Arsenic poisoning

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Arsenic poisoning
Other names	Arsenicosis
An 1889 newspaper advertisement for "arsenic complexion wafers". Arsenic was known to be poisonous during the Victorian era.
Specialty	Toxicology
Symptoms	Acute: vomiting, abdominal pain, watery diarrhea Chronic: thickened skin, darker skin, cancer
Causes	Arsenic
Diagnostic method	Urine, blood, or hair testing
Prevention	Drinking water without arsenic
Treatment	Dimercaptosuccinic acid, dimercaptopropane sulfonate
Frequency	>200 million

Arsenic poisoning is a medical condition that occurs due to elevated levels of arsenic in the body. If arsenic poisoning occurs over a brief period of time, symptoms may include vomiting, abdominal pain, encephalopathy, and watery diarrhea that contains blood. Long-term exposure can result in thickening of the skin, darker skin, abdominal pain, diarrhea, heart disease, numbness, and cancer.

The most common reason for long-term exposure is contaminated drinking water. Groundwater most often becomes contaminated naturally; however, contamination may also occur from mining or agriculture. It may also be found in the soil and air. Recommended levels in water are less than 10–50 µg/L (10–50 parts per billion). Other routes of exposure include toxic waste sites and pseudo-medicine. Most cases of poisoning are accidental. Arsenic acts by changing the functioning of around 200 enzymes. Diagnosis is by testing the urine, blood, or hair.

Prevention is by using water that does not contain high levels of arsenic. This may be achieved by the use of special filters or using rainwater. There is not good evidence to support specific treatments for long-term poisoning. For acute poisonings treating dehydration is important. Dimercaptosuccinic acid or dimercaptopropane sulfonate may be used while dimercaprol (BAL) is not recommended. Hemodialysis may also be used.

Through drinking water, more than 200 million people globally are exposed to higher-than-safe levels of arsenic. The areas most affected are Bangladesh and West Bengal. Exposure is also more common in people of low income and minorities. Acute poisoning is uncommon. The toxicity of arsenic has been described as far back as 1500 BC in the Ebers papyrus.

Signs and symptoms

Symptoms of arsenic poisoning begin with headaches, confusion, severe diarrhea, and drowsiness. As the poisoning develops, convulsions and changes in fingernail pigmentation called leukonychia striata (Mees's lines, or Aldrich-Mees's lines) may occur. When the poisoning becomes acute, symptoms may include diarrhea, vomiting, vomiting blood, blood in the urine, cramping muscles, hair loss, stomach pain, and more convulsions. The organs of the body that are usually affected by arsenic poisoning are the lungs, skin, kidneys, and liver. The final result of arsenic poisoning is coma and death.

Arsenic is related to heart disease (hypertension-related cardiovascular disease), cancer, stroke (cerebrovascular diseases), chronic lower respiratory diseases, impaired lung function, compromised immune response to H1N1 (swine) flu (a respiratory virus infection) and diabetes. Skin effects can include skin cancer in the long term, but often prior to skin cancer are different skin lesions. Other effects may include darkening of skin and thickening of skin.

Chronic exposure to arsenic is related to vitamin A deficiency, which is related to heart disease and night blindness. The acute minimal lethal dose of arsenic in adults is estimated to be 70 to 200 mg or 1 mg/kg/day.

Cancer

Arsenic increases the risk of cancer. Exposure is related to skin, lung, liver, and kidney cancer among others.

Its comutagenic effects may be explained by interference with base and nucleotide excision repair, eventually through interaction with zinc finger structures. Dimethylarsinic acid, DMA(V), caused DNA single strand breaks resulting from inhibition of repair enzymes at levels of 5 to 100 mM in human epithelial type II cells.

MMA(III) and DMA(III) were also shown to be directly genotoxic by effectuating scissions in supercoiled ΦX174 DNA. Increased arsenic exposure is associated with an increased frequency of chromosomal aberrations, micronuclei and sister-chromatid exchanges. An explanation for chromosomal aberrations is the sensitivity of the protein tubulin and the mitotic spindle to arsenic. Histological observations confirm effects on cellular integrity, shape and locomotion.

DMA(III) is able to form reactive oxygen species by reaction with molecular oxygen. Resulting metabolites are the dimethylarsenic radical and the dimethylarsenic peroxyl radical. Both DMA(III) and DMA(V) were shown to release iron from horse spleen as well as from human liver ferritin if ascorbic acid was administered simultaneously. Thus, formation of reactive oxygen species can be promoted. Moreover, arsenic could cause oxidative stress by depleting the cell's antioxidants, especially the ones containing thiol groups. The accumulation of reactive oxygen species like that cited above and hydroxyl radicals, superoxide radicals and hydrogen peroxides causes aberrant gene expression at low concentrations and lesions of lipids, proteins and DNA in higher concentrations which eventually lead to cellular death. In a rat animal model, urine levels of 8-hydroxy-2'-deoxyguanosine (as a biomarker of DNA damage byreactive oxygen species) were measured after treatment with DMA(V). In comparison to control levels, they turned out to be significantly increased. This theory is further supported by a cross-sectional study which found elevated mean serum lipid peroxides in the As exposed individuals which correlated with blood levels of inorganic arsenic and methylated metabolites and inversely correlated with nonprotein sulfhydryl (NPSH) levels in whole blood. Another study found an association of As levels in whole blood with the level of reactive oxidants in plasma and an inverse relationship with plasma antioxidants. A finding of the latter study indicates that methylation might in fact be a detoxification pathway with regard to oxidative stress: the results showed that the lower the As methylation capacity was, the lower the level of plasma antioxidant capacity. As reviewed by Kitchin (2001), the oxidative stress theory provides an explanation for the preferred tumor sites connected with arsenic exposure. Considering that a high partial pressure of oxygen is present in lungs and DMA(III) is excreted in gaseous state via the lungs, this seems to be a plausible mechanism for special vulnerability. The fact that DMA is produced by methylation in the liver, excreted via the kidneys and later on stored in the bladder accounts for the other tumor localizations.

