Kitchin (2001) proposed a model of altered growth factors which lead to cell proliferation and thus to  carcinogenesis . [ 60 ]  From observations, it is known that chronic low-dose arsenic poisoning can lead to increased tolerance to its acute toxicity. [ 63 ] [ 64 ]  MRP1-overexpressing lung tumor GLC4/Sb30 cells poorly accumulate arsenite and arsenate. This is mediated through MRP-1 dependent efflux. [ 65 ]  The efflux requires glutathione, but no arsenic-glutathione complex formation. [ 66 ]


Although many mechanisms have been proposed, no definite model can be given for the mechanisms of chronic arsenic poisoning. The prevailing events of toxicity and carcinogenicity might be quite tissue-specific. Current consensus on the mode of carcinogenesis is that it acts primarily as a tumor promoter. Its co-carcinogenicity has been demonstrated in several models. However, the finding of several studies that chronically arsenic-exposed Andean populations (as most extremely exposed to UV-light) do not develop skin cancer with chronic arsenic exposure, is puzzling. [ 67 ]


The two forms of inorganic arsenic, reduced (trivalent As(III)) and oxidized (pentavalent As(V)), can be absorbed, and accumulated in tissues and body fluids. [ 68 ]  In the liver, the metabolism of arsenic involves enzymatic and non-enzymatic methylation; the most frequently excreted metabolite (≥ 90%) in the urine of mammals is  dimethylarsinic acid  or cacodylic acid, DMA(V). [ 69 ]  Dimethylarsenic acid is also known as  Agent Blue  and was used as herbicide in the American war in  Vietnam .


In humans inorganic arsenic is reduced nonenzymatically from pentoxide to trioxide, using glutathione or it is mediated by enzymes. Reduction of arsenic pentoxide to arsenic trioxide increases its toxicity and bio availability, Methylation occurs through methyltransferase enzymes. S-adenosylmethionine (SAM) may serve as methyl donor. Various pathways are used, the principal route being dependent on the current environment of the cell. [ 70 ]  Resulting metabolites are monomethylarsonous acid, MMA(III), and dimethylarsinous acid, DMA(III).


Methylation had been regarded as a detoxification process,  [ by whom? ]  but reduction from +5 As to +3 As may be considered as a bioactivation  [ clarification needed ]  instead. [ 71 ]  Another suggestion is that methylation might be a detoxification if "As[III] intermediates are not permitted to accumulate" because the pentavalent organoarsenics have a lower affinity to  thiol groups  than inorganic pentavalent arsenics. [ 70 ]  Gebel (2002) stated that methylation is a detoxification through accelerated excretion. [ 72 ]  With regard to carcinogenicity it has been suggested that methylation should be regarded as a toxification. [ 60 ] [ 73 ] [ 74 ]


Arsenic, especially +3 As, binds to single, but with higher affinity to  vicinal   sulfhydryl groups , thus reacts with a variety of  proteins  and inhibits their activity. It was also proposed that binding of arsenite at nonessential sites might contribute to detoxification. [ 75 ]  Arsenite inhibits members of the disulfide oxidoreductase family like glutathione reductase [ 76 ]  and thioredoxin reductase. [ 77 ]


The remaining unbound arsenic (≤ 10%) accumulates in cells, which over time may lead to skin, bladder, kidney, liver, lung, and prostate cancers. [ 69 ]  Other forms of arsenic toxicity in humans have been observed in blood, bone marrow, cardiac, central nervous system, gastrointestinal, gonadal, kidney, liver, pancreatic, and skin tissues. [ 69 ]


The acute minimal lethal dose of arsenic in adults is estimated to be 70 to 200 mg or 1 mg/kg/day. [ 78 ]


Another aspect is the similarity of arsenic effects to the heat shock response. Short-term arsenic exposure has effects on signal transduction inducing heat shock proteins with masses of 27, 60, 70, 72, 90, and 110 kDa as well as  metallothionein ,  ubiquitin , mitogen-activated [MAP] kinases,  extracellular regulated kinase  [ERK], c-jun terminal kinases [JNK] and p38. [ 54 ] [ 79 ]
Via JNK and p38 it activates c-fos, c-jun and egr-1 which are usually activated by growth factors and cytokines. [ 54 ] [ 80 ] [ 81 ]  The effects are largely dependent on the dosing regime and may be as well inversed.


As shown by some experiments reviewed by Del Razo (2001), reactive oxygen species induced by low levels of inorganic arsenic increase the transcription and the activity of the activator protein 1 (AP-1) and the nuclear factor-κB ( NF-κB ) (maybe enhanced by elevated MAPK levels), which results in c-fos/c-jun activation, over-secretion of pro-inflammatory and growth promoting cytokines stimulating cell proliferation. [ 79 ] [ 82 ]  Germolec et al. (1996) found an increased cytokine expression and cell proliferation in skin biopsies from individuals chronically exposed to arsenic-contaminated drinking water. [ 83 ]


Increased AP-1 and NF-κB obviously also result in an up-regulation of mdm2 protein, which decreases p53 protein levels. [ 84 ]  Thus, taking into account p53's function, a lack of it could cause a faster accumulation of mutations contributing to carcinogenesis. However, high levels of inorganic arsenic inhibit NF-κB activation and cell proliferation. An experiment of Hu et al. (2002) demonstrated increased binding activity of AP-1 and NF-κB after acute (24 h) exposure to +3 sodium arsenite, whereas long-term exposure (10–12 weeks) yielded the opposite result. [ 85 ]  The authors conclude that the former may be interpreted as a defense response while the latter could lead to carcinogenesis. [ 85 ]  As the contradicting findings and connected mechanistic hypotheses indicate, there is a difference in acute and chronic effects of arsenic on signal transduction which is not clearly understood yet. [ citation needed ]


Studies have demonstrated that the oxidative stress generated by arsenic may disrupt the signal transduction pathways of the nuclear transcriptional factors PPARs, AP-1, and NF-κB, [ 69 ] [ 85 ] [ 86 ]  as well as the pro-inflammatory cytokines IL-8 and TNF-α. [ 69 ] [ 85 ] [ 86 ] [ 87 ] [ 88 ] [ 89 ] [ 90 ] [ 91 ]   The interference of oxidative stress with signal transduction pathways may affect physiological processes associated with cell growth, metabolic syndrome X, glucose homeostasis, lipid metabolism, obesity,  insulin resistance , inflammation, and diabetes-2. [ 92 ] [ 93 ] [ 94 ]  Recent scientific evidence has elucidated the physiological roles of the PPARs in the ω- hydroxylation of fatty acids and the inhibition of pro-inflammatory transcription factors (NF-κB and AP-1), pro-inflammatory cytokines (IL-1, −6, −8, −12, and TNF-α), cell4 adhesion molecules (ICAM-1 and VCAM-1), inducible nitric oxide synthase, proinflammatory nitric oxide (NO), and anti-apoptotic factors. [ 69 ] [ 87 ] [ 92 ] [ 94 ] [ 95 ]


Epidemiological studies have suggested a correlation between chronic consumption of drinking water contaminated with arsenic and the incidence of type 2 diabetes. [ 69 ]  The human liver after exposure to therapeutic drugs may exhibit hepatic non-cirrhotic portal hypertension, fibrosis, and cirrhosis. [ 69 ]  However, the literature provides insufficient scientific evidence to show cause and effect between arsenic and the onset of diabetes mellitus Type 2. [ 69 ]


Arsenic may be measured in blood or urine to monitor excessive environmental or occupational exposure, confirm a diagnosis of poisoning in hospitalized victims or to assist in the forensic investigation in a case of fatal over dosage. Some analytical techniques are capable of distinguishing organic from inorganic forms of the element. Organic arsenic compounds tend to be eliminated in the urine in unchanged form, while inorganic forms are largely converted to organic arsenic compounds in the body prior to urinary excretion. The current biological exposure index for U.S. workers of 35 μg/L total urinary arsenic may easily be exceeded by a healthy person eating a seafood meal. [ 96 ]


Tests are available to diagnose poisoning by measuring arsenic in blood, urine, hair, and fingernails. The urine test is the most reliable test for arsenic exposure within the last few days. Urine testing needs to be done within 24–48 hours for an accurate analysis of an acute exposure. Tests on hair and fingernails can measure exposure to high levels of arsenic over the past 6–12 months. These tests can determine if one has been exposed to above-average levels of arsenic. They cannot predict, however, whether the arsenic levels in the body will affect health. [ 97 ]  Chronic arsenic exposure can remain in the body systems for a longer period of time than a shorter term or more isolated exposure and can be detected in a longer time frame after the introduction of the arsenic, important in trying to determine the source of the exposure.


Hair is a potential bioindicator for arsenic exposure due to its ability to store trace elements from blood. Incorporated elements maintain their position during growth of hair. Thus for a temporal estimation of exposure, an assay of hair composition needs to be carried out with a single hair which is not possible with older techniques requiring homogenization and dissolution of several strands of hair. This type of biomonitoring has been achieved with newer microanalytical techniques like synchrotron radiation based X-ray fluorescence spectroscopy and microparticle induced X-ray emission. The highly focused and intense beams study small spots on biological samples allowing analysis to micro level along with the chemical speciation. In a study, this method has been used to follow arsenic level before, during and after treatment with arsenious oxide in patients with acute promyelocytic leukemia. [ 98 ]


Dimercaprol  and  dimercaptosuccinic acid  are  chelating agents  that sequester the arsenic away from blood proteins and are used in treating acute arsenic poisoning.  The most important side effect is  hypertension .  Dimercaprol is considerably more toxic than succimer. [ citation needed ] [ 99 ]  Dimercaptosuccinic acid monoesters, e.g. MiADMSA, are promising antidotes for arsenic poisoning. [ 100 ]


Supplemental potassium decreases the risk of experiencing a life-threatening heart rhythm problem from arsenic trioxide. [ 101 ]


Beginning in about 3000 BC arsenic was mined and added to copper in the alloying of  bronze , but the adverse health effects of working with arsenic led to it being abandoned when a viable alternative, tin, was discovered. [ 104 ]


In addition to its presence as a poison, for centuries arsenic was used medicinally. It has been used for over 2,400 years as a part of traditional Chinese medicine. [ 105 ]  In the western world, arsenic compounds, such as  salvarsan , were used extensively to treat  syphilis  before  penicillin  was introduced. It was eventually replaced as a therapeutic agent by  sulfa drugs  and then by other  antibiotics . Arsenic was also an ingredient in many tonics (or " patent medicines ").


In addition, during the  Elizabethan era , some  women  used a mixture of  vinegar ,  chalk , and arsenic applied topically to whiten their skin. This use of arsenic was intended to prevent aging and creasing of the skin, but some arsenic was inevitably absorbed into the blood stream. [ citation needed ]


During the  Victorian era  (late 19th century) in the United States, U.S. newspapers advertised "arsenic complexion wafers" that promised to remove facial blemishes such as moles and pimples. [ 103 ]


Some pigments, most notably the popular  Emerald Green  (known also under several other names), were based on arsenic compounds. Overexposure to these pigments was a frequent cause of accidental poisoning of artists and craftsmen.


