisms such as  Escherichia coli  are killed by molecular iodine but require iodine from host thyroid hormone, [ 28 ]  indicating that not all organisms that need iodine are resistant to the toxic effects of pure iodine. [ 23 ]


The  U.S. Institute of Medicine  (IOM) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for iodine in 2000. For people age 14 and up, the iodine RDA is 150 μg/day; the RDA for pregnant women is 220 μg/day and the RDA during lactation is 290 μg/day. For children aged 1–8 years, the RDA is 90 μg/day; for children aged 8–13 years, it is 130 μg/day. [ 49 ]  As a safety consideration, the IOM sets  tolerable upper intake levels  (ULs) for vitamins and minerals when evidence is sufficient. The UL for iodine for adults is 1,100 μg/day. This UL was assessed by analyzing the effect of supplementation on  thyroid-stimulating hormone . [ 8 ]  Collectively, the EARs, RDAs, AIs and ULs are referred to as  Dietary Reference Intakes  (DRIs). [ 49 ]


The  European Food Safety Authority  (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR; AI and UL are defined the same as in the United States. For women and men ages 18 and older, the PRI for iodine is set at 150 μg/day; the PRI during pregnancy or lactation is 200 μg/day. For children aged 1–17 years, the PRI increases with age from 90 to 130 μg/day. These PRIs are comparable to the U.S. RDAs with the exception of that for lactation. [ 50 ]  The EFSA reviewed the same safety question and set its adult UL at 600 μg/day, which is a bit more than half the U.S. value. [ 51 ]  Notably, Japan reduced its adult iodine UL from 3,000 to 2,200 μg/day in 2010, but then increased it back to 3,000 μg/day in 2015. [ 52 ]


As of 2000, the median observed intake of iodine from food in the United States was 240 to 300 μg/day for men and 190 to 210 μg/day for women. [ 49 ]  In Japan, consumption is much higher due to the frequent consumption of  seaweed  or  kombu  kelp. [ 8 ]  The average daily intake in Japan ranges from 1,000 to 3,000 μg/day; previous estimates suggested an average intake as high as 13,000 μg/day. [ 53 ]


For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of  Daily Value  (%DV). For iodine specifically, 100% of the Daily Value is considered 150 μg, and this figure remained at 150 μg in the May 27, 2016 revision. [ 54 ] [ 55 ]
A table of the old and new adult daily values is provided at  Reference Daily Intake .


Natural sources of iodine include many marine organisms, such as  kelp  and certain seafood products, as well as plants grown on iodine-rich soil. [ 56 ] [ 57 ]   Iodized salt  is fortified with iodine. [ 57 ]  According to a Food Fortification Initiative 2016 report, 130 countries have mandatory iodine fortification of salt and an additional 10 have voluntary fortification. [ citation needed ]


Worldwide,  iodine deficiency  affects two billion people and is the leading preventable cause of  intellectual disability . [ 58 ]  Mental disability is a result which occurs primarily when babies or small children are rendered  hypothyroidic  by a lack of dietary iodine (new hypothyroidism in adults may cause temporary mental slowing, but not permanent damage).


In areas where there is little iodine in the diet, typically remote inland areas and semi-arid equatorial climates where no marine foods are eaten, iodine deficiency also gives rise to  hypothyroidism , the most serious symptoms of which are epidemic  goitre  (swelling of the thyroid gland), extreme fatigue, mental slowing, depression, weight gain, and low basal body temperatures. [ 59 ]


The addition of iodine to table salt (so-called  iodized salt ) has largely eliminated the most severe consequences of iodine deficiency in wealthier nations, but deficiency remains a serious public health problem in the developing world. [ 60 ]  Iodine deficiency is also a problem in certain areas of Europe; in Germany, an estimated one billion dollars in healthcare costs is spent each year in combating and treating iodine deficiency. [ 8 ]


Source: [ 61 ]


Elemental iodine is an  oxidizing  irritant, and direct contact with skin can cause  lesions , so iodine crystals should be handled with care. Solutions with high elemental iodine concentration such as  tincture of iodine  are capable of causing tissue damage if use for cleaning and antisepsis is prolonged. Although elemental iodine is used in the formulation of  Lugol's solution , a common medical disinfectant, it becomes  triiodide  upon reacting with the  potassium iodide  used in the solution and is therefore non-toxic. [ citation needed ]  Only a small amount of elemental iodine will dissolve in water, but triiodides are highly soluble; potassium iodide thus serves as a  phase transfer catalyst  in the tincture.  This allows Lugol's iodine to be produced in strengths varying from 2% to 15% iodine.