Regarding DNA methylation, some studies suggest interaction of As with methyltransferases which leads to an inactivation of tumor suppressor genes through hypermethylation; others state that hypomethylation might occur due to a lack of SAM resulting in aberrant gene activation. An experiment by Zhong et al. (2001) with arsenite-exposed human lung A549, kidney UOK123, UOK109 and UOK121 cells isolated eight different DNA fragments by methylation-sensitive arbitrarily primed polymerase chain reactions. It turned out that six of the fragments were hyper- and two of them were hypomethylated. Higher levels of DNA methyltransferase mRNA and enzyme activity were found.

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

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.

Causes

Organic arsenic is less harmful than inorganic arsenic. Seafood is a common source of the less toxic organic arsenic in the form of arsenobetaine. The arsenic reported in 2012 in fruit juice and rice by Consumer Reports was primarily inorganic arsenic. Because of its high toxicity, arsenic is seldom used in the Western world, although in Asia it is still a popular pesticide. Arsenic is mainly encountered occupationally in the smelting of zinc and copper ores.

Drinking water

Arsenic is naturally found in groundwater and presents serious health threats when high amounts exist. Chronic arsenic poisoning results from drinking contaminated well water over a long period of time. Many aquifers contain high concentration of arsenic salts. The World Health Organization (WHO) Guidelines for drinking water quality established in 1993 a provisional guideline value of 0.01 mg/L (10 parts per billion) for maximum contaminant levels of arsenic in drinking water. This recommendation was established based on the limit of detection for most laboratories' testing equipment at the time of publication of the WHO water quality guidelines. More recent findings show that consumption of water with levels as low as 0.00017 mg/L (0.17 parts per billion) over long periods of time can lead to arsenicosis.

From a 1988 study in China, the US protection agency quantified the lifetime exposure of arsenic in drinking water at concentrations of 0.0017 mg/L (1.7 ppb), 0.00017 mg/L, and 0.000017 mg/L are associated with a lifetime skin cancer risk of 1 in 10,000, 1 in 100,000, and 1 in 1,000,000 respectively. WHO asserts that a water level of 0.01 mg/L (10 ppb) poses a risk of 6 in 10,000 chance of lifetime skin cancer risk and contends that this level of risk is acceptable.

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" 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.

Mining techniques such as hydraulic fracturing may mobilize arsenic in groundwater and aquifers due to enhanced methane transport and resulting changes in redox conditions, and inject fluid containing additional arsenic.

Groundwater

Main article: Arsenic contamination of groundwater

In the US, the U.S. Geological Survey estimates that the median groundwater concentration is 1 μg/L or less, although some groundwater aquifers, particularly in the western United States, can contain much higher levels. For example, median levels in Nevada were about 8 μg/L but levels of naturally occurring arsenic as high as 1000 μg/L have been measured in the United States in drinking water.

Geothermally active zones occur at hotspots where mantle-derived plumes ascend, such as in Hawaii and Yellowstone National Park, US. Arsenic is an incompatible element (does not fit easily into the lattices of common rock-forming minerals). Concentrations of arsenic are high mainly in geothermal waters that leach continental rocks. Arsenic in hot geothermal fluids was shown to be derived mainly from leaching of host rocks at Yellowstone National Park, in Wyoming, US, rather than from magmas.

In the western US, there are As (arsenic) inputs to groundwater and surface water from geothermal fluids in and near Yellowstone National Park, and in other western mineralized areas. Groundwater associated with volcanics in California contain As at concentrations ranging up to 48,000 μg/L, with As-bearing sulfide minerals as the main source. Geothermal waters on Dominica in the Lesser Antilles also contain concentrations of As >50 μg/L.

In general, because arsenic is an incompatible element, it accumulates in differentiated magmas, and in other western mineralized areas. Weathering of pegmatite veins in Connecticut, US, was thought to contribute As to groundwater.

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.

In Pennsylvania, As concentrations in water discharging from abandoned anthracite mines ranged from <0.03 to 15 μg/L and from abandoned bituminous mines, from 0.10 to 64 μg/L, with 10% of samples exceeding the United States Environmental Protection Agency MLC of 10 μg/L.

In Wisconsin, As concentrations of water in sandstone and dolomite aquifers were as high as 100 μg/L. Oxidation of pyrite hosted by these formations was the likely source of the As.

In the Piedmont of Pennsylvania and New Jersey, groundwater in Mesozoic age aquifers contains elevated levels of As—domestic well waters from Pennsylvania contained up to 65 μg/L, whereas in New Jersey the highest concentration measured recently was 215 μg/L.

Food

In the United States, Schoof et al. estimated an average adult intake of 3.2 μg/day, with a range of 1–20 μg/day. Estimates for children were similar. Food also contains many organic arsenic compounds. The key organic arsenic compounds that can be routinely found in food (depending on food type) include monomethylarsonic acid (MMAsV), dimethylarsinic acid (DMAsV), arsenobetaine, arsenocholine, arsenosugars, and arsenolipids. DMAsV or MMAsV can be found in various types of fin fish, crabs, and mollusks, but often at very low levels.

