Sarin (NATO designation GB [short for G-series, "B"]), is an extremely toxic synthetic organophosphorus compound. A colorless, odorless liquid, it is used as a chemical weapon due to its extreme potency as a nerve agent. Exposure is lethal even at very low concentrations, where death can occur within one to ten minutes after direct inhalation of a lethal dose, due to suffocation from lung muscle paralysis, unless antidotes are quickly administered. People who absorb a non-lethal dose, but do not receive immediate medical treatment, may suffer permanent neurological damage.
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 Bs" of bronchorrhea and bronchospasm because they are the leading cause of death, and SLUDGE - salivation, lacrimation, urination, defecation, gastrointestinal distress, and emesis (vomiting). Death may follow in one to ten minutes after direct inhalation.
Sarin has a high volatility (ease with which a liquid can turn into a gas) relative to similar nerve agents, therefore inhalation is very easy and even vapor 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.
Specifically, sarin is a potent inhibitor of acetylcholinesterase, an enzyme that degrades the neurotransmitteracetylcholine 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 system 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 acetylcholinesterase, means the neurotransmitter continues to act on the muscle fibre, so that any nerve impulses are effectively continually transmitted.
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 acetylcholinesterase levels. A single acute 0.5 mg dose caused mild symptoms of intoxication and an average reduction of 38% in both measures of acetylcholinesterase 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 isopropyl methylphosphonic acid (IMPA), a sarin hydrolysis product, ranged from 2-135 µg/L in survivors of a terrorist attack during the first four hours post-exposure. Sarin or its metabolites may be determined in blood or urine by gas or liquid chromatography, while acetylcholinesterase activity is usually measured by enzymatic methods.
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 five to eight weeks according to at least one study.
As a nerve gas, sarin in its purest form is estimated to be 26 times more deadly than cyanide. The LD50 of subcutaneously injected sarin in mice is 172 ?g/kg.
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 sarin to some current and historic chemical warfare agents, with a direct comparison to the respiratory LCt50:
It is usually manufactured and weaponized as a racemic mixture--an equal mixture of both enantiomeric forms, as this is a simpler process and provides an adequate weapon.
A number of production pathways can be used to create sarin. The final reaction typically involves attachment of the isopropoxy group to the phosphorus with an alcoholysis with isopropyl alcohol. Two variants of this process are common. One is the reaction of methylphosphonyl difluoride with isopropyl alcohol, which produces hydrofluoric acid as a byproduct:
The scheme below describes an example of Di-Di process. The selection of reagents is arbitrary and reaction conditions and product yield depend on the selected reagents. Inert atmosphere and anhydrous conditions are used for synthesis of sarin and other organophosphates.
As both reactions leave considerable acid in the product, bulk sarin produced without further treatment has a very poor shelf life and would be rather destructive to containers or weapon systems. Various methods have been tried to resolve these problems. In addition to industrial refining techniques to purify the chemical itself, various additives have been tried to combat the effects of the acid, such as:
Isopropylamine was included as part of the M687 155 mm field artillery shell, which was a binary sarin weapon system developed by the US Army.
Another byproduct of these two chemical processes is diisopropyl methylphosphonate, formed when a second isopropyl alcohol reacts with the sarin itself. This chemical degrades into isopropyl methylphosphonic acid.
The most important chemical reactions of phosphoryl halides is the hydrolysis of the bond between phosphorus and the fluoride. This P-F bond is easily broken by nucleophilic agents, such as water and hydroxide. At high pH, sarin decomposes rapidly to nontoxic phosphonic acid derivatives. The initial breakdown of sarin is into isopropyl methylphosphonic acid (IMPA), a chemical that is not commonly found in nature except as a breakdown product of sarin (this is useful for detecting the recent deployment of sarin as a weapon). IMPA then degrades into methylphosphonic acid (MPA), which can also be produced by other organophosphates.
Sarin with residual acid