Sarin, or GB (G-series, 'B'), is a colorless, odorless liquid, used as a chemical weapon due to its extreme potency as a nerve agent. It is generally considered a weapon of mass destruction. Production and stockpiling of sarin was outlawed as of April 1997 by the Chemical Weapons Convention of 1993, and it is classified as a Schedule 1 substance. In June 1994, the UN Special Commission on Iraqi disarmament destroyed the nerve agent sarin under Security Council resolution 687 (1991) concerning the disposal of Iraq's weapons of mass destruction.
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Sarin is an organophosphorus compound with the formula [(CH3)2CHO]CH3P(O)F. It can be lethal even at very low concentrations, where death can occur within one[7][8] to ten minutes after direct inhalation of a lethal dose, due to suffocation from lung muscle paralysis, unless some antidotes, typically atropine and an oxime, such as pralidoxime, are quickly administered.[5] People who absorb a non-lethal dose, but do not receive immediate medical treatment, may suffer permanent neurological damage.
Health effects
Sarin (red), acetylcholinesterase (yellow), acetylcholine (blue)
Like all other nerve agents, sarin attacks the nervous system by interfering with the degradation of the neurotransmitter acetylcholine at neuromuscular junctions. Death will usually occur as a result of asphyxia due to the inability to control the muscles involved in breathing function.
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Initial symptoms following exposure to sarin are a runny nose, tightness in the chest and constriction of the pupils. Soon after, the person will have difficulty breathing and they will experience nausea and drooling. As they continue to lose control of bodily functions, they may vomit, defecate and urinate. This phase is followed by twitching and jerking. Ultimately, the person becomes comatose and suffocates in a series of convulsive spasms. Moreover, common mnemonics for the symptomatology of organophosphate poisoning, including sarin gas, are the "killer B's" of bronchorrhea and bronchospasm because they are the leading cause of death,[9] and SLUDGE – salivation, lacrimation, urination, defecation, gastrointestinal distress, and emesis. Death may follow in 1 to 10 minutes after direct inhalation.
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Sarin has a high volatility (ease with which a liquid can turn into a gas) relative to similar nerve agents, therefore inhalation can be very dangerous and even vapor concentrations may immediately penetrate the skin. A person’s clothing can release sarin for about 30 minutes after it has come in contact with sarin gas, which can lead to exposure of other people.[10]
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Management
Treatment measures have been described.[10] Treatment is typically with the antidotes, atropine and pralidoxime.[5] Atropine, an antagonist to muscarinic acetylcholine receptors, is given to treat the physiological symptoms of poisoning. Since muscular response to acetylcholine is mediated through nicotinic acetylcholine receptors, atropine does not counteract the muscular symptoms. Pralidoxime can regenerate cholinesterases if administered within approximately five hours. Biperiden, a synthetic acetylcholine antagonist, has been suggested as an alternative to atropine due to its better blood–brain barrier penetration and higher efficacy.[11]
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Mechanism of action
Specifically, sarin is a potent inhibitor of acetylcholinesterase,[12] an enzyme that degrades the neurotransmitter acetylcholine after it is released into the synaptic cleft. In vertebrates, acetylcholine is the neurotransmitter used at the neuromuscular junction, where signals are transmitted between neurons from the central nervous systems to muscle fibres. Normally, acetylcholine is released from the neuron to stimulate the muscle, after which it is degraded by acetylcholinesterase, allowing the muscle to relax. A build-up of acetylcholine in the synaptic cleft, due to the inhibition of cholinesterase, means the neurotransmitter continues to act on the muscle fibre, so that any nerve impulses are effectively continually transmitted.
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Sarin acts on cholinesterase by forming a covalent bond with the particular serine residue at the active site. Fluoride is the leaving group, and the resulting phosphoester is robust and biologically inactive.[13][14]
Its mechanism of action resembles that of some commonly used insecticides, such as malathion. In terms of biological activity, it resembles carbamate insecticides, such as Sevin, and the medicines pyridostigmine, neostigmine, and physostigmine.
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Diagnostic tests
Controlled studies in healthy men have shown that a nontoxic 0.43 mg oral dose administered in several portions over a 3-day interval caused average maximum depressions of 22 and 30%, respectively, in plasma and erythrocyte cholinesterase levels. A single acute 0.5 mg dose caused mild symptoms of intoxication and an average reduction of 38% in both measures of cholinesterase activity. Sarin in blood is rapidly degraded either in vivo or in vitro. Its primary inactive metabolites have in vivo serum half-lives of approximately 24 hours. The serum level of unbound isopropylmethylphosphonic acid (IMPA), a sarin hydrolysis product, ranged from 2-135 µg/L in survivors of a terrorist attack during the first 4 hours post-exposure. Sarin or its metabolites may be determined in blood or urine by gas or liquid chromatography, while cholinesterase activity is usually measured by enzymatic methods.[15]
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A newer method called "fluoride regeneration" or "fluoride reactivation" detects the presence of nerve agents for a longer period after exposure than the methods described above. Fluoride reactivation is a technique that has been explored since at least the early 2000s. This technique obviates some of the deficiencies of older procedures. Sarin not only reacts with the water in the blood plasma through hydrolysis (forming so-called ‘free metabolites’), but also reacts with various proteins to form ‘protein adducts’. These protein adducts are not so easily removed from the body, and remain for a longer period of time than the free metabolites. One clear advantage of this process is that the period, post-exposure, for determination of Sarin exposure is much longer, possibly 5 to 8 weeks according to at least one study.[16][17]
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Toxicity
As a nerve gas, sarin in its purest form is estimated to be 26 times more deadly than cyanide.[18] The LD50 of subcutaneously injected sarin in mice is 172 μg/kg.[19]
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Sarin is highly toxic, whether by contact with the skin or breathed in. The toxicity of sarin in humans is largely based on calculations from studies with animals. The lethal concentration of sarin in air is approximately 35 mg per cubic meter per minute for a two-minute exposure time by a healthy adult breathing normally (exchanging 15 liters of air per minute). This number represents the estimated lethal concentration for 50% of exposed victims, the LCt50 value.
There are many ways to make relative comparisons between toxic substances. The list below compares some current and historic chemical warfare agents with sarin, with a direct comparison to the respiratory Lct50:
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Hydrogen cyanide, 2860 mg-min/cubic meter[20] – sarin is 81 times more lethal
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Phosgene, 1500 mg-min/cubic meter[20] – sarin is 43 times more lethal
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Sulfur mustard, 1000 mg-min/cubic meter[20] – sarin is 28 times more lethal
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Chlorine, 19000 mg-min/cubic meter[21] – sarin is 543 times more lethal
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