Arsenobetaine is the major form of arsenic in marine animals, and, by all accounts, it is considered a compound that is nontoxic under conditions of human consumption. Arsenocholine, which is mainly found in shrimp, is chemically similar to arsenobetaine, and is considered to be "essentially nontoxic". Although arsenobetaine is little studied, available information indicates it is not mutagenic, immunotoxic, or embryotoxic.

Arsenosugars and arsenolipids have recently been identified. Exposure to these compounds and toxicological implications are currently being studied. Arsenosugars are detected mainly in seaweed but are also found to a lesser extent in marine mollusks. Studies addressing arsenosugar toxicity, however, have largely been limited to in vitro studies, which show that arsenosugars are significantly less toxic than both inorganic arsenic and trivalent methylated arsenic metabolites.

It has been found that rice is particularly susceptible to accumulation of arsenic from soil. Rice grown in the United States has an average 260 ppb of arsenic, according to a study; but U.S. arsenic intake remains far below World Health Organization-recommended limits. China has set a standard for arsenic limits in food (150 ppb), as levels in rice exceed those in water.

Arsenic is a ubiquitous element present in American drinking water. In the United States, levels of arsenic that are above natural levels, but still well below danger levels set in federal safety standards, have been detected in commercially raised chickens. The source of the arsenic appears to be the feed additives roxarsone and nitarsone, which are used to control the parasitic infection coccidiosis as well as to increase weight and skin coloring of the poultry.

High levels of inorganic arsenic were reportedly found in 83 California wines in 2015.

Soil

Exposure to arsenic in soil can occur through multiple pathways. Compared with the intake of naturally occurring arsenic from water and the diet, soil arsenic constitutes only a small fraction of intake.

Air

The European Commission (2000) reports that levels of arsenic in air range 0–1 ng/m³ in remote areas, 0.2–1.5 ng/m³ in rural areas, 0.5–3 ng/m³ in urban areas, and up to about 50 ng/m³ in the vicinity of industrial sites. Based on these data, the European Commission (2000) estimated that in relation to food, cigarette smoking, water, and soil, air contributes less than 1% of total arsenic exposure.

Pesticides

The use of lead arsenate pesticides has been effectively eliminated for over 50 years. However, because of the pesticide's environmental persistence, it is estimated that millions of acres of land are still contaminated with lead arsenate residues. This presents a potentially significant public health concern in some areas of the United States (e.g., New Jersey, Washington, and Wisconsin), where large areas of land used historically as orchards have been converted into residential developments.

Some modern uses of arsenic-based pesticides still exist. Chromated copper arsenate has been registered for use in the United States since the 1940s as a wood preservative, protecting wood from insects and microbial agents. In 2003, manufacturers of chromated copper arsenate instituted a voluntary recall of residential uses of wood treated with the chemical. The Environmental Protection Agency Act2008 final report stated that chromated copper arsenate is still approved for use in nonresidential applications, such as in marine facilities (pilings and structures), utility poles, and sand highway structures.

Copper smelting

Exposure studies in the copper smelting industry are much more extensive and have established definitive links between arsenic, a by-product of copper smelting, and lung cancer via inhalation. Dermal and neurological effects were also increased in some of these studies. Although as time went on, occupational controls became more stringent and workers were exposed to reduced arsenic concentrations, the arsenic exposures measured from these studies ranged from about 0.05 to 0.3 mg/m³ and are significantly higher than airborne environmental exposures to arsenic (which range from 0 to 0.000003 mg/m³).

Pathophysiology

Arsenic interferes with cellular longevity by allosteric inhibition of an essential metabolic enzyme pyruvate dehydrogenase complex, which catalyzes the oxidation of pyruvate to acetyl-CoA by NAD⁺. With the enzyme inhibited, the energy system of the cell is disrupted resulting in cellular apoptosis. Biochemically, arsenic prevents use of thiamine resulting in a clinical picture resembling thiamine deficiency. Poisoning with arsenic can raise lactate levels and lead to lactic acidosis. Low potassium levels in the cells increases the risk of experiencing a life-threatening heart rhythm problem from arsenic trioxide. Arsenic in cells clearly stimulates the production of hydrogen peroxide (H₂O₂). When the H₂O₂ reacts with certain metals such as iron or manganese it produces a highly reactive hydroxyl radical. Inorganic arsenic trioxide found in ground water particularly affects voltage-gated potassium channels, disrupting cellular electrolytic function resulting in neurological disturbances, cardiovascular episodes such as prolonged QT interval, neutropenia, high blood pressure, central nervous system dysfunction, anemia, and death.

Arsenic exposure plays a key role in the pathogenesis of vascular endothelial dysfunction as it inactivates endothelial nitric oxide synthase, leading to reduction in the generation and bioavailability of nitric oxide. In addition, the chronic arsenic exposure induces high oxidative stress, which may affect the structure and function of cardiovascular system. Further, the arsenic exposure has been noted to induce atherosclerosis by increasing the platelet aggregation and reducing fibrinolysis. Moreover, arsenic exposure may cause arrhythmia by increasing the QT interval and accelerating the cellular calcium overload. The chronic exposure to arsenic upregulates the expression of tumor necrosis factor-α, interleukin-1, vascular cell adhesion molecule and vascular endothelial growth factor to induce cardiovascular pathogenesis.