Elemental iodine (I 2 ) is poisonous if taken orally in large amounts; 2–3 grams is a lethal dose for an adult human. [ 71 ] [ 72 ]


Iodine vapor  is very irritating to the  eye , to mucous membranes, and in the respiratory tract. Concentration of iodine in the air should not exceed 1 mg/m 3  (eight-hour time-weighted average).


When mixed with  ammonia  and water, elemental iodine forms  nitrogen triiodide , which is extremely shock-sensitive and can explode unexpectedly.


Compared to the elemental form, potassium iodide has a  median lethal dose  (LD 50 ) that is relatively high in several animals: in rabbits, it is 10 g/kg; in rats, 14 g/kg, and in mice, 22 g/kg. [ 73 ]  The tolerable upper intake level for iodine as established by the  Food and Nutrition Board  is 1,100 μg/day for adults. The safe upper limit of consumption set by the Ministry of Health, Labor and Welfare in Japan is 3,000 μg/day. [ 74 ]


The biological half-life of iodine differs between the various organs of the body, from 100 days in the thyroid, to 14 days in the kidneys and spleen, to 7 days in the reproductive organs. Typically the daily urinary elimination rate ranges from 100 to 200 μg/L in humans. [ 75 ]  However, the Japanese diet, high in iodine-rich  kelp , contains 1,000 to 3,000 μg of iodine per day, and research indicates the body can readily eliminate excess iodine that is not needed for thyroid hormone production. [ 74 ]  The literature reports as much as 30,000 μg/L (30 mg/L) of iodine being safely excreted in the urine in a single day, with levels returning to the standard range in a couple of days, depending on seaweed intake. [ 76 ]  One study concluded the range of total body iodine content in males was 12.1 mg to 25.3 mg, with a mean of 14.6 mg. [ 77 ]  It is presumed that once  thyroid-stimulating hormone  is suppressed, the body simply eliminates excess iodine, and as a result, long-term supplementation with high doses of iodine has no additional effect once the body is replete with enough iodine. It is unknown if the thyroid gland is the rate-limiting factor in generating thyroid hormone from iodine and tyrosine, but assuming it is not, a short-term loading dose of one or two weeks at the tolerable upper intake level may quickly restore thyroid function in iodine-deficient patients. [ citation needed ]


Excessive iodine intake presents symptoms similar to those of iodine deficiency. Commonly encountered symptoms are abnormal growth of the  thyroid  gland and disorders in functioning, [ 78 ]  as well as in growth of the organism as a whole. Iodide toxicity is similar to (but not the same as) toxicity to ions of the other  halogens , such as  bromides  or  fluorides . Excess  bromine  and  fluorine  can prevent successful iodine uptake, storage and use in organisms, as both elements can selectively replace iodine biochemically.


Excess iodine may also be more  cytotoxic  in combination with  selenium deficiency . [ 79 ]  Iodine supplementation in selenium-deficient populations is theoretically problematic, partly for this reason. [ 8 ]   Selenocysteine  (abbreviated as  Sec  or  U , in older publications also as  Se-Cys ) [ 80 ]  is the 21st  proteinogenic amino acid , and is the root of iodide ion toxicity when there is a simultaneous insufficiency of biologically available selenium. Selenocysteine exists naturally in all kingdoms of life as a building block of  selenoproteins . [ 81 ]


Some people develop a  hypersensitivity  to compounds of iodine but there are no known cases of people being directly  allergic  to elemental iodine itself. [ 82 ]  Notable sensitivity reactions that have been observed in humans include:


Medical use of iodine compounds (i.e. as a  contrast agent ) can cause  anaphylactic shock  in highly sensitive patients, presumably due to sensitivity to the chemical carrier. Cases of sensitivity to iodine compounds should not be formally classified as iodine allergies, as this perpetuates the erroneous belief that it is the iodine to which patients react, rather than to the specific allergen. Sensitivity to iodine-containing compounds is rare but has a considerable effect given the extremely widespread use of  iodine-based contrast media ; however, the only adverse effect of contrast material that can convincingly be ascribed to free iodide is iodide mumps and other manifestations of iodism. [ 84 ]


Iron  is an important biological element. [ 1 ] [ 2 ] [ 3 ]  It is used in both the ubiquitous  iron-sulfur proteins [ 1 ]  and in  vertebrates  it is used in  hemoglobin  which is essential for  blood  and oxygen transport. [ 4 ]


Iron is required for life. [ 1 ] [ 2 ] [ 3 ]  The  iron–sulfur clusters  are pervasive and include  nitrogenase , the enzymes responsible for biological  nitrogen fixation . Iron-containing proteins participate in transport, storage and use of oxygen. [ 1 ]  Iron proteins are involved in  electron transfer . [ 5 ]  The ubiquity of Iron in life has led to the  Iron–sulfur world hypothesis  that iron was a central component of the environment of early life. [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ]


Examples of iron-containing proteins in higher organisms include hemoglobin,  cytochrome  (see  high-valent iron ), and  catalase . [ 1 ] [ 11 ]  The average adult human contains about 0.005% body weight of iron, or about four grams, of which three quarters is in hemoglobin – a level that remains constant despite only about one milligram of iron being absorbed each day, [ 5 ]  because the human body recycles its hemoglobin for the iron content. [ 12 ]


Microbial growth may be assisted by oxidation of iron(II) or by reduction of iron (III). [ 13 ]


Iron acquisition poses a problem for aerobic organisms because  ferric  iron is poorly soluble near neutral pH. Thus, these organisms have developed means to absorb iron as complexes, sometimes taking up ferrous iron before oxidising it back to ferric iron. [ 1 ]  In particular, bacteria have evolved very high-affinity  sequestering  agents called  siderophores . [ 14 ] [ 15 ] [ 16 ]


After uptake in human  cells , iron storage is precisely regulated. [ 1 ] [ 17 ]  A major component of this regulation is the protein  transferrin , which binds iron ions absorbed from the  duodenum  and carries it in the  blood  to cells. [ 1 ] [ 18 ]  Transferrin contains Fe 3+  in the middle of a distorted  octahedron , bonded to one nitrogen, three oxygens and a chelating  carbonate  anion that traps the Fe 3+  ion: it has such a high  stability constant  that it is very effective at taking up Fe 3+  ions even from the most stable complexes. At the bone marrow, transferrin is reduced from Fe 3+  and Fe 2+  and stored as  ferritin  to be incorporated into hemoglobin. [ 5 ]


The most commonly known and studied  bioinorganic  iron compounds (biological iron molecules) are the  heme proteins : examples are  hemoglobin ,  myoglobin , and  cytochrome P450 . [ 1 ]  These compounds participate in transporting gases, building  enzymes , and transferring  electrons . [ 5 ]   Metalloproteins  are a group of proteins with metal ion  cofactors . Some examples of iron metalloproteins are  ferritin  and  rubredoxin . [ 5 ]  Many enzymes vital to life contain iron, such as  catalase , [ 19 ]   lipoxygenases , [ 20 ]  and  IRE-BP . [ 21 ]