Arsenic became a favored method for murder of the  Middle Ages  and  Renaissance , particularly among ruling classes in Italy allegedly. Because the symptoms are similar to those of  cholera , which was common at the time, arsenic poisoning often went undetected. [ 106 ] : 63    By the 19th century, it had acquired the nickname "inheritance powder", perhaps because impatient heirs were known or suspected to use it to ensure or accelerate their inheritances. [ 106 ] : 21   It was also a common murder technique in the 19th century in domestic violence situations, such as the case of  Rebecca Copin , who attempted to poison her husband by "putting arsenic in his coffee". [ 107 ]


In post-WW1  Hungary , arsenic extracted by boiling fly paper was used in an estimated 300 murders by the  Angel Makers of Nagyrév .


In imperial China, arsenic trioxide and sulfides were used in murder, as well as for capital punishment for members of the royal family or aristocracy.  Forensic studies have determined that the  Guangxu Emperor  (d. 1908) was murdered by arsenic, most likely ordered by the  Empress Dowager Cixi  or Generalissimo  Yuan Shikai .  Likewise, in ancient  Korea , and particularly in the  Joseon Dynasty , arsenic-sulfur compounds had been used as a major ingredient of  sayak  (사약; 賜藥), which was a poison cocktail used in  capital punishment  of high-profile political figures and members of the royal family. [ 108 ]  Due to social and political prominence of the condemned, many of these events were well-documented, often in the  Annals of Joseon Dynasty ; they are sometimes portrayed in historical television  miniseries  because of their dramatic nature. [ 109 ]


One of the worst incidents of  arsenic poisoning via well water occurred in Bangladesh , which the World Health Organization called the "largest mass poisoning of a population in history" [ 110 ]  and was recognized as a major public health concern. The contamination in the Ganga-Brahmaputra fluvial plains in India and Padma-Meghna fluvial plains in Bangladesh demonstrated adverse impacts on human health. [ 111 ]


Arsenic poisoning from exposure to groundwater is believed to be responsible for the illness experienced by those that witnessed the  2007 Carancas impact event  in  Peru , as local residents inhaled steam which was contaminated with arsenic, produced from groundwater which boiled from the intense heat and pressure produced by a  chondrite  meteorite impacting the ground. [ 112 ]


In the U.S. in 1975, under the authority of the Safe Drinking Water Act, the U.S. Environmental Protection Agency determined the National Interim Primary Drinking Water Regulation levels of arsenic (inorganic contaminant – IOCs) to be 0.05 mg/L (50 parts per billion – ppb). [ 113 ]


Throughout the years, many studies reported dose-dependent effects of arsenic in drinking water and skin cancer. In order to prevent new cases and death from cancerous and non-cancerous diseases, the Safe Drinking Water Act directed the Environmental Protection Agency to revise arsenic's levels and specified the maximum contaminant level (MCL). MCLs are set as close to the health goals as possible, considering cost, benefits and the ability of public water systems to detect and remove contaminants using suitable treatment technologies. [ 113 ] [ 114 ]


In 2001, Environmental Protection Agency adopted a lower standard of MCL 0.01 mg/L (10 ppb) for arsenic in drinking water that applies to both community water systems and non-transient non-community water systems. [ 113 ]


In some other countries, when developing national drinking water standards based on the guideline values, it is necessary to take account of a variety of geographical, socio-economic, dietary and other conditions affecting potential exposure. These factors lead to national standards that differ appreciably from the guideline values. That is the case in countries such as India and Bangladesh, where the permissible limit of arsenic in absence of an alternative source of water is 0.05 mg/L. [ 115 ] [ 116 ]


Arsenic removal technologies are traditional treatment processes which have been tailored to improve removal of arsenic from drinking water. Although some of the removal processes, such as precipitative processes, adsorption processes, ion exchange processes, and separation (membrane) processes, may be technically feasible, their cost may be prohibitive. [ 113 ]


For underdeveloped countries, the challenge is finding the means to fund such technologies. The Environmental Protection Agency, for example, has estimated the total national annualized cost of treatment, monitoring, reporting, record keeping, and administration to enforce the MCL rule to be approximately $181 million. Most of the cost is due to the installation and operation of the treatment technologies needed to reduce arsenic in public water systems. [ 117 ]


Arsenic exposure through groundwater is highly concerning throughout the perinatal period. Pregnant people are a high-risk population because not only are they at risk for adverse outcomes, but in-utero exposure also poses health risks to the foetus.


There is a  dose-dependent relationship  between perinatal exposure to arsenic and infant mortality, meaning that infants born to people exposed to higher concentrations, or exposed for longer periods of time, have a higher mortality rate. [ 118 ]


Studies have shown that ingesting arsenic through groundwater during pregnancy poses dangers to the pregnant person including, but not limited to abdominal pain, vomiting, diarrhea, skin pigmentation changes, and cancer. [ 119 ]  Research has also demonstrated that arsenic exposure also causes low birth weight, low birth size, infant mortality, and a variety of other outcomes in infants. [ 119 ] [ 120 ]  Some of these effects, like lower birth-rate and size may be due to the effects of arsenic on weight gain during pregnancy. [ 120 ]


Berylliosis , or  chronic beryllium disease  ( CBD ), is a chronic allergic-type lung response and chronic lung  disease  caused by exposure to  beryllium  and its compounds, a form of  beryllium poisoning . It is distinct from  acute beryllium poisoning , which became rare following occupational exposure limits established around 1950. [ 1 ]  Berylliosis is an  occupational lung disease .


While there is no cure, symptoms can be treated. [ 2 ]


With single or prolonged exposure by inhalation the lungs may become sensitized to beryllium. Berylliosis has a slow onset and progression. Some people who are sensitized to beryllium may not have symptoms. [ 1 ]  Continued exposure causes the development of small inflammatory nodules, called  granulomas . [ 3 ]  Of note, the authors of a 2006 study suggested that beryllium inhalation was not the only form of exposure and perhaps skin exposure was also a cause, as they found that a reduction in beryllium inhalation did not result in a reduction in chronic beryllium disease or beryllium sensitization. [ 4 ]


Granuloma formation is seen in other diseases such as  tuberculosis  and  sarcoidosis . Sarcoidosis, like berylliosis, also produces  granulomas without a necrotic core , and so distinction between the two processes can be difficult.


Ultimately, this process leads to  restrictive lung disease  (a decrease in  diffusion capacity ).


The earliest symptoms are typically  cough  and  shortness of breath . [ 5 ]  Other symptoms include  chest pain ,  joint aches ,  weight loss , and  fever .


Rarely, one can get granulomas in other organs including the  liver .


The onset of symptoms can range from weeks up to tens of years from the initial exposure. In some individuals, a single exposure to beryllium can cause berylliosis.


In susceptible persons, beryllium exposure can lead to a cell-mediated immune response. The T-cells become sensitized to beryllium. Each subsequent exposure leads to an immune response involving  CD4+ helper T-lymphocytes  and  macrophages  accumulating in the lungs. As this response continues macrophages, CD4+ T-lymphocytes and plasma cells aggregate together to form the  noncaseating granulomas . [ 6 ] [ 7 ]  When beryllium is  phagocytized  by macrophages, the beryllium triggers macrophage apoptosis, thereby reducing beryllium clearance from the lungs and eventually resulting in secondary necrosis and lysis. [ 8 ]  Eventually, the outcome is  fibrosis  of the lung. [ 9 ] [ 10 ]


Several studies have shown that there is a genetic component to beryllium sensitivity. Specifically, those beryllium-exposed workers with a mutation at the  HLA-DPB1  Glu 69  position have increased prevalence of beryllium sensitization and chronic beryllium disease. [ 11 ]   The HLA-DPB1 gene is important for  MHC class II  molecule function on  antigen presenting cells . [ 11 ]  A study of the immune response to beryllium in individuals who express the  HLA-DP2  allele found that CD4 T-cells do not detect the  Be 2+  cation itself, but instead detect surface changes in the HLA-DP2/peptide complex in which  Be 2+  is embedded. Those researchers concluded that chronic beryllium disease is a predisposition that lies between " allergic hypersensitivity  and  autoimmunity ." [ 12 ]


According to the  International Agency for Research on Cancer , beryllium and beryllium compounds are  Category 1 carcinogens ; they are carcinogenic to both animals and humans. [ 13 ]


The differential diagnosis for berylliosis includes: [ 14 ]


Diagnosis of berylliosis is based on history of beryllium exposures, documented beryllium sensitivity, and granulomatous inflammation on  lung biopsy . Given the invasive nature of a lung biopsy, diagnosis can also be based on clinical history consistent with berylliosis, abnormal  chest x-ray  or  CT scan  findings, and abnormalities in  pulmonary function tests . [ 15 ]


The radiologic and pathologic features of berylliosis are very similar to sarcoidosis.  Due to the strong clinical and histopathological resemblance of sarcoidosis and berylliosis, patients are sometimes misdiagnosed with sarcoidosis until the history of exposure to beryllium is elicited and beryllium hypersensitivity demonstrated with specific testing. Some studies suggest that up to 6% of all cases of sarcoidosis are actually berylliosis. [ 16 ]   [ 17 ]


The beryllium lymphocyte proliferation test (BeLPT) is the standard way of determining sensitivity to beryllium. [ 15 ]  The test is performed by acquiring either peripheral blood or fluid from a bronchial alveolar lavage, and lymphocytes are cultured with beryllium sulfate. Cells are then counted and those with elevated number of cells are considered abnormal. [ 18 ]  Those exposed persons with two abnormal BeLPT tested with peripheral blood, or one abnormal and one borderline result, are considered beryllium sensitized. Also, those with one abnormal BeLPT tested with fluid from a bronchial alveolar lavage are considered sensitized. [ 15 ]


Chest radiography findings of berylliosis are non-specific. Early in the disease radiography findings are usually normal. In later stages interstitial fibrosis,  pleural irregularities, hilar  lymphadenopathy  and  ground-glass opacities  have been reported. [ 19 ] [ 20 ]  Findings on CT are also not specific to berylliosis. Findings that are common in CT scans of people with berylliosis include parenchymal nodules in early stages. One study found that ground-glass opacities were more commonly seen on CT scan in berylliosis than in sarcoidosis. In later stages hilar lymphadenopathy, interstitial pulmonary fibrosis and pleural thickening. [ 20 ]


Berylliosis is an  occupational disease . [ 1 ]  Relevant occupations are those where beryllium is mined, processed or converted into metal alloys, or where machining of metals containing beryllium and recycling of scrap alloys occurs. [ 21 ]  It is associated with aerospace manufacturing, microwave semiconductor electronics, beryllium mining or manufacturing of fluorescent light bulbs (which once contained beryllium compounds in their internal phosphor coating). [ 22 ] [ 23 ] [ 24 ]   Beryllia  was used in lamp manufacture because of ceramic's obvious virtues for insulation and heat resistance, and also because beryllia could be made transparent. [ 25 ]  Certain welding anodes along with other electrical contacts and even non-sparking tools are made of  beryllium copper  alloy and the subsequent machining of such materials would cause the disease as well.