— Pitchai Balakumar and Jagdeep Kaur, "Arsenic Exposure and Cardiovascular Disorders: An Overview", Cardiovascular Toxicology, December 2009

Arsenic has also been shown to induce cardiac hypertrophy by activating certain transcription factors involved in pathologically remodeling the heart. Tissue culture studies have shown that arsenic compounds block both IKr and Iks channels and, at the same time, activate IK-ATP channels. Arsenic compounds also disrupt ATP production through several mechanisms. At the level of the citric acid cycle, arsenic inhibits pyruvate dehydrogenase and by competing with phosphate it uncouples oxidative phosphorylation, thus inhibiting energy-linked reduction of NAD+, mitochondrial respiration, and ATP synthesis. Hydrogen peroxide production is also increased, which might form reactive oxygen species and oxidative stress. These metabolic interferences lead to death from multi-system organ failure, probably from necrotic cell death, not apoptosis. A post mortem reveals brick red colored mucosa, due to severe hemorrhage. Although arsenic causes toxicity, it can also play a protective role.

Mechanism

Arsenite inhibits not only the formation of acetyl-CoA but also the enzyme succinic dehydrogenase. Arsenate can replace phosphate in many reactions. It is able to form Glc-6-arsenate in vitro; therefore it has been argued that hexokinase could be inhibited. (Eventually this may be a mechanism leading to muscle weakness in chronic arsenic poisoning.) In the glyceraldehyde 3-phosphate dehydrogenase reaction arsenate attacks the enzyme-bound thioester. The formed 1-arseno-3-phosphoglycerate is unstable and hydrolyzes spontaneously. Thus, ATP formation in glycolysis is inhibited while bypassing the phosphoglycerate kinase reaction. (Moreover, the formation of 2,3-bisphosphoglycerate in erythrocytes might be affected, followed by a higher oxygen affinity of hemoglobin and subsequently enhanced cyanosis.) As shown by Gresser (1981), submitochondrial particles synthesize adenosine-5'-diphosphate-arsenate from ADP and arsenate in presence of succinate. Thus, by a variety of mechanisms arsenate leads to an impairment of cell respiration and subsequently diminished ATP formation. This is consistent with observed ATP depletion of exposed cells and histopathological findings of mitochondrial and cell swelling, glycogen depletion in liver cells and fatty change in liver, heart and kidney.

Experiments demonstrated enhanced arterial thrombosis in a rat animal model, elevations of serotonin levels, thromboxane A[2] and adhesion proteins in platelets, while human platelets showed similar responses. The effect on vascular endothelium may eventually be mediated by the arsenic-induced formation of nitric oxide. It was demonstrated that +3 As concentrations substantially lower than concentrations required for inhibition of the lysosomal protease cathepsin L in B cell line TA3 were sufficient to trigger apoptosis in the same B cell line, while the latter could be a mechanism mediating immunosuppressive effects.

Kinetics

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. 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). 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. Resulting metabolites are monomethylarsonous acid, MMA(III), and dimethylarsinous acid, DMA(III).

Methylation had been regarded as a detoxification process, but reduction from +5 As to +3 As may be considered as a bioactivation instead. 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. Gebel (2002) stated that methylation is a detoxification through accelerated excretion. With regard to carcinogenicity it has been suggested that methylation should be regarded as a toxification.

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. Arsenite inhibits members of the disulfide oxidoreductase family like glutathione reductase and thioredoxin reductase.

The remaining unbound arsenic (≤ 10%) accumulates in cells, which over time may lead to skin, bladder, kidney, liver, lung, and prostate cancers. 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.

Heat shock response

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. Via JNK and p38 it activates c-fos, c-jun and egr-1 which are usually activated by growth factors and cytokines. 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. Germolec et al. (1996) found an increased cytokine expression and cell proliferation in skin biopsies from individuals chronically exposed to arsenic-contaminated drinking water.

Increased AP-1 and NF-κB obviously also result in an up-regulation of mdm2 protein, which decreases p53 protein levels. 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. The authors conclude that the former may be interpreted as a defense response while the latter could lead to carcinogenesis. 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.

Oxidative stress

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, as well as the pro-inflammatory cytokines IL-8 and TNF-α. 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. 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.

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

Diagnosis

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.

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. 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.

Treatment

Chelation

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. Dimercaptosuccinic acid monoesters, e.g. MiADMSA, are promising antidotes for arsenic poisoning.

Nutrition

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

History

See also: Arsenic poisoning cases

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.

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. 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.

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.

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. 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. 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".

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. 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.

Legislation

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).

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.

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.

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.

Challenges to implementation

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.

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.

Pregnancy

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

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

Studies have shown that ingesting arsenic through groundwater during pregnancy poses dangers to the mother including, but not limited to abdominal pain, vomiting, diarrhea, skin pigmentation changes, and cancer. 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. Some of these effects, like lower birth-rate and size may be due to the effects of arsenic on maternal weight gain during pregnancy.

Iceberg

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Iceberg

An iceberg in the Arctic Ocean

An iceberg is a piece of freshwater ice more than 15 m long that has broken off a glacier or an ice shelf and is floating freely in open (salt) water.  Smaller chunks of floating glacially-derived ice are called "growlers" or "bergy bits". The sinking of the Titanic in 1912 led to the formation of the International Ice Patrol in 1914. Much of an iceberg is below the water's surface, which led to the expression "tip of the iceberg" to illustrate a small part of a larger unseen issue. Icebergs are considered a serious maritime hazard.