Hemoglobin is an oxygen carrier that occurs in  red blood cells  and contributes their color, transporting oxygen in the arteries from the lungs to the muscles where it is transferred to  myoglobin , which stores it until it is needed for the metabolic oxidation of  glucose , generating energy. [ 1 ]  Here the hemoglobin binds to  carbon dioxide , produced when glucose is oxidized, which is transported through the veins by hemoglobin (predominantly as  bicarbonate  anions) back to the lungs where it is exhaled. [ 5 ]  In hemoglobin, the iron is in one of four  heme  groups and has six possible coordination sites; four are occupied by nitrogen atoms in a  porphyrin  ring, the fifth by an  imidazole  nitrogen in a  histidine  residue of one of the protein chains attached to the heme group, and the sixth is reserved for the oxygen molecule it can reversibly bind to. [ 5 ]  When hemoglobin is not attached to oxygen (and is then called deoxyhemoglobin), the Fe 2+  ion at the center of the  heme  group (in the hydrophobic protein interior) is in a  high-spin configuration . It is thus too large to fit inside the porphyrin ring, which bends instead into a dome with the Fe 2+  ion about 55 picometers above it. In this configuration, the sixth coordination site reserved for the oxygen is blocked by another histidine residue. [ 5 ]


When deoxyhemoglobin picks up an oxygen molecule, this histidine residue moves away and returns once the oxygen is securely attached to form a  hydrogen bond  with it. This results in the Fe 2+  ion switching to a low-spin configuration, resulting in a 20% decrease in ionic radius so that now it can fit into the porphyrin ring, which becomes planar. [ 5 ]  (Additionally, this hydrogen bonding results in the tilting of the oxygen molecule, resulting in a Fe–O–O bond angle of around 120° that avoids the formation of Fe–O–Fe or Fe–O 2 –Fe bridges that would lead to electron transfer, the oxidation of Fe 2+  to Fe 3+ , and the destruction of hemoglobin.) This results in a movement of all the protein chains that leads to the other subunits of hemoglobin changing shape to a form with larger oxygen affinity. Thus, when deoxyhemoglobin takes up oxygen, its affinity for more oxygen increases, and vice versa. [ 5 ]  Myoglobin, on the other hand, contains only one heme group and hence this cooperative effect cannot occur. Thus, while hemoglobin is almost saturated with oxygen in the high partial pressures of oxygen found in the lungs, its affinity for oxygen is much lower than that of myoglobin, which oxygenates even at low partial pressures of oxygen found in muscle tissue. [ 5 ]  As described by the  Bohr effect  (named after  Christian Bohr , the father of  Niels Bohr ), the oxygen affinity of hemoglobin diminishes in the presence of carbon dioxide. [ 5 ]


Carbon monoxide  and [[phosphorus trifluoride¿†¿ ⟨⟩ ]] are poisonous to humans because they bind to hemoglobin similarly to oxygen, but with much more strength, so that oxygen can no longer be transported throughout the body. Hemoglobin bound to carbon monoxide is known as  carboxyhemoglobin . This effect also plays a minor role in the toxicity of  cyanide , but there the major effect is by far its interference with the proper functioning of the electron transport protein cytochrome a. [ 5 ]  The cytochrome proteins also involve heme groups and are involved in the metabolic oxidation of glucose by oxygen. The sixth coordination site is then occupied by either another imidazole nitrogen or a  methionine  sulfur, so that these proteins are largely inert to oxygen – with the exception of cytochrome a, which bonds directly to oxygen and thus is very easily poisoned by cyanide. [ 5 ]  Here, the electron transfer takes place as the iron remains in low spin but changes between the +2 and +3 oxidation states. Since the reduction potential of each step is slightly greater than the previous one, the energy is released step-by-step and can thus be stored in  adenosine triphosphate . Cytochrome a is slightly distinct, as it occurs at the mitochondrial membrane, binds directly to oxygen, and transports protons as well as electrons, as follows: [ 5 ]


Although the heme proteins are the most important class of iron-containing proteins, the  iron–sulfur proteins  are also very important, being involved in electron transfer, which is possible since iron can exist stably in either the +2 or +3 oxidation states. These have one, two, four, or eight iron atoms that are each approximately tetrahedrally coordinated to four sulfur atoms; because of this tetrahedral coordination, ths in the surrounding peptide chains. Another important class of iron–sulfur proteins is the  ferredoxins , which have multiple iron atoms. Transferrin does not belong to either of these classes. [ 5 ]