Because it can be difficult to control industrial exposures to beryllium, it is advisable to use any methods possible to reduce airborne and surface contamination by beryllium, to minimize the use of beryllium and beryllium-containing alloys whenever possible, and to educate people about the potential hazards if they are likely to encounter beryllium dust or fumes. [ 26 ]  It is important to damp wipe  metallographic  preparation equipment to prevent accumulation of dry particles. Sectioning, grinding, and polishing must be performed under sufficiently vented hoods equipped with special filters. [ 27 ]


On 29 January 2009, the Los Alamos National Laboratory announced it was notifying nearly 2,000 current and former employees and visitors that they may have been exposed to beryllium in the lab and may be at risk of disease. Concern over possible exposure to the material was first raised in November 2008, when a box containing beryllium was received at the laboratory's short-term storage facility. [ 28 ]


There is no cure for berylliosis; the goals of treatment are to reduce symptoms and slow the progression of disease. [ 10 ] [ 29 ]


Although the evidence that stopping exposure to beryllium decreases progression of the disease is limited, [ 30 ]  it is still considered to be an accepted approach to treatment in any stage of disease. [ 31 ]


People with early stages of disease, without lung function abnormalities or clinical symptoms, are periodically monitored with physical exams, pulmonary function testing and radiography. [ 29 ]


Once clinical symptoms or significant abnormalities in pulmonary function testing appear, treatments include oxygen and oral  corticosteroids  and whatever  supportive therapy  is required. [ 1 ] [ 15 ] [ 29 ]


Overall mortality rates are 5–38%. [ 32 ]


The number of workers in the United States exposed to beryllium vary but has been estimated to be as high as 800,000 during the 1960s and 1970s. [ 33 ]  A more recent study from 2004 estimated the number of exposed workers in the United States to be around 134,000. [ 34 ]


The rate of workers becoming sensitized to beryllium varies based on genetics and exposure levels. In one study researchers found the prevalence of beryllium sensitization to range from 9–19% depending on the industry. [ 35 ]  Many workers who are found to be sensitive to beryllium also meet the diagnostic criteria for chronic beryllium disease. [ 35 ]  In one study of nuclear workers, among those who were sensitized to beryllium, 66% were found to have chronic beryllium disease as well. [ 36 ]  The rate of progression from beryllium sensitization to chronic beryllium disease has been estimated to be approximately 6–8% per year. [ 30 ] [ 37 ]  Stopping exposure to beryllium in those sensitized has not been definitively shown to stop the progression to chronic beryllium disease. [ 30 ]


The overall prevalence of chronic beryllium disease among workers exposed to beryllium has ranged from 1–5% depending on industry and time period of study. [ 35 ] [ 36 ] [ 38 ]


The general population is unlikely to develop acute or chronic beryllium disease because ambient air levels of beryllium are normally very low (<0.03 ng/m 3 ). [ 39 ]   However, a study found 1% of people living within 3/4 of a mile of a beryllium plant in Lorain, Ohio, had berylliosis after exposure to concentrations estimated to be less than 1 milligram per cubic metre of air. In the United States the Beryllium Case Registry contained 900 records, early cases relating to extraction and fluorescent lamp manufacture, later ones coming from the aerospace, ceramics and metallurgical industries. [ 40 ] [ 41 ]


Since the 1920s, beryllium has been used in electronics, ceramics, research and development labs, aircraft, and the atomic energy and defense industry. [ 26 ]  Cases of bronchitis and pneumonia-like symptoms were reported in Germany and Russia in the 1930s among workers mining and refining beryllium. By 1946, a cluster of cases associated with fluorescent lamp manufacturers were apparent in the United States, and the lamp industry stopped using beryllium in 1949. [ 31 ]  At that time, most construction trades and industries were unaware of the potential risks associated with beryllium exposure. [ 42 ]


It occasionally killed early workers in nuclear weapons design, such as  Herbert L. Anderson . [ 43 ]  The physicist  W. W. Hansen  who was instrumental in the development of the  klystron  also died of the disease in 1949.


Beryllium sensitivity testing was first performed as a cutaneous beryllium patch test in the early 1950s, but was discontinued due to the test stimulating sensitization or aggravating existing chronic beryllium disease. [ 44 ] : 115


In the 1990s, the  DOE  began screening employees using the BeLPT test in facilities where beryllium was used, to take preventive measures against beryllium exposure. Somewhat alarmingly, clerical staff who were never involved in handling the material had developed asymptomatic sensitivities. [ 45 ]


Acute beryllium poisoning  is acute  chemical pneumonitis  resulting from the toxic effect of  beryllium  in its elemental form or in various chemical compounds, and is distinct from  berylliosis  (also called chronic beryllium disease). After  occupational safety  procedures were put into place following the realization that the metal caused berylliosis around 1950, acute beryllium poisoning became extremely rare. [ 1 ]


Generally associated with exposure to beryllium levels at or above 100 μg/m 3 , [ 1 ]  it produces severe cough, sore nose and throat, weight loss, labored breathing, anorexia, and increased fatigue. [ 2 ] : 46


In addition to beryllium's toxicity when inhaled, when brought into contact with skin at relatively low doses, beryllium can cause local irritation and  contact dermatitis , and contact with skin that has been scraped or cut may cause rashes or ulcers. [ 3 ]  Beryllium dust or powder can irritate the eyes. [ 4 ]


Acute beryllium poisoning is an  occupational disease . [ 1 ]  Relevant occupations are those where beryllium is mined, processed or converted into metal alloys, or where machining of metals containing beryllium or recycling of scrap alloys occurs. [ 5 ]


Metallographic preparation equipment and laboratory work surfaces must be damp-wiped occasionally to inhibit buildup of particles. Cutting, grinding, and polishing procedures that generate dust or fumes must be handled within sufficiently vented coverings supplied with particulate filters. [ 6 ]


Therapy is supportive and includes removal from further beryllium exposure. [ 1 ]  For very severe cases mechanical ventilation may be required. [ 7 ]


The signs and symptoms of acute beryllium pneumonitis usually resolve over several weeks to months, but may be fatal in 10 percent of cases, [ 1 ]  and about 15–20% of cases may progress to  chronic beryllium disease . [ 8 ]


Acute beryllium poisoning approximately doubles the risk of lung cancer. [ 9 ]  The mechanism by which beryllium is carcinogenic is unclear, but may be due to ionic beryllium binding to nucleic acids; it is not mutagenic. [ 9 ]


Acute beryllium disease was first reported in Europe in 1933 and in the United States in 1943. [ 10 ]


This article incorporates  public domain material  from  Beryllium .  Occupational Safety and Health Administration . Retrieved  28 March  2016 .
  This article incorporates  public domain material  from  ToxGuide for Beryllium   (PDF) .  United States Department of Health and Human Services .


A  bioeffector   is a viable  microorganism  or active natural compound which directly or indirectly affects plant performance ( biofertilizer ), and thus has the potential to reduce  fertilizer  and  pesticide  use in crop production. [ 1 ]


Bioeffectors directly or indirectly affect plant performance by influencing the functional implementation or activation of biological mechanisms, particularly those interfering with soil-plant-microbe interactions. [ 2 ]
In contrast to conventional fertilizers and pesticides, the effectiveness of bioeffectors is not based on a substantial direct input of mineral plant nutrients, either in inorganic or organic forms.


Under the Acronym  Biofector  the European Union supports the Research of Bioeffectors under the leadership of the  University of Hohenheim . Coordinator  Guenter Neumann , Projectmembers:  Jiří Balík ,  Borbala Biro ,  Karl Fritz Lauer ,  Uwe Ludewig ,  Torsten Müller ,  Alessandro Piccolo ,  Manfred G. Raupp ,  Kornelia Smalla ,  Pavel Tlustoš ,  Markus Weinmann .


The results of the project will be evaluated by the members of the  Association Biostimulants in Agriculture  (ABISTA) and provided agriculture for use and EU institutions for the legislative and registration procedures. [ 4 ]


Other Biostimulants Organisations are  European Biostimulant Industry Council ,  International Biocontrol Manufacturers' Association  and  Annual Biocontrol Industry Meeting .


Biogenic silica  (bSi), also referred to as  opal , biogenic opal, or  amorphous  opaline  silica , forms one of the most widespread biogenic  minerals . For example, microscopic particles of silica called  phytoliths  can be found in grasses and other plants.


Silica is an amorphous metalloid  oxide  formed by complex  inorganic   polymerization  processes. This is opposed to the other major  biogenic  minerals, comprising  carbonate  and  phosphate , which occur in nature as crystalline iono-covalent solids (e.g.  salts ) whose  precipitation  is dictated by  solubility equilibria . [ 1 ]  Chemically, bSi is  hydrated silica  (SiO 2 · n H 2 O), which is essential to many plants and animals.


Diatoms in both fresh and salt water extract  dissolved silica  from the water to use as a component of their cell walls. Likewise, some  holoplanktonic   protozoa  ( Radiolaria ), some  sponges , and some plants (leaf  phytoliths ) use silicon as a structural material. Silicon is known to be required by chicks and rats for growth and skeletal development. Silicon is in human  connective tissues ,  bones ,  teeth ,  skin ,  eyes ,  glands  and  organs .


Silicate , or  silicic acid  (H 4 SiO 4 ), is an important  nutrient  in the ocean. Unlike the other major nutrients such as  phosphate ,  nitrate , or  ammonium , which are needed by almost all marine  plankton , silicate is an essential chemical requirement for very specific  biota , including  diatoms ,  radiolaria ,  silicoflagellates , and  siliceous sponges . These organisms extract dissolved silicate from open ocean surface waters for the buildup of their particulate silica (SiO 2 ), or opaline, skeletal structures (i.e. the biota's hard parts). [ 2 ] [ 3 ]  Some of the most common siliceous structures observed at the cell surface of silica-secreting organisms include: spicules, scales, solid plates, granules, frustules, and other elaborate geometric forms, depending on the species considered. [ 4 ]


Five major sources of  dissolved  silica to the marine environment can be distinguished: [ 3 ]


Once the organism has perished, part of the siliceous skeletal material  dissolves , as it settles through the  water column , enriching the deep waters with dissolved silica. [ 3 ]  Some of the siliceous scales can also be preserved over time as  microfossils  in  deep-sea   sediments , providing a window into modern and ancient  plankton / protists  communities. This biologic process has operated, since at least early  Paleozoic  time, to regulate the balance of silica in the ocean. [ 4 ]


Radiolarians ( Cambrian / Ordovician - Holocene ),  diatoms  ( Cretaceous - Holocene ), and silicoflagellates ( Cretaceous - Holocene ) form the ocean's main contributors to the global silica biogenic cycle throughout  geologic time . Diatoms account for 43% of the ocean primary production, and are responsible for the bulk of silica extraction from ocean waters in the modern ocean, and during much of the past fifty million years. In contrast, oceans of  Jurassic  and older ages, were characterized by  radiolarians  as major silica-utilizing phyla. [ 2 ]  Nowadays, radiolarians are the second (after diatoms) major producers of suspended amorphous silica in ocean waters. Their distribution ranges from the  Arctic  to the  Antarctic , being most abundant in the equatorial zone. In equatorial  Pacific  waters, for example, about 16,000 specimens per cubic meter can be observed. [ 4 ]


The silicon cycle has gained increasingly in scientific attention the past decade for several reasons:


Firstly , the modern  marine  silica cycle is widely believed to be dominated by diatoms for the fixation and export of  particulate matter  (including  organic   carbon ), from the  euphotic zone  to the deep ocean, via a process known as the  biological pump .  As a result, diatoms, and other silica-secreting organisms, play a crucial role in the global  carbon cycle , and have the ability to affect  atmospheric  CO 2  concentrations on a variety of time scales, by  sequestering  CO 2  in the ocean. This connection between  biogenic silica  and organic carbon, together with the significantly higher  preservation potential  of biogenic siliceous compounds, compared to organic carbon, makes opal accumulation records very interesting for  paleoceanography  and  paleoclimatology .