Icebergs vary considerably in size and shape. Icebergs that calve from glaciers in Greenland are often irregularly shaped while Antarctic ice shelves often produce large tabular (table top) icebergs. The largest iceberg in recent history, named B-15, was measured at nearly 300 by 40 kilometres (186 by 25 mi) in 2000. The largest iceberg on record was an Antarctic tabular iceberg measuring 335 by 97 kilometres (208 by 60 mi) sighted 240 kilometres (150 mi) west of Scott Island, in the South Pacific Ocean, by the USS Glacier on November 12, 1956. This iceberg was larger than Belgium.

Etymology

The word iceberg is a partial loan translation from the Dutch word ijsberg, literally meaning ice mountain, cognate to Danish isbjerg, German Eisberg, Low Saxon Iesbarg and Swedish isberg.

Overview

Typically about one-tenth of the volume of an iceberg is above water, which follows from Archimedes's Principle of buoyancy; the density of pure ice is about 920 kg/m³ (57 lb/cu ft), and that of seawater about 1,025 kg/m³ (64 lb/cu ft). The contour of the underwater portion can be difficult to judge by looking at the portion above the surface.

Northern edge of Iceberg B-15A in the Ross Sea, Antarctica, 29 January 2001

Iceberg size classifications according to the International Ice Patrol

Size class	Height (m)	Length (m)
Growler	<1	<5
Bergy bit	1–5	5–15
Small	5–15	15–60
Medium	15–45	60–122
Large	45–75	122–213
Very large	>75	>213

The largest icebergs recorded have been calved, or broken off, from the Ross Ice Shelf of Antarctica. Icebergs may reach a height of more than 100 metres (300 ft) above the sea surface and have mass ranging from about 100,000 tonnes up to more than 10 million tonnes. Icebergs or pieces of floating ice smaller than 5 meters above the sea surface are classified as "bergy bits"; smaller than 1 meter—"growlers". The largest known iceberg in the North Atlantic was 168 metres (551 ft) above sea level, reported by the USCG icebreaker Eastwind in 1958, making it the height of a 55-story building. These icebergs originate from the glaciers of western Greenland and may have interior temperatures of −15 to −20 °C (5 to −4 °F).

Grotto in an iceberg, photographed during the British Antarctic Expedition of 1911–1913, 5 Jan 1911

Drift

A given iceberg's trajectory through the ocean can be modelled by integrating the equation

${\displaystyle m\frac{d\overrightarrow{v}}{dt}=-mf\overrightarrow{k}\times \overrightarrow{v}+{\overrightarrow{F}}_{\text{a}}+{\overrightarrow{F}}_{\text{w}}+{\overrightarrow{F}}_{\text{r}}+{\overrightarrow{F}}_{\text{s}}+{\overrightarrow{F}}_{\text{p}},}$

where m is the iceberg mass, v the drift velocity, and the variables f, k, and F correspond to the Coriolis force, the vertical unit vector, and a given force. The subscripts a, w, r, s, and p correspond to the air drag, water drag, wave radiation force, sea ice drag, and the horizontal pressure gradient force.

Icebergs deteriorate through melting and fracturing, which changes the mass m, as well as the surface area, volume, and stability of the iceberg. Iceberg deterioration and drift, therefore, are interconnected iceberg thermodynamics, and fracturing must be considered when modelling iceberg drift.

Winds and currents may move icebergs close to coastlines, where they can become frozen into pack ice (one form of sea ice), or drift into shallow waters, where they can come into contact with the seabed, a phenomenon called seabed gouging.

Bubbles

Air trapped in snow forms bubbles as the snow is compressed to form firn and then glacial ice. Icebergs can contain up to 10% air bubbles by volume. These bubbles are released during melting, producing a fizzing sound that some may call "Bergie Seltzer". This sound results when the water-ice interface reaches compressed air bubbles trapped in the ice. As each bubble bursts it makes a "popping" sound and the acoustic properties of these bubbles can be used to study iceberg melt.

Stability

An iceberg may flip, or capsize, as it melts and breaks apart, changing the center of gravity. Capsizing can occur shortly after calving when the iceberg is young and establishing balance. Icebergs are unpredictable and can capsize anytime and without warning. Large icebergs that break off from a glacier front and flip onto the glacier face can push the entire glacier backwards momentarily, producing 'glacial earthquakes' that generate as much energy as an atomic bomb.

Color

Icebergs are generally white because they are covered in snow, but can be green, blue, yellow, black, striped, or even rainbow-colored. Seawater, algae and lack of air bubbles in the ice can create diverse colors. Sediment can create the dirty black coloration present in some icebergs.

Shape

Different shapes of icebergs

Tabular iceberg, near Brown Bluff in the Antarctic Sound off Tabarin Peninsula

In addition to size classification (Table 1), icebergs can be classified on the basis of their shapes. The two basic types of iceberg forms are tabular and non-tabular. Tabular icebergs have steep sides and a flat top, much like a plateau, with a length-to-height ratio of more than 5:1.

This type of iceberg, also known as an ice island, can be quite large, as in the case of Pobeda Ice Island. Antarctic icebergs formed by breaking off from an ice shelf, such as the Ross Ice Shelf or Filchner–Ronne Ice Shelf, are typically tabular. The largest icebergs in the world are formed this way.

Non-tabular icebergs have different shapes and include:

• Dome: An iceberg with a rounded top.
• Pinnacle: An iceberg with one or more spires.
• Wedge: An iceberg with a steep edge on one side and a slope on the opposite side.
• Dry-dock: An iceberg that has eroded to form a slot or channel.
• Blocky: An iceberg with steep, vertical sides and a flat top. It differs from tabular icebergs in that its aspect ratio, the ratio between its width and height, is small, more like that of a block than a flat sheet.

Monitoring and control

History

One of the icebergs suspected of sinking the RMS Titanic; a smudge of red paint much like the Titanic's red hull stripe was seen near its base at the waterline.

Prior to 1914 there was no system in place to track icebergs to guard ships against collisions. Despite fatal sinkings of ships by icebergs. In 1907, SS Kronprinz Wilhelm, a German liner, rammed an iceberg and suffered a crushed bow, but was still able to complete her voyage. The advent of water tight compartmentalization in ship construction led designers to declare their ships "unsinkable".

The April 1912 sinking of the Titanic, which killed more than 1,500 of its estimated 2,224 passengers and crew, discredited this claim. For the remainder of the ice season of that year, the United States Navy patrolled the waters and monitored ice movements. In November 1913, the International Conference on the Safety of Life at Sea met in London to devise a more permanent system of observing icebergs. Within three months the participating maritime nations had formed the International Ice Patrol (IIP). The goal of the IIP was to collect data on meteorology and oceanography to measure currents, ice-flow, ocean temperature, and salinity levels. They monitored iceberg dangers near the Grand Banks of Newfoundland and provided the "limits of all known ice" in that vicinity to the maritime community. The IIP published their first records in 1921, which allowed for a year-by-year comparison of iceberg movement.

Technological development

An iceberg being pushed by three U.S. Navy ships in McMurdo Sound, Antarctica

Aerial surveillance of the seas in the early 1930s allowed for the development of charter systems that could accurately detail the ocean currents and iceberg locations. In 1945, experiments tested the effectiveness of radar in detecting icebergs. A decade later, oceanographic monitoring outposts were established for the purpose of collecting data; these outposts continue to serve in environmental study. A computer was first installed on a ship for the purpose of oceanographic monitoring in 1964, which allowed for a faster evaluation of data. By the 1970s, ice-breaking ships were equipped with automatic transmissions of satellite photographs of ice in Antarctica. Systems for optical satellites had been developed but were still limited by weather conditions. In the 1980s, drifting buoys were used in Antarctic waters for oceanographic and climate research. They are equipped with sensors that measure ocean temperature and currents.

Side looking airborne radar (SLAR) made it possible to acquire images regardless of weather conditions. On November 4, 1995, Canada launched RADARSAT-1. Developed by the Canadian Space Agency, it provides images of Earth for scientific and commercial purposes. This system was the first to use synthetic aperture radar (SAR), which sends microwave energy to the ocean surface and records the reflections to track icebergs. The European Space Agency launched ENVISAT (an observation satellite that orbits the Earth's poles) on March 1, 2002. ENVISAT employs advanced synthetic aperture radar (ASAR) technology, which can detect changes in surface height accurately. The Canadian Space Agency launched RADARSAT-2 in December 2007, which uses SAR and multi-polarization modes and follows the same orbit path as RADARSAT-1.

Modern monitoring

Iceberg concentrations and size distributions are monitored worldwide by the U.S. National Ice Center (NIC), established in 1995, which produces analyses and forecasts of Arctic, Antarctic, Great Lakes and Chesapeake Bay ice conditions. More than 95% of the data used in its sea ice analyses are derived from the remote sensors on polar-orbiting satellites that survey these remote regions of the Earth.

Iceberg A22A in the South Atlantic Ocean

The NIC is the only organization that names and tracks all Antarctic Icebergs. It assigns each iceberg larger than 10 nautical miles (19 km) along at least one axis a name composed of a letter indicating its point of origin and a running number. The letters used are as follows:

A – longitude 0° to 90° W (Bellingshausen Sea, Weddell Sea)

B – longitude 90° W to 180° (Amundsen Sea, Eastern Ross Sea)

C – longitude 90° E to 180° (Western Ross Sea, Wilkes Land)

D – longitude 0° to 90° E (Amery Ice Shelf, Eastern Weddell Sea)

The Danish Meteorological Institute monitors iceberg populations around Greenland using data collected by the synthetic aperture radar (SAR) on the Sentinel-1 satellites.

Iceberg management

In Labrador and Newfoundland, iceberg management plans have been developed to protect offshore installations from impacts with icebergs.

Commercial use

In the late 2010s, a business from the UAE wanted to tow an iceberg from Antarctica to the Middle East, but the plan failed as the estimated cost of $200 million was too high. In 2019, a German company, Polewater, announced plans to tow Antarctic icebergs to places like South Africa.

Companies have used iceberg water in products such as bottled water, fizzy ice cubes and alcoholic drinks. For example, Iceberg Beer by Quidi Vidi Brewing Company is made from icebergs found around St. John's, Newfoundland. Although annual iceberg supply in Newfoundland and Labrador exceeds the total freshwater consumption of the United States, in 2016 the province introduced a tax on iceberg harvesting and imposed a limit on how much fresh water can be exported yearly.

Oceanography and ecology

Icebergs in Disko Bay

The freshwater injected into the ocean by melting icebergs can change the density of the seawater in the vicinity of the iceberg. Fresh melt water released at depth is lighter, and therefore more buoyant, than the surrounding seawater causing it to rise towards the surface. Icebergs can also act as floating breakwaters, impacting ocean waves.