The ability of sea  mussels  to maintain their grip on rocks in the ocean is facilitated by their use of  organometallic  iron-based bonds in their protein-rich  cuticles . Based on synthetic replicas, the presence of iron in these structures increased  elastic modulus  770 times,  tensile strength  58 times, and  toughness  92 times. The amount of stress required to permanently damage them increased 76 times. [ 23 ]


In vertebrates, iron is an essential component of  hemoglobin , the oxygen transport protein. [ 4 ]


Most well-nourished people in industrialized countries have 4 to 5 grams of iron in their bodies (~38 mg iron/kg body weight for women and ~50 mg iron/kg body for men). [ 24 ]  Of this, about  2.5 g  is contained in the hemoglobin needed to carry oxygen through the blood (around 0.5 mg of iron per mL of blood), [ 25 ]  and most of the rest (approximately 2 grams in adult men, and somewhat less in women of childbearing age) is contained in  ferritin  complexes that are present in all cells, but most common in bone marrow,  liver , and  spleen . The liver stores of ferritin are the primary physiologic source of reserve iron in the body. The reserves of iron in industrialized countries tend to be lower in children and women of child-bearing age than in men and in the elderly. Women who must use their stores to compensate for iron lost through  menstruation ,  pregnancy  or  lactation  have lower non-hemoglobin body stores, which may consist of  500 mg , or even less.


Of the body's total iron content, about  400 mg  is devoted to cellular proteins that use iron for important cellular processes like storing oxygen (myoglobin) or performing energy-producing redox reactions ( cytochromes ). A relatively small amount (3–4 mg) circulates through the  plasma , bound to transferrin. [ 26 ]  Because of its toxicity, free soluble iron is kept in low concentration in the body.


Like most mineral nutrients, the majority of the iron absorbed from digested food or supplements is absorbed in the  duodenum  by  enterocytes  of the duodenal lining. These cells have special molecules that allow them to move iron into the body. To be absorbed, dietary iron can be absorbed as part of a protein such as heme protein or iron must be in its ferrous Fe 2+  form. A ferric reductase enzyme on the enterocytes'  brush border , duodenal cytochrome B ( Dcytb ), reduces ferric Fe 3+  to Fe 2+ . [ 27 ]  A protein called divalent metal transporter 1 ( DMT1 ), which can transport several  divalent  metals across the plasma membrane, then transports iron across the enterocyte's  cell membrane  into the cell. If the iron is bound to heme it is instead transported across the apical membrane by  heme carrier protein 1  (HCP1). [ 28 ]


These intestinal lining cells can then either store the iron as  ferritin , which is accomplished by Fe 2+  binding to apoferritin (in which case the iron will leave the body when the cell dies and is sloughed off into  feces ), or the cell can release it into the body via the only known iron exporter in mammals,  ferroportin .  Hephaestin , a  ferroxidase  that can oxidize Fe 2+  to Fe 3+  and is found mainly in the small intestine, helps ferroportin transfer iron across the basolateral end of the intestine cells. In contrast, ferroportin is post-translationally repressed by  hepcidin , a 25-amino acid peptide hormone. The body regulates iron levels by regulating each of these steps. For instance, enterocytes synthesize more Dcytb, DMT1 and ferroportin in response to iron deficiency anemia. [ 29 ]  Iron absorption from diet is enhanced in the presence of vitamin C and diminished by excess calcium, zinc, or manganese. [ 30 ]


Most of the iron in the body is hoarded and recycled by the reticuloendothelial system, which breaks down aged red blood cells. In contrast to iron uptake and recycling, there is no physiologic regulatory mechanism for  excreting  iron. People lose a small but steady amount by gastrointestinal blood loss, sweating and by shedding cells of the skin and the  mucosal  lining of the  gastrointestinal tract . The total amount of loss for healthy people in the developed world amounts to an estimated average of  1 mg  a day for men, and 1.5–2 mg a day for women with regular menstrual periods. [ 31 ]  People with gastrointestinal parasitic infections, more commonly found in developing countries, often lose more. [ 32 ]  Those who cannot regulate absorption well enough get disorders of iron overload. In these diseases, the toxicity of iron starts overwhelming the body's ability to bind and store it. [ 33 ]