Secondly , biogenic silica accumulation on the sea floor contains lot of information about where in the ocean  export production  has occurred on time scales ranging from hundreds to millions of years. For this reason, opal deposition records provide valuable information regarding large-scale oceanographic reorganizations in the geological past, as well as paleoproductivity.


Thirdly , the mean oceanic  residence time  for silicate is approximately 10,000–15,000 yr. This relative short residence time, makes oceanic silicate concentrations and fluxes sensitive to  glacial / interglacial  perturbations, and thus an excellent  proxy  for evaluating climate changes. [ 3 ] [ 5 ]


Increasingly,  isotope ratios  of oxygen (O 18 :O 16 ) and silicon (Si 30 :Si 28 ) are analysed from biogenic silica preserved in lake and marine sediments to derive records of past  climate change  and  nutrient cycling  (De La Rocha, 2006; Leng and Barker, 2006). This is a particularly valuable approach considering the role of  diatoms  in global carbon cycling. In addition, isotope analyses from BSi are useful for tracing past climate changes in regions such as in the  Southern Ocean , where few biogenic  carbonates  are preserved.


The remains of diatoms and other silica-utilizing organisms are found, as opal sediments within pelagic deep-sea deposits.  Pelagic sediments , containing significant quantities of siliceous biogenic remains, are commonly referred to as  siliceous ooze . Siliceous ooze are particularly abundant in the modern ocean at high latitudes in the northern and southern hemispheres. A striking feature of siliceous ooze distribution is a ca. 200 km wide belt stretching across the  Southern Ocean . Some equatorial regions of  upwelling , where  nutrients  are abundant and  productivity  is high, are also characterized by local siliceous ooze. [ 2 ]


Siliceous oozes are composed primarily of the remains of diatoms and radiolarians, but may also include other siliceous organisms, such as silicoflagellates and  sponge   spicules . Diatom ooze occurs mainly in high-latitude areas and along some continental margins, whereas radiolarian ooze are more characteristic of equatorial areas. Siliceous ooze are modified and transformed during burial into bedded  cherts . [ 2 ]


Southern Ocean sediments are a major sink for biogenic silica (50-75% of the oceanic total of 4.5 × 10 14  g SiO 2  yr −1 ; DeMaster, 1981), but only a minor sink for organic  carbon  (<1% of the oceanic 2 × 10 14  g of organic C yr −1 ). These relatively high rates of biogenic silica accumulation in the Southern Ocean sediments (predominantly beneath the Polar Front) relative to organic carbon (60:1 on a weight basis) results from the preferential preservation of biogenic silica in the Antarctic water column.


In contrast to what was previously thought, these high rates of biogenic silica accumulation are not the result from high rates of  primary production . Biological production in the Southern Ocean is strongly limited due to the low levels of  irradiance  coupled with deep mixed layers and/or by limited amounts of  micronutrients , such as  iron . [ 6 ]


This preferential preservation of biogenic silica relative to organic carbon is evident in the steadily increasing ratio of silica/organic C as function of depth in the water column. About thirty-five percent of the biogenic silica produced in the  euphotic  zone survives dissolution within the surface layer; whereas only 4% of the organic carbon escapes  microbial  degradation in these near-surface waters.


Consequently, considerable decoupling of organic C and silica occurs during settling through the water column. The accumulation of biogenic silica in the seabed represents 12% of the surface production, whereas the seabed organic-carbon accumulation rate accounts for solely <0.5% of the surface production. As a result, polar sediments account for most of the ocean's biogenic silica accumulation, but only a small amount of the sedimentary organic-carbon flux. [ 6 ]


Large-scale oceanic circulation has a direct impact on  opal  deposition. The Pacific (characterized by nutrient poor surface waters, and deep nutrient rich waters) and Atlantic Ocean circulations favor the  production / preservation  of silica and carbonate respectively. For instance, Si/N and Si/P ratios increase from the Atlantic to the Pacific and Southern Ocean, favoring opal versus  carbonate  producers. Consequently, the modern configuration of large-scale oceanic circulation resulted in the localization of major opal burial zones in the Equatorial Pacific, in the eastern boundary current upwelling systems, and by far the most important, the Southern Ocean. [ 5 ]


Waters from the modern Pacific and Southern ocean, typically observe an increase in Si/N ratio at intermediate depth, which results in an increase in opal export (~ increase in opal production). In the Southern Ocean and North Pacific, this relationship between opal export and Si/N ratio switches from linear to exponential for Si/N ratios greater than 2. This gradual increase in the importance of silicate (Si) relative to nitrogen (N) has tremendous consequences for the ocean biological production. The change in nutrient ratios contributes to select  diatoms  as main producers, compared to other (e.g., calcifying) organisms. For example,  microcosm  experiments have demonstrated that diatoms are DSi supercompetitors and dominate other producers above 2 μM DSi. Consequently, opal vs. carbonate export will be favored, resulting in increasing opal production. The Southern Ocean and the North Pacific also display maximum biogenic silicate/C organic  flux ratios, and consist thus in an enrichment in biogenic silicate, compared to C organic  export flux. This combined increase in opal preservation and export makes the Southern Ocean the most important  sink  for DSi today. [ 5 ]


In the Atlantic Ocean, intermediate and deep waters are characterized by a lower content in DSi, compared to the modern Pacific and Southern Ocean. This lower interbasin difference in DSi has the effect of decreasing the  preservation potential  of opal in the Atlantic compared to its Pacific and Southern ocean counterparts. Atlantic DSi depleted waters tends to produce relatively less  silicified  organisms, which has a strong influence on the preservation of their  frustules . This mechanism in best illustrated when comparing the Peru and northwest Africa upwelling systems. The  dissolution /production ratio is much higher in the Atlantic upwelling than in the Pacific upwelling. This is due to the fact that coastal upwelling source waters are much richer in DSi off Peru, than off NW Africa. [ 5 ]


Rivers and submarine  hydrothermal  emanations supply 6.1 × 10 14  g SiO 2  yr −1  to the marine environment. Approximately two-thirds of this silica input is stored in  continental margin  and  deep-sea  deposits. Siliceous deep-sea sediments located beneath the  Antarctic Convergence  ( convergence zone ) host some 25% of the silica supplied to the oceans (i.e. 1.6 × 10 14  g SiO 2  yr −1 ) and consequently form one of Earth's major silica sinks. The highest biogenic silica accumulation rates in this area are observed in the South Atlantic, with values as large as 53 cm.kyr −1  during the last 18,000 yr. Further, extensive biogenic silica accumulation has been recorded in the deep-sea sediments of the  Bering Sea ,  Sea of Okhotsk , and  Subarctic   North Pacific . Total biogenic silica accumulation rates in these regions amounts nearly 0.6 × 10 14  g SiO 2  yr −1 , which is equivalent to 10% of the dissolved silica input to the oceans.


Continental margin upwelling areas, such as the  Gulf of California , the Peru and Chile coast, are characteristic for some of the highest biogenic silica accumulation rates in the world. For example, biogenic silica accumulation rates of 69 g SiO 2 /cm 2 /kyr have been reported for the Gulf of California. Due to the laterally confined character of these rapid biogenic silica accumulation zones, upwelling areas solely account for approximately 5% of the dissolved silica supplied to the oceans. At last, extremely low biogenic silica accumulation rates have been observed in the extensive deep-sea deposits of the Atlantic, Indian and Pacific Oceans, rendering these oceans insignificant for the global marine silica budget. [ 7 ]


The mean daily BSi rate strongly depends on the region:


Likewise, the integrated annual BSi production strongly depends on the region:


BSi production is controlled by:


BSi dissolution is controlled by:


BSi preservation is measured by:


BSi preservation is controlled by:


In the  Gusev crater  of Mars, the  Mars Exploration Rover   Spirit  inadvertently discovered opaline silica.  One of its wheels had earlier become immobilized and thus was effectively trenching the Martian  regolith  as it dragged behind the traversing rover.  Later analysis showed that the silica was evidence for hydrothermal conditions. [ 8 ]


Fluorine  may interact with biological systems in the form of fluorine-containing compounds. Though elemental fluorine (F 2 ) is very rare in everyday life, fluorine-containing compounds such as  fluorite  occur naturally as minerals. Naturally occurring  organofluorine  compounds are extremely rare. Man-made fluoride compounds are common and are used in medicines, pesticides, and materials. Twenty percent of all commercialized pharmaceuticals contain fluorine, including  Lipitor  and  Prozac . [ 1 ] [ 2 ]  In many contexts, fluorine-containing compounds are harmless or even beneficial to living organisms; in others, they are  toxic .


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


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


Since the mid-20th century, it has been discerned from population studies (though incompletely understood) that fluoride reduces  tooth decay . Initially, researchers hypothesized that fluoride helped by converting  tooth enamel  from the more acid-soluble mineral  hydroxyapatite  to the less acid-soluble mineral fluorapatite. However, more recent studies showed no difference in the frequency of  caries  (cavities) between teeth that were pre-fluoridated to different degrees. Current thinking is that fluoride prevents cavities primarily by helping teeth that are in the very early stages of tooth decay. [ 3 ]


When teeth begin to decay from the acid produced by sugar-consuming bacteria,  calcium  is lost ( demineralization ). However, teeth have a limited ability to recover calcium if decay is not too far advanced ( remineralization ). Fluoride appears to reduce demineralization and increase remineralization. Also, there is some evidence that fluoride interferes with the bacteria that consume sugars in the mouth and make tooth-destroying acids. [ 3 ]  In any case, it is only the fluoride that is directly present in the mouth ( topical treatment ) that prevents cavities; fluoride ions that are swallowed do not benefit the teeth. [ 3 ]


Water fluoridation  is the controlled addition of fluoride to a  public water supply  in an effort to reduce tooth decay in people who drink the water. [ 4 ]  Its use began in the 1940s, following studies of children in a region where water is naturally fluoridated. It is now used widely in public water systems in the United States and some other parts of the world, such that about two-thirds of the U.S. population is exposed to fluoridated water supplies [ 5 ]  and about 5.7% of people worldwide. [ 6 ]  Although the best available evidence shows no association with adverse effects other than fluorosis ( dental  and, in worse cases,  skeletal ), most of which is mild, [ 7 ]  water fluoridation has been contentious for ethical, safety, and efficacy reasons, [ 6 ]  and  opposition to water fluoridation  exists despite its widespread support by  public health  organizations. [ 8 ]  The benefits of water fluoridation have lessened recently, presumably because of the availability of fluoride in other forms, but are still measurable, particularly for low-income groups. [ 9 ]   Systematic reviews  in 2000 and 2007 showed significant reduction of cavities in children exposed to water fluoridation. [ 10 ]


Sodium fluoride ,  tin difluoride , and, most commonly,  sodium monofluorophosphate , are used in  toothpaste . In 1955, the first fluoride toothpaste was introduced in the United States. Now, almost all toothpaste in developed countries is fluoridated. For example, 95% of European toothpaste contains fluoride. [ 9 ]  Gels and foams are often advised for special patient groups, particularly those undergoing radiation therapy to the head (cancer patients). The patient receives a four-minute application of a high amount of fluoride. Varnishes, which can be more quickly applied, exist and perform a similar function. Fluoride is also often present in prescription and non-prescription  mouthwashes  and is a trace component of foods manufactured using fluoridated water supplies. [ 11 ]


Of all commercialized pharmaceutical drugs, twenty percent contain fluorine, including important drugs in many different pharmaceutical classes. [ 12 ]  Fluorine is often added to drug molecules during  drug design , as even a single atom can greatly change the chemical properties of the molecule in desirable ways.


Because of the considerable stability of the  carbon–fluorine bond , many drugs are fluorinated to delay their  metabolism , which is the chemical process in which the drugs are turned into compounds that allows them to be eliminated. This prolongs their  half-lives  and allows for longer times between dosing and activation. For example, an  aromatic ring  may prevent the metabolism of a drug, but this presents a safety problem, because some aromatic compounds are metabolized in the body into poisonous  epoxides  by the organism's native  enzymes . Substituting a fluorine into a  para  position, however, protects the aromatic ring and prevents the epoxide from being produced. [ 13 ]


Adding fluorine to biologically active organic compounds increases their  lipophilicity  (ability to dissolve in fats), because the carbon–fluorine bond is even more hydrophobic than the  carbon–hydrogen bond . This effect often increases a drug's  bioavailability  because of increased cell membrane penetration. [ 14 ]  Although the potential of fluorine being released in a fluoride  leaving group  depends on its position in the molecule, [ 15 ]  organofluorides are generally very stable, since the carbon–fluorine bond is strong.


Fluorines also find their uses in common  mineralocorticoids , a class of drugs that increase the  blood pressure . Adding a fluorine increases both its medical power and anti-inflammatory effects. [ 16 ]  Fluorine-containing  fludrocortisone  is one of the most common of these drugs. [ 17 ]   Dexamethasone  and  triamcinolone , which are among the most potent of the related synthetic  corticosteroid  class of drugs, contain fluorine as well. [ 17 ]


Several inhaled general  anesthetic  agents, including the most commonly used inhaled agents, also contain fluorine. The first fluorinated anesthetic agent,  halothane , proved to be much safer (neither explosive nor flammable) and longer-lasting than those previously used. Modern fluorinated anesthetics are longer-lasting still and almost insoluble in blood, which accelerates the awakening. [ 18 ]  Examples include  sevoflurane ,  desflurane ,  enflurane , and  isoflurane , all  hydrofluorocarbon  derivatives. [ 19 ]


Prior to the 1980s,  antidepressants  altered not only  serotonin  uptake but also the uptake of altered  norepinephrine ; the latter caused most of the side effects of antidepressants. The first drug to alter only the serotonin uptake was  Prozac ; it gave birth to the extensive  selective serotonin reuptake inhibitor  (SSRI) antidepressant class and is the best-selling antidepressant. Many other SSRI antidepressants are fluorinated organics, including  Celexa ,  Luvox , and  Lexapro . [ 20 ]   Fluoroquinolones  are a commonly used family of  broad-spectrum antibiotics . [ 21 ]


Compounds containing fluorine-18, a radioactive isotope that emits  positrons , are often used in  positron emission tomography  (PET) scanning, because the isotope's half-life of about 110 minutes is usefully long by positron-emitter standards. One such  radiopharmaceutical  is  2-deoxy-2-( 18 F)fluoro-D-glucose  (generically referred to as fludeoxyglucose), commonly abbreviated as  18 F-FDG, or simply FDG. [ 22 ]  In PET imaging, FDG can be used for assessing glucose metabolism in the brain and for imaging cancer tumors. After injection into the blood, FDG is taken up by "FDG-avid" tissues with a high need for glucose, such as the brain and most types of malignant tumors. [ 23 ]   Tomography , often  assisted by a computer  to form a PET/CT (CT stands for "computer tomography") machine, can then be used to diagnose or monitor treatment of cancers, especially  Hodgkin's lymphoma , lung cancer, and breast cancer. [ 24 ]


Natural fluorine is monoisotopic, consisting solely of  fluorine-19 . Fluorine compounds are highly amenable to  nuclear magnetic resonance  (NMR), because fluorine-19 has a  nuclear spin  of  1 ⁄ 2 , a high  nuclear magnetic moment , and a high  magnetogyric ratio . Fluorine compounds typically have a fast NMR  relaxation , which enables the use of fast averaging to obtain a  signal-to-noise ratio  similar to  hydrogen-1  NMR spectra. [ 25 ]  Fluorine-19 is commonly used in NMR study of metabolism, protein structures and conformational changes. [ 26 ]  In addition, inert fluorinated gases have the potential to be a cheap and efficient tool for imaging lung ventilation. [ 27 ]


Liquid  fluorocarbons  have a very high capacity for holding gas in solution. They can hold more oxygen or carbon dioxide than blood does. For that reason, they have attracted ongoing interest related to the possibility of artificial blood or of liquid breathing. [ 28 ]


Blood substitutes are the subject of research because the demand for blood transfusions grows faster than donations. In some scenarios, artificial blood may be more convenient or safe. Because fluorocarbons do not normally mix with water, they must be mixed into emulsions (small droplets of perfluorocarbon suspended in water) in order to be used as blood. [ 29 ] [ 30 ]  One such product,  Oxycyte , has been through initial clinical trials. [ 31 ] [ 32 ]


Possible medical uses of liquid breathing (which uses pure perfluorocarbon liquid, not a water emulsion) involve assistance for premature babies or for burn patients (if normal lung function is compromised). Both partial and complete filling of the lungs have been considered, although only the former has undergone any significant tests in humans. Several animal tests have been performed and there have been some human partial liquid ventilation trials. [ 33 ]  One effort, by Alliance Pharmaceuticals, reached clinical trials but was abandoned because of insufficient advantage compared to other therapies. [ 34 ]


Nanocrystals represent a possible method of delivering water- or fat-soluble drugs within a perfluorochemical fluid. The use of these particles is being developed to help treat babies with damaged lungs. [ 35 ]


Perfluorocarbons are banned from sports, where they may be used to increase oxygen use for endurance athletes. One cyclist,  Mauro Gianetti , was investigated after a near-fatality where PFC use was suspected. [ 36 ] [ 37 ]  Other posited applications include deep-sea diving and space travel, applications that both require total, not partial, liquid ventilation. [ 38 ] [ 39 ]  The 1989 film  The Abyss  depicted a fictional use of perfluorocarbon for human diving but also filmed a real rat surviving while cooled and immersed in perfluorocarbon. [ 40 ]  (See also  list of fictional treatments  of perfluorocarbon breathing.)


An estimated 30% of  agrichemical compounds  contain fluorine. [ 41 ]  Most of them are used as poisons, but a few stimulate growth instead.


Sodium fluoroacetate  has been used as an insecticide, but it is especially effective against mammalian pests. [ 42 ]  The name "1080" refers to the catalogue number of the poison, which became its brand name. [ 43 ]  Fluoroacetate is similar to acetate, which has a pivotal role in the  Krebs cycle  (a key part of cell metabolism). Fluoroacetate halts the cycle and causes cells to be deprived of energy. [ 43 ]  Several other insecticides contain sodium fluoride, which is much less toxic than fluoroacetate. [ 44 ]  Insects fed 29-fluorostigmasterol use it to produce fluoroacetates. If a fluorine is transferred to a body cell, it blocks metabolism at the position occupied. [ 45 ]


Trifluralin  was widely used in the 20th century, for example, in over half of U.S. cotton field acreage in 1998. [ 46 ]  Because of its suspected carcinogenic properties some Northern European countries banned it in 1993. [ 47 ]  As of 2015, the European Union has banned it, although Dow made a case to cancel the decision in 2011. [ 48 ]


Biologically synthesized organofluorines are few in number, although some are widely produced. [ 49 ] [ 50 ]  The most common example is  fluoroacetate , with an active poison molecule identical to commercial "1080". It is used as a  defense against herbivores  by at least 40 green plants in Australia, Brazil, and Africa; [ 43 ]  other biologically synthesized organofluorines include ω-fluoro  fatty acids ,  fluoroacetone , and 2-fluorocitrate. [ 50 ]  In bacteria, the enzyme  adenosyl-fluoride synthase , which makes the carbon–fluorine bond, has been isolated. The discovery was touted as possibly leading to biological routes for organofluorine synthesis. [ 51 ]


Fluoride is considered a semi-essential element for humans: not necessary to sustain life, but contributing (within narrow limits of daily intake) to dental health and bone strength. Daily requirements for fluorine in humans vary with age and sex, ranging from 0.01 mg in infants below 6 months to 4 mg in adult males, with an upper tolerable limit of 0.7 mg in infants to 10 mg in adult males and females. [ 52 ] [ 53 ]  Small amounts of fluoride may be beneficial for bone strength, but this is an issue only in the formulation of artificial diets. [ 54 ]  (See also  fluoride deficiency .)


Elemental fluorine is highly toxic. Above a concentration of 25 ppm, it causes significant irritation while attacking the eyes, airways and lungs and affecting the liver and kidneys. At a concentration of 100 ppm, human eyes and noses are seriously damaged. [ 57 ]  People can be exposed to fluorine in the workplace by breathing it in, skin contact, or eye contact. The  Occupational Safety and Health Administration  (OSHA) has set the legal limit ( Permissible exposure limit ) for fluorine exposure in the workplace as 0.1 ppm (0.2 mg/m 3 ) over an 8-hour workday. The  National Institute for Occupational Safety and Health  (NIOSH) has set a  recommended exposure limit  (REL) of 0.1 ppm (0.2 mg/m 3 ) over an 8-hour workday. At levels of 25 ppm, fluorine is  immediately dangerous to life and health . [ 58 ]


Hydrofluoric acid , the water solution of hydrogen fluoride (HF), is a contact poison. Even though it is from a chemical perspective a relatively weak acid, it is far more dangerous than conventional strong  mineral acids , such as  nitric acid ,  sulfuric acid , or  hydrochloric acid . Owing to its lesser chemical dissociation in water (remaining a neutral molecule), hydrogen fluoride penetrates tissue more quickly than typical acids. Poisoning can occur readily through the skin or eyes or when inhaled or swallowed. From 1984 to 1994, at least nine workers died in the United States from accidents with HF. [ 60 ]


Once in the blood, hydrogen fluoride reacts with calcium and magnesium, resulting in electrolyte imbalances, potentially including  hypocalcemia . The consequent effect on the heart ( cardiac arrhythmia ) may be fatal. [ 60 ]  Formation of insoluble  calcium fluoride  also causes severe pain. [ 61 ]  Burns with areas larger than 160 cm 2 , about the size of a man's hand, can cause serious systemic toxicity. [ 62 ]


Symptoms of exposure to hydrofluoric acid may not be immediately evident, with an eight-hour delay for 50% HF and up to 24 hours for lower concentrations. Hydrogen fluoride interferes with nerve function, meaning that burns may not initially be painful. If the burn has been initially noticed, then HF should be washed off with a forceful stream of water for ten to fifteen minutes to prevent its further penetration into the body. Clothing used by the person burned may also present a danger. [ 63 ]  Hydrofluoric acid exposure is often treated with  calcium gluconate , a source of Ca 2+  that binds with the fluoride ions. Skin burns can be treated with a water wash and 2.5 percent calcium gluconate gel [ 64 ] [ 65 ]  or special rinsing solutions. [ 66 ]  Because HF is absorbed, further medical treatment is necessary. Calcium gluconate may be injected or administered intravenously. Use of  calcium chloride  is contraindicated and may lead to severe complications. Sometimes surgical excision of tissue or amputation is required. [ 62 ] [ 67 ]


Soluble fluorides are moderately toxic. For sodium fluoride, the lethal dose for adults is 5–10 g, which is equivalent to 32–64 mg of elemental fluoride per kilogram of body weight. [ 68 ]  The dose that may lead to adverse health effects is about one fifth of the lethal dose. [ 69 ]  Chronic excess fluoride consumption can lead to  skeletal fluorosis , a disease of the bones that affects millions in Asia and Africa. [ 69 ] [ 70 ]


The fluoride ion is readily absorbed by the stomach and intestines. Ingested fluoride forms hydrofluoric acid in the stomach. In this form, fluoride crosses cell membranes and then binds with calcium and interferes with various enzymes. Fluoride is  excreted  through urine. Fluoride exposure limits are based on urine testing, which is used to determine the human body's capacity for ridding itself of fluoride. [ 69 ] [ 71 ]


Historically, most cases of fluoride poisoning have been caused by accidental ingestion of insecticides containing inorganic fluoride. [ 72 ]  Most calls to poison control centers for possible fluoride poisoning come from the ingestion of fluoride-containing toothpaste. [ 69 ]  Malfunction of water fluoridation equipment has occurred several times, including an Alaskan incident that sickened nearly 300 people and killed one. [ 73 ]


Because of the strength of the carbon–fluorine bond, organofluorines endure in the environment.  Perfluorinated compounds  (PFCs) have attracted particular attention as  persistent global contaminants .  These compounds can enter the environment from their direct uses in waterproofing treatments and firefighting foams or indirectly from leaks from fluoropolymer production plants (where they are intermediates). Because of the acid group, PFCs are water-soluble in low concentrations. [ 74 ]   While there are other PFAAs, the lion's share of environmental research has been done on the two most well-known:  perfluorooctanesulfonic acid  (PFOS) and  perfluorooctanoic acid  (PFOA).  The U.S. Environmental Protection Agency classifies these materials as "emerging contaminants" based on the growing but still incomplete understanding of their environmental impact. [ 75 ] [ 76 ] [ 77 ]


Trace quantities of PFCs have been detected worldwide, in organisms from polar bears in the Arctic to the global human population.  Both PFOS and PFOA have been detected in breast milk and the blood of newborns.  A 2013 review showed widely varying amounts of PFOS and PFOA in different soils and groundwater, with no clear pattern of one chemical dominating. PFC concentrations were generally higher in areas with more human population or industrial activity, and areas with more PFOS generally also had more PFOA. [ 78 ]   the two chemicals have been found at different concentrations in different populations; for example, one study showed more PFOS than PFOA in Germans, while another study showed the reverse for Americans. PFCs may be starting to decrease in the biosphere: one study indicated that PFOS levels in wildlife in Minnesota were decreasing, presumably because  3M  discontinued its production. [ 75 ] [ 76 ]


In the body, PFCs bind to proteins such as  serum albumin . Their tissue distribution in humans is unknown, but studies in rats suggest it is present mostly in the liver, kidney, and blood. They are not metabolized by the body but are excreted by the kidneys. Dwell time in the body varies greatly by species.  Rodents have half-lives of days, while in humans they remain for years. Many animals show sex differences in the ability to rid the body of PFAAs, but without a clear pattern. Gender differences of half lives vary by animal species. [ 75 ] [ 76 ] [ 79 ]


The potential health impact of PFCs is unclear. Unlike chlorinated hydrocarbons, PFCs are not  lipophilic  (stored in fat), nor  genotoxic  (damaging genes). Both PFOA and PFOS in high doses cause cancer and the death of newborns in rodents. Studies on humans have not been able to prove an impact at current exposures.  Bottlenose dolphins  have some of the highest PFOS concentrations of any wildlife studied; one study suggests an impact on their immune systems. [ 75 ] [ 76 ] [ 79 ]


The biochemical causes of toxicity are also unclear and may differ by molecule, health effect, and even animal.  PPAR-alpha  is a protein that interacts with PFAAs and is commonly implicated in contaminant-caused rodent cancers. [ 75 ] [ 76 ] [ 79 ]


Less fluorinated chemicals (i.e. not perfluorinated compounds) can also be detected in the environment. Because biological systems do not metabolize fluorinated molecules easily, fluorinated pharmaceuticals like antibiotics and antidepressants can be found in treated city sewage and wastewater. [ 80 ]  Fluorine-containing agrichemicals are measurable in farmland  runoff  and nearby rivers. [ 81 ]


Biometals  (also called  biocompatible metals ,  bioactive metals ,  metallic biomaterials ) are  metals  normally present, in small but important and measurable amounts, in  biology ,  biochemistry , and  medicine . The metals  copper ,  zinc ,  iron , and  manganese  are examples of metals that are essential for the normal functioning of most  plants  and the bodies of most  animals , such as the  human body . A few ( calcium ,  potassium ,  sodium ) are present in relatively larger amounts, whereas most others are  trace metals , present in smaller but important amounts (the image shows the percentages for humans). Approximately 2/3 of the existing periodic table is composed of metals with varying properties, [ 1 ]  accounting for the diverse ways in which metals (usually in  ionic  form) have been utilized in nature and medicine.


At first, the study of biometals was referred to as  bioinorganic chemistry . Each branch of bioinorganic chemistry studied separate, particular sub-fields of the subject. However, this led to an isolated view of each particular aspect in a biological system. This view was revised into a holistic approach of biometals in  metallomics . [ 2 ]


Metal ions in  biology  were studied in various specializations. In  nutrition , it was to define the essentials for life; in  toxicology , to define how the adverse effects of certain metal ions in biological systems and in  pharmacology  for their therapeutic effects. [ 2 ]  In each field, at first, they were studied and separated on a basis of concentration. In low amounts, metal ions in a biological system could perform at their optimal functionality whereas in higher concentrations, metal ions can prove fatal to biological systems. However, the concentration gradients were proved to be arbitrary as low concentrations of non-essential metals (like  lithium  or  helium ) in essential metals (like  sodium  or  potassium ) can cause an adverse effect in biological systems and vice versa. [ 2 ]


Investigations into biometals and their effects date back to the 19th century and even further back to the 18th century with the identification of iron in blood. [ 2 ]   Zinc  was identified to be essential in fungal growth of  yeast  as shown by  Jules Raulin  in 1869 yet no proof for the need of zinc in human cells was shown until the late 1930s where its presence was demonstrated in  carbonic anhydrase  and the 1960s where it was identified as a necessary element for humans. [ 2 ]  Since then, understanding of zinc in human biology has advanced to the point that it is considered as important as iron. Modern advancements in analytical technology have made it clear the importance of biometals in  signalling pathways  and the initial thoughts on the  chemical basis of life . [ 2 ]


Metal ions are essential to the function of many proteins present in living organisms, such as  metalloproteins  and enzymes that require metal ions as  cofactors . [ 3 ]  Processes including oxygen transport and DNA replication are carried out using enzymes such as  DNA polymerase , which in humans requires magnesium and zinc to function properly. [ 4 ]  Other biomolecules also contain metal ions in their structure, such as iodine in human thyroid hormones. [ 5 ]


The uses of some of them are listed below. The list is not exhaustive, because it covers only the principal class members; others that are  trace metals  of especially low bioconcentration are not explored herein. Some elements that are  nonmetals  or  metalloids  (such as  selenium ) are beyond the scope of this article.


Calcium  is the most abundant metal in the eukaryotes and by extension humans. The body is made up of approximate 1.5% calcium and this abundance is reflected in its lack of redox toxicity and its participation in the structure stability of membranes and other biomolecules. [ 6 ]  Calcium plays a part in  fertilization  of an egg, controls several developmental process and may regulate cellular processes like  metabolism  or learning. Calcium also plays a part in  bone  structure as the rigidity of vertebrae bone matrices are akin to the nature of the  calcium hydroxyapatite . [ 6 ]  Calcium usually binds with other proteins and molecules in order to perform other functions in the body. The calcium bound proteins usually play an important role in  cell-cell adhesion ,  hydrolytic processes  (such as hydrolytic enzymes like  glycosidases  and  sulfatases ) and  protein folding  and sorting. [ 6 ]  These processes play into the larger part of  cell structure  and metabolism.


Magnesium  is the most abundant free cation in plant  cytosol , is the central atom in  chlorophyll  and offers itself as a bridging ion for the  aggregation  of  ribosomes  in plants. [ 7 ]  Even small changes in the concentration of magnesium in plant cytosol or  chloroplasts  can drastically affect the key enzymes present in the chloroplasts. It is most commonly used as a  co-factor  in  eukaryotes  and functions as an important functional key in enzymes like  RNA Polymerase  and  ATPase . [ 7 ]  In phosphorylating enzymes like ATPase or  kinases  and  phosphates , magnesium acts as a stabilizing ion in  polyphosphate  compounds due its  Lewis acidity . [ 6 ]  Magnesium has also been noted as a possible secondary messenger for neural transmissions. [ 6 ]  Magnesium acts as an  allosteric inhibitor  for the enzyme  vacuolar   pyrophosphatase  (V-PP i ase).  In vitro , the concentration of free magnesium acts as a strict regulator and stabilizer for the enzyme activity of V-PP i ase. [ 7 ]


Manganese  like magnesium plays a crucial role as a co-factor in various enzymes though its concentration is noticeably lower than the other. [ 6 ]  Enzymes that use manganese as a co-factor are known as "manganoproteins." These proteins include enzymes, like  oxidoreductases ,  transferases  and  hydrolases , which are necessary for metabolic functions and antioxidant responses. [ 6 ]  Manganese plays a significant role in host defense, blood clotting, reproduction, digestion and various other functions in the body. In particular, when concerning host defense, manganese acts as a preventative measure for oxidative stress by destroying  free radicals  which are  ions  that have an unpaired electron in their outer shells.


Zinc  is the second most abundant  transition metal  present in living organisms second only to iron. It is critical for the growth and survival of cells. In humans, zinc is primarily found in various organs and tissues such as the brain, intestines, pancreas and mammary glands. [ 8 ]  In  prokaryotes , zinc can function as an  antimicrobial , zinc oxide nano-particles can function as an  antibacterial  or antibiotic. Zinc  homeostasis  is highly controlled to allow for its benefits without risk of death via its high toxicity. [ 8 ]  Because of zinc's antibiotic nature, it is often used in many drugs against bacterial infections in humans. Inversely, due to the bacterial nature of mitochondria, zinc antibiotics are also lethal to mitochondria and results in cell death at high concentrations. [ 8 ]  Zinc is also used in a number of transcription factors, proteins and enzymes.


Sodium is a metal where humans have discovered a great deal of its total roles in the body as well as being one of the only two  alkali metals  that play a major role in the bodily functions. It plays an important role in maintenance of the cell membrane potential and the electrochemical gradient in the body via the  sodium-potassium pump  and  sodium-glucose transport proteins . Sodium also serves a purpose in the  nervous system  and cell communication as they flood into  axons  during an action potential to preserve the strength of the signal. [ 9 ]  It has also been shown that sodium affects immune response both in efficiency and speed. Macrophages have increased proliferation rates at high-salt concentrations and the body uses high-sodium concentrations in isolated regions to generate an heightened immune response which fades after the infection has been dealt with. [ 10 ]


In plants, potassium plays a key role in maintaining plant health. High concentrations of potassium in plants play a key role in synthesis of essential proteins in plants as well as development of plant organelles like cell walls to prevent damage from viruses and insects. [ 11 ]  It also lowers the concentration of low molecular weight molecules like sugars and amino acids and increases the concentration of high weight molecular weight molecules like protein which also prevent the development and propagation of viruses. [ 11 ]  Potassium absorption has a positive correlation with  aquaporins  and the uptake of water in plant cells via cell membrane proteins. [ 11 ]  Because of this correlation, it has been noted that potassium also plays a key part in stomatal movement and regulation as high concentrations of potassium are moved into the plant  stomata  to keep them open and promote  photosynthesis . [ 11 ]  In animals, potassium also plays a key part along with sodium in maintaining resting cell membrane potential and in cell-cell communication via repolarization of axon pathways after an action potential between neurons. [ 9 ]  Potassium may also play a key part in maintaining blood pressure in animals as shown in a study where increased severity of periodontal disease and hypertension were inversely correlated to urinary potassium excretion (a telltale sign of low potassium intake). [ 12 ]


Iron is also the most abundant  transition metal  in the human body and it is used in various processes like oxygen transport and ATP production. It plays a key role in the function of enzymes like  cytochrome a ,  b  and  c  as well as  iron-sulfur complexes  which play an important role in ATP production. [ 13 ]  It is present in every type of cell in the brain as the brain itself has a very high energy requirement and by extension a very high iron requirement. [ 13 ]  In animals, iron plays a very important role in transporting oxygen from the lungs to tissues and CO 2  from tissues to the lungs. It does this via two important transport proteins called  hemoglobin  and  myoglobin . [ 14 ]  Hemoglobin in the blood transports oxygen from the lungs to myoglobin in tissues. Both proteins are  tetramer  complexes with iron protein complexes called  hemes  built into each  subunit  of the tetramer. The oxygen binds to the iron in the heme via  affinity-based binding  or liganding and dissociates from the protein once it has reached its destination. [ 14 ]  Iron can also be a potential  carcinogen  in three ways; first being the production of  hydroxyl radicals .  Ferric  ions can be  reduced  via  superoxide  and the product can be  reoxidized  via  peroxide  to form hydroxyl radicals. Hydroxyl radicals and other  reactive oxygen species  when generated near  DNA  can cause  point mutations ,  cross-linkage  and  breaks . [ 15 ]  The second being the bolstering of the growth of  neoplastic cells  by suppressing host defenses. Excessive iron inhibits the activity of  CD 4  lymphocytes  and suppresses the  tumoricidal  activity of  macrophages . [ 15 ]  The third way it can act as a carcinogen is by functioning as an essential nutrient for unrestricted proliferation of tumor cells. [ 15 ]


Lithium  is present in biological systems in  trace amounts ; its functions are uncertain. Lithium salts have proven to be useful as a  mood stabilizer  and  antidepressant  in the treatment of mental illness such as  bipolar disorder .


The term biometal can be used as a synonym to a metallic element that is involved in the function of a  biomolecule , [ 16 ]  hence also artificial systems can be considered when talking about biometals. Systems such as  metalloproteins ,  metallopeptides  and  artificial metalloenzymes  are examples of  biomolecules  containing metallic elements. The  de novo design  of structures involving metals in the function of the  biomolecule  itself is done in a  biomimetic  fashion but also to enable non-natural activity in  biomolecules . [ 17 ]


Metal ions and metallic compounds are often used in medical treatments and diagnoses. [ 18 ]  Compounds containing metal ions can be used as medicine, such as  lithium compounds  and  auranofin . [ 19 ] [ 20 ]  Metal compounds and ions can also produce harmful effects on the body due to the toxicity of several types of metals. [ 18 ]  For example,  arsenic  works as a potent poison due to its effects as an enzyme inhibitor, disrupting  ATP  production. [ 21 ]  On the other hand, Ni–Ti–Cu wires are used for artificial heart muscles [ 22 ]  and iron and gold particles can guide magnetic drug delivery or destroy tumor cells. [ 22 ]


Bigger biometal structures (relying on  metallic elements  and  alloys ) in medicine can be classified into three types:  fibre , bulk scaffolds, and  nanotubes . [ 23 ]  And in some cases the term biometal is also used to refer to metal system with application in  biomedicine  not directly correlated to the  biochemical  function of  biomolecules  but to the  biocompatibility  of these metal systems. [ 24 ]  Examples are scaffolds of  stainless steel  or  titanium   alloy  to create  screws  or plates for  osteosynthesis , and  titanium  bulk for precise engineering of  bone tissue . [ 24 ] [ 22 ]  For analytical purposes biometals can be employed in magnetic separation of different materials. [ 22 ]


Calcium (Ca) deficiency  is a plant disorder that can be caused by insufficient level of biologically available  calcium  in the growing medium, but is more frequently a product of low  transpiration  of the whole plant or more commonly the affected tissue.  Plants are susceptible to such localized calcium deficiencies in low or non-transpiring tissues because calcium is not transported in the  phloem . [ 1 ]  This may be due to water shortages, which slow the transportation of  calcium  to the plant, poor uptake of calcium through the stem, [ 2 ]  or too much  nitrogen  in the soil. [ 3 ]


Acidic, sandy, or coarse  soils  often contain less calcium. Uneven soil moisture and overuse of  fertilizers  can also cause calcium deficiency. At times, even with sufficient calcium in the soil, it can be in an insoluble form and is then unusable by the plant or it could be attributed to a "transport protein". [ 2 ]  Soils containing high phosphorus are particularly susceptible to creating insoluble forms of calcium. [ citation needed ]


Calcium and  magnesium  are opposed within the plant cells, and have antagonistic interactions. As a result, a homeostatic balance between Ca and Mg within the plant is necessary for optimal growth and proper development. [ 4 ]


Calcium deficiency symptoms appear initially as localized tissue  necrosis  leading to stunted plant growth,  necrotic   leaf margins  on young leaves or curling of the leaves, and eventual death of  terminal buds  and  root tips . Generally, the new growth and rapidly growing tissues of the plant are affected first. The mature leaves are rarely if ever affected because calcium accumulates to high concentrations in older leaves. [ 5 ]  Calcium deficiencies in plants are associated with reduced height, fewer nodes, and less leaf area. [ 6 ]


Crop-specific symptoms include: [ citation needed ]


Calcium deficiency can sometimes be rectified by adding  agricultural lime  to acid soils, aiming at a  pH  of 6.5, [ 10 ]  unless the subject plants specifically prefer acidic soil. Organic matter should be added to the soil to improve its moisture-retaining capacity. [ 10 ]   However, because of the nature of the disorder (i.e. poor transport of calcium to low transpiring tissues), the problem cannot generally be cured by the addition of calcium to the roots. [ 10 ]   In some species, the problem can be reduced by prophylactic spraying with  calcium chloride  of tissues at risk. [ 3 ]


Plant damage is difficult to reverse, so  corrective action should be taken immediately, supplemental applications of  calcium nitrate  at 200 ppm nitrogen, for example. Soil  pH  should be tested, and corrected if needed, because calcium deficiency is often associated with low pH. [ 14 ] [ 15 ] [ citation needed ]
 [ 16 ]
Early fruit will generally have the worst symptoms, with them typically lessening as the season progresses. Preventative measures, such as irrigating prior to especially high temperatures and stable irrigation will minimize the occurrence.


Calcium  ions  (Ca 2+ ) contribute to the  physiology  and  biochemistry  of organisms'  cells . They play an important role in  signal transduction  pathways, [ 2 ] [ 3 ]  where they act as a  second messenger , in  neurotransmitter  release from  neurons , in contraction of all  muscle  cell types, and in  fertilization . Many  enzymes  require calcium ions as a  cofactor , including several of the  coagulation factors . Extracellular calcium is also important for maintaining the  potential difference  across  excitable cell   membranes , as well as proper bone formation.


Plasma calcium levels in mammals are tightly regulated, [ 2 ] [ 3 ]  with  bone  acting as the major  mineral storage  site. Calcium  ions , Ca 2+ , are released from bone into the bloodstream under controlled conditions. Calcium is transported through the bloodstream as dissolved ions or bound to proteins such as  serum albumin .   Parathyroid hormone  secreted by the  parathyroid gland  regulates the  resorption  of Ca 2+  from bone,  reabsorption  in the kidney back into circulation, and increases in the activation of  vitamin D 3  to  calcitriol . Calcitriol, the active form of vitamin D 3 , promotes  absorption  of calcium from the intestines and bones.  Calcitonin  secreted from the  parafollicular cells  of the  thyroid gland  also affects calcium levels by opposing parathyroid hormone; however, its physiological significance in humans is dubious.


Intracellular  calcium is stored in  organelles  which repetitively release and then reaccumulate Ca 2+  ions in response to specific cellular events: storage sites include  mitochondria  and the  endoplasmic reticulum . [ 4 ]


Characteristic concentrations of calcium in model organisms are: in  E. coli  3  mM  (bound), 100  nM  (free), in budding yeast 2 mM (bound), in mammalian cell 10–100 nM (free) and in blood plasma 2 mM. [ 5 ]


In 2022, it was the 277th most commonly prescribed medication in the United States, with more than 700,000 prescriptions. [ 8 ] [ 9 ]


The US Institute of Medicine (IOM) established  Recommended Dietary Allowances  (RDAs) for calcium in 1997 and updated those values in 2011. [ 6 ]  See table. The
 European Food Safety Authority  (EFSA) uses the term Population Reference Intake (PRIs) instead of RDAs and sets slightly different numbers: ages 4–10 800 mg, ages 11–17 1150 mg, ages 18–24 1000 mg, and >25 years 950 mg. [ 10 ]


Because of concerns of long-term adverse side effects such as calcification of arteries and kidney stones, the IOM and EFSA both set  Tolerable Upper Intake Levels  (ULs) for the combination of dietary and supplemental calcium. From the IOM, people ages 9–18 years are not supposed to exceed 3,000 mg/day; for ages 19–50 not to exceed 2,500 mg/day; for ages 51 and older, not to exceed 2,000 mg/day. [ 11 ]  The EFSA set UL at 2,500 mg/day for adults but decided the information for children and adolescents was not sufficient to determine ULs. [ 12 ]


For US food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value (%DV). For calcium labeling purposes, 100% of the Daily Value was 1000 mg, but as of 27 May 2016, it was revised to 1300 mg to bring it into agreement with the RDA. [ 13 ] [ 14 ]  A table of the old and new adult daily values is provided at  Reference Daily Intake .


Although as a general rule, dietary supplement labeling and marketing are not allowed to make disease prevention or treatment claims, the FDA has for some foods and dietary supplements reviewed the science, concluded that there is significant scientific agreement, and published specifically worded allowed health claims. An initial ruling allowing a health claim for calcium dietary supplements and  osteoporosis  was later amended to include calcium and  vitamin D  supplements, effective 1 January 2010. Examples of allowed wording are shown below. In order to qualify for the calcium health claim, a dietary supplement must contain at least 20% of the Reference Dietary Intake, which for calcium means at least 260 mg/serving. [ 15 ]


In 2005, the FDA approved a Qualified Health Claim for calcium and hypertension, with suggested wording "Some scientific evidence suggests that calcium supplements may reduce the risk of hypertension. However, FDA has determined that the evidence is inconsistent and not conclusive." Evidence for pregnancy-induced hypertension and preeclampsia was considered inconclusive. [ 16 ]  The same year, the FDA approved a QHC for calcium and colon cancer, with suggested wording "Some evidence suggests that calcium supplements may reduce the risk of colon/rectal cancer, however, FDA has determined that this evidence is limited and not conclusive." Evidence for breast cancer and prostate cancer was considered inconclusive. [ 17 ]  Proposals for QHCs for calcium as protective against kidney stones or against menstrual disorders or pain were rejected. [ 18 ] [ 19 ]


The  European Food Safety Authority  (EFSA) concluded that "Calcium contributes to the normal development of bones." [ 20 ]  The EFSA rejected a claim that a cause-and-effect relationship existed between the dietary intake of calcium and potassium and maintenance of normal acid-base balance. [ 21 ]  The EFSA also rejected claims for calcium and nails, hair, blood lipids, premenstrual syndrome and body weight maintenance. [ 22 ]


The  United States Department of Agriculture  (USDA) web site has a very complete searchable table of calcium content (in milligrams) in foods, per common measures such as per 100 grams or per a normal serving. [ 23 ] [ 24 ]


The amount of calcium in  blood  (more specifically, in  blood plasma ) can be measured as  total calcium , which includes both protein-bound and free calcium. In contrast,  ionized calcium  is a measure of free calcium. An abnormally high level of calcium in plasma is termed  hypercalcemia  and an abnormally low level is termed  hypocalcemia , with "abnormal" generally referring to levels outside the  reference range .


The main methods to measure serum calcium are: [ 32 ]


The total amount of Ca 2+  present in a tissue may be measured using  Atomic absorption spectroscopy , in which the tissue is vaporized and combusted.  To measure Ca 2+  concentration or spatial distribution within the cell  cytoplasm   in vivo  or  in vitro , a range of  fluorescent  reporters may be used. These include cell permeable, calcium-binding fluorescent  dyes  such as  Fura-2  or genetically engineered variant of  green fluorescent protein  (GFP) named  Cameleon .


As access to an ionized calcium is not always available a corrected calcium may be used instead. To calculate a corrected calcium in mmol/L one takes the total calcium in mmol/L and adds it to ((40 minus the serum  albumin  in g/L) multiplied by 0.02). [ 33 ]  There is, however, controversy around the usefulness of corrected calcium as it may be no better than total calcium. [ 34 ]  It may be more useful to correct total calcium for both albumin and the  anion gap . [ 35 ] [ 36 ]


In  vertebrates , calcium ions, like many other ions, are of such vital importance to many physiological processes that its concentration is maintained within specific limits to ensure adequate homeostasis. This is evidenced by human  plasma  calcium, which is one of the most closely regulated physiological variables in the human body. Normal plasma levels vary between 1 and 2% over any given time. Approximately half of all ionized calcium circulates in its unbound form, with the other half being complexed with plasma proteins such as  albumin , as well as  anions  including  bicarbonate ,  citrate ,  phosphate , and  sulfate . [ 37 ]


Different  tissues  contain calcium in different concentrations. For instance, Ca 2+  (mostly  calcium phosphate  and some  calcium sulfate ) is the most important (and specific) element of  bone  and calcified  cartilage . In humans, the total body content of calcium is present mostly in the form of bone mineral (roughly 99%). In this state, it is largely unavailable for exchange/bioavailability. The way to overcome this is through the process of  bone resorption , in which calcium is liberated into the bloodstream through the action of bone  osteoclasts . The remainder of calcium is present within the extracellular and intracellular fluids.


Within a typical cell, the intracellular concentration of ionized calcium is roughly 100 nM, but is subject to increases of 10- to 100-fold during various cellular functions. The intracellular calcium level is kept relatively low with respect to the extracellular fluid, by an approximate magnitude of 12,000-fold. This gradient is maintained through various plasma membrane  calcium pumps  that utilize  ATP  for energy, as well as a sizable storage within intracellular compartments. In  electrically excitable cells , such as skeletal and cardiac muscles and neurons, membrane depolarization leads to a Ca 2+  transient with cytosolic Ca 2+  concentration reaching around 1 μM. [ 39 ]  Mitochondria are capable of sequestering and storing some of that Ca 2+ . It has been estimated that mitochondrial matrix free calcium concentration rises to the tens of micromolar levels  in situ  during neuronal activity. [ 40 ]


The effects of calcium on human cells are specific, meaning that different types of cells respond in different ways. However, in certain circumstances, its action may be more general. Ca 2+  ions are one of the most widespread  second messengers  used in  signal transduction . They make their entrance into the  cytoplasm  either from outside the cell through the  cell membrane  via calcium channels (such as  calcium-binding proteins  or voltage-gated calcium channels), or from some internal  calcium storages  such as the  endoplasmic reticulum [ 4 ]  and  mitochondria . Levels of intracellular calcium are regulated by  transport proteins  that remove it from the cell. For example, the  sodium-calcium exchanger  uses energy from the  electrochemical gradient  of sodium by coupling the influx of sodium into cell (and down its concentration gradient) with the transport of calcium out of the cell. In addition, the  plasma membrane Ca 2+  ATPase  (PMCA) obtains energy to pump calcium out of the cell by  hydrolysing   adenosine triphosphate  (ATP). In  neurons ,  voltage-dependent, calcium-selective ion channels  are important for  synaptic  transmission through the release of  neurotransmitters  into the  synaptic cleft  by  vesicle fusion  of  synaptic vesicles .


Calcium's function in  muscle contraction  was found as early as 1882 by Ringer. Subsequent investigations were to reveal its role as a messenger about a century later. Because its action is interconnected with  cAMP , they are called synarchic messengers. Calcium can bind to several different calcium-modulated proteins such as  troponin-C  (the first one to be identified) and  calmodulin , proteins that are necessary for promoting contraction in muscle.


In the endothelial cells which line the inside of blood vessels, Ca 2+  ions can regulate several signaling pathways which cause the smooth muscle surrounding blood vessels to relax. [ citation needed ]   Some of these Ca 2+ -activated pathways include the stimulation of eNOS to produce nitric oxide, as well as the stimulation of K ca  channels to efflux K +  and cause hyperpolarization of the cell membrane.  Both nitric oxide and hyperpolarization cause the smooth muscle to relax in order to regulate the amount of tone in blood vessels. [ 41 ]   However, dysfunction within these Ca 2+ -activated pathways can lead to an increase in tone caused by unregulated smooth muscle contraction.  This type of dysfunction can be seen in cardiovascular diseases, hypertension, and diabetes. [ 42 ]


Calcium coordination plays an important role in defining the structure and function of proteins. An example a protein with calcium coordination is  von Willebrand factor  (vWF) which has an essential role in blood clot formation process. It was discovered using single molecule  optical tweezers  measurement that calcium-bound vWF acts as a shear force sensor in the blood. Shear force leads to unfolding of the A2 domain of vWF whose refolding rate is dramatically enhanced in the presence of calcium. [ 43 ]


Ca 2+  ion flow regulates several secondary messenger systems in  neural adaptation  for visual, auditory, and the olfactory system. It may often be bound to  calmodulin  such as in the olfactory system to either enhance or repress cation channels. [ 44 ]  Other times the calcium level change can actually release  guanylyl cyclase  from inhibition, like in the photoreception system. [ 45 ]  Ca 2+  ion can also determine the speed of adaptation in a neural system depending on the receptors and proteins that have varied affinity for detecting levels of calcium to open or close channels at high concentration and low concentration of calcium in the cell at that time. [ 46 ]


Substantial decreases in extracellular Ca 2+  ion concentrations may result in a condition known as  hypocalcemic   tetany , which is marked by spontaneous  motor neuron  discharge. In addition, severe  hypocalcaemia  will begin to affect aspects of  blood coagulation  and signal transduction.


Ca 2+  ions can damage cells if they enter in excessive numbers (for example, in the case of  excitotoxicity , or over-excitation of  neural circuits , which can occur in  neurodegenerative diseases , or after insults such as  brain trauma  or  stroke ). Excessive entry of  calcium  into a cell may damage it or even cause it to undergo  apoptosis , or death by  necrosis . Calcium also acts as one of the primary regulators of osmotic stress ( osmotic shock ). Chronically elevated plasma calcium ( hypercalcemia ) is associated with  cardiac arrhythmias  and decreased neuromuscular excitability. One cause of hypercalcemia is a condition known as  hyperparathyroidism .


Some  invertebrates  use calcium compounds for building their  exoskeleton  ( shells  and  carapaces ) or  endoskeleton  ( echinoderm  plates and  poriferan  calcareous  spicules ).