Icebergs contain variable concentrations of nutrients and minerals that are released into the ocean during melting. Iceberg-derived nutrients, particularly the iron contained in sediments, can fuel blooms of phytoplankton. Samples collected from icebergs in Antarctica, Patagonia, Greenland, Svalbard, and Iceland, however, show that iron concentrations vary significantly, complicating efforts to generalize the impacts of icebergs on marine ecosystems.

Recent large icebergs

The calving of Iceberg A-38 off Filchner-Ronne Ice Shelf

Iceberg B15 calved from the Ross Ice Shelf in 2000 and initially had an area of 11,000 square kilometres (4,200 sq mi). It broke apart in November 2002. The largest remaining piece of it, Iceberg B-15A, with an area of 3,000 square kilometres (1,200 sq mi), was still the largest iceberg on Earth until it ran aground and split into several pieces October 27, 2005, an event that was observed by seismographs both on the iceberg and across Antarctica. It has been hypothesized that this breakup may also have been abetted by ocean swell generated by an Alaskan storm 6 days earlier and 13,500 kilometres (8,400 mi) away.

• 1987, Iceberg B-9, 5,390 km² (2,080 sq mi)
• 1998, Iceberg A-38, about 6,900 km² (2,700 sq mi)
• 1999, Iceberg B-17B 140 km² (54 sq mi), shipping alert issued December 2009.
• 2000, Iceberg B-15 11,000 km² (4,200 sq mi)
• 2002, Iceberg C-19, 5,500 km² (2,100 sq mi)
• 2002, Iceberg B-22, 5,490 km² (2,120 sq mi)
• 2003 broke off, Iceberg B-15A, 3,100 km² (1,200 sq mi)
• 2006, Iceberg D-16, 310 km² (120 sq mi)
• 2010, Ice sheet, 260 km² (100 sq mi), broken off of Petermann Glacier in northern Greenland on August 5, 2010, considered to be the largest Arctic iceberg since 1962. About a month later, this iceberg split into two pieces upon crashing into Joe Island in the Nares Strait next to Greenland. In June 2011, large fragments of the Petermann Ice Islands were observed off the Labrador coast.
• 2014, Iceberg B-31, 615 km² (237 sq mi), 2014
• 2017, Iceberg A-68, (Larsen C) 5,800 km² (2,200 sq mi)
• 2018, Iceberg B-46, 225 km² (87 sq mi)
• 2019, Iceberg D-28, 1,636 km² (632 sq mi)
• 2021, Iceberg A-74 from the Brunt Ice Shelf, 1,270 km² (490 sq mi)
• 2021, Iceberg A-76 from the Ronne Ice Shelf, 4,320 km² (1,670 sq mi)

In culture

One of the most prominently known icebergs in recorded history is that which sank the Titanic on 15 April 1912. Icebergs in both the northern and southern hemispheres have often been compared in size to multiples of the 59.1 square kilometres (22.8 sq mi)-area of Manhattan Island.

Exoskeleton

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Exoskeleton

Discarded exoskeleton (exuviae) of dragonfly nymph

Exoskeleton of cicada attached to a Tridax procumbens (colloquially known as the tridax daisy)

An exoskeleton (from Greek έξω éxō "outer" and σκελετός skeletós "skeleton") is an external skeleton that supports and protects an animal's body, in contrast to an internal skeleton (endoskeleton) in for example, a human. Some large exoskeletons are known as "shells". Examples of exoskeletons within animals include the arthropod exoskeleton shared by chelicerates, myriapods, crustaceans, and insects, as well as the shell of certain sponges and the mollusc shell shared by snails, clams, tusk shells, chitons, and nautilus. Some animals, such as the turtle, have both an endoskeleton and an exoskeleton.

Role

Exoskeletons contain rigid and resistant components that fulfill a set of functional roles in many animals including protection, excretion, sensing, support, feeding, and acting as a barrier against desiccation in terrestrial organisms. Exoskeletons have roles in defense from pests and predator and in providing an attachment framework for musculature.

Arthropod exoskeletons contain chitin; the addition of calcium carbonate makes them harder and stronger, at the price of increased weight. Ingrowths of the arthropod exoskeleton known as apodemes serve as attachment sites for muscles. These structures are composed of chitin and are approximately six times stronger and twice the stiffness of vertebrate tendons. Similar to tendons, apodemes can stretch to store elastic energy for jumping, notably in locusts. Calcium carbonates constitute the shells of molluscs, brachiopods, and some tube-building polychaete worms. Silica forms the exoskeleton in the microscopic diatoms and radiolaria. One mollusk species, the scaly-foot gastropod, even uses the iron sulfides greigite and pyrite.

Some organisms, such as some foraminifera, agglutinate exoskeletons by sticking grains of sand and shell to their exterior. Contrary to a common misconception, echinoderms do not possess an exoskeleton and their test is always contained within a layer of living tissue.

Exoskeletons have evolved independently many times; 18 lineages evolved calcified exoskeletons alone. Further, other lineages have produced tough outer coatings, such as some mammals, that are analogous to an exoskeleton. This coating is constructed from bone in the armadillo, and hair in the pangolin. The armor of reptiles like turtles and dinosaurs like Ankylosaurs is constructed of bone; crocodiles have bony scutes and horny scales.

Growth

Main article: Ecdysis

Since exoskeletons are rigid, they present some limits to growth. Organisms with open shells can grow by adding new material to the aperture of their shell, as is the case in snails, bivalves, and other molluscans. A true exoskeleton, like that found in arthropods, must be shed (molted) when it is outgrown. A new exoskeleton is produced beneath the old one. The new skeleton is soft and pliable as the old one is shed. The animal will typically stay in a den or burrow for this time, as it is quite vulnerable during this period. Once at least partially set, the organism will plump itself up to try to expand the exoskeleton. The new exoskeleton is still capable of growing to some degree, however. In contrast, molting reptiles shed only the outer layer of skin and often exhibit indeterminate growth. These animals produce new skin and integuments throughout their life, replacing it according to growth. Arthropod growth, however, is limited by the space within its current exoskeleton. Failure to shed the exoskeleton once outgrown can result in the animal's death or prevent subadults from reaching maturity, thus preventing them from reproducing. This is the mechanism behind some insect pesticides, such as Azadirachtin.

Paleontological significance

Borings in exoskeletons can provide evidence of animal behavior. In this case, boring sponges attacked this hard clam shell after the death of the clam, producing the trace fossil Entobia.

Exoskeletons, as hard parts of organisms, are greatly useful in assisting the preservation of organisms, whose soft parts usually rot before they can be fossilized. Mineralized exoskeletons can be preserved as shell fragments. The possession of an exoskeleton permits a couple of other routes to fossilization. For instance, the strong layer can resist compaction, allowing a mold of the organism to be formed underneath the skeleton, which may later decay. Alternatively, exceptional preservation may result in chitin being mineralized, as in the Burgess Shale, or transformed to the resistant polymer keratin, which can resist decay and be recovered.

However, our dependence on fossilized skeletons also significantly limits our understanding of evolution. Only the parts of organisms that were already mineralized are usually preserved, such as the shells of molluscs. It helps that exoskeletons often contain "muscle scars", marks where muscles have been attached to the exoskeleton, which may allow the reconstruction of much of an organism's internal parts from its exoskeleton alone. The most significant limitation is that, although there are 30-plus phyla of living animals, two-thirds of these phyla have never been found as fossils, because most animal species are soft-bodied and decay before they can become fossilized.

Mineralized skeletons first appear in the fossil record shortly before the base of the Cambrian period, 550 million years ago. The evolution of a mineralized exoskeleton is considered a possible driving force of the Cambrian explosion of animal life, resulting in a diversification of predatory and defensive tactics. However, some Precambrian (Ediacaran) organisms produced tough outer shells while others, such as Cloudina, had a calcified exoskeleton. Some Cloudina shells even show evidence of predation, in the form of borings.

Evolution

Further information: Small shelly fauna

The fossil record primarily contains mineralized exoskeletons, since these are by far the most durable. Since most lineages with exoskeletons are thought to have started with a non-mineralized exoskeleton which they later mineralized, it is difficult to comment on the very early evolution of each lineage's exoskeleton. It is known, however, that in a very short course of time, just before the Cambrian period, exoskeletons made of various materials – silica, calcium phosphate, calcite, aragonite, and even glued-together mineral flakes – sprang up in a range of different environments. Most lineages adopted the form of calcium carbonate which was stable in the ocean at the time they first mineralized, and did not change from this mineral morph - even when it became less favorable.

Some Precambrian (Ediacaran) organisms produced tough but non-mineralized outer shells, while others, such as Cloudina, had a calcified exoskeleton, but mineralized skeletons did not become common until the beginning of the Cambrian period, with the rise of the "small shelly fauna". Just after the base of the Cambrian, these miniature fossils become diverse and abundant – this abruptness may be an illusion since the chemical conditions which preserved the small shells appeared at the same time. Most other shell-forming organisms appear during the Cambrian period, with the Bryozoans being the only calcifying phylum to appear later, in the Ordovician. The sudden appearance of shells has been linked to a change in ocean chemistry which made the calcium compounds of which the shells are constructed stable enough to be precipitated into a shell. However, this is unlikely to be a sufficient cause, as the main construction cost of shells is in creating the proteins and polysaccharides required for the shell's composite structure, not in the precipitation of the mineral components. Skeletonization also appeared at almost the same time that animals started burrowing to avoid predation, and one of the earliest exoskeletons was made of glued-together mineral flakes, suggesting that skeletonization was likewise a response to increased pressure from predators.

Ocean chemistry may also control which mineral shells are constructed of. Calcium carbonate has two forms, the stable calcite and the metastable aragonite, which is stable within a reasonable range of chemical environments but rapidly becomes unstable outside this range. When the oceans contain a relatively high proportion of magnesium compared to calcium, aragonite is more stable, but as the magnesium concentration drops, it becomes less stable, hence harder to incorporate into an exoskeleton, as it will tend to dissolve.

Except for the molluscs, whose shells often comprise both forms, most lineages use just one form of the mineral. The form used appears to reflect the seawater chemistry – thus which form was more easily precipitated – at the time that the lineage first evolved a calcified skeleton, and does not change thereafter. However, the relative abundance of calcite- and aragonite-using lineages does not reflect subsequent seawater chemistry – the magnesium/calcium ratio of the oceans appears to have a negligible impact on organisms' success, which is instead controlled mainly by how well they recover from mass extinctions. A recently discovered modern gastropod Chrysomallon squamiferum that lives near deep-sea hydrothermal vents illustrates the influence of both ancient and modern local chemical environments: its shell is made of aragonite, which is found in some of the earliest fossil mollusks; but it also has armor plates on the sides of its foot, and these are mineralized with the iron sulfides pyrite and greigite, which had never previously been found in any metazoan but whose ingredients are emitted in large quantities by the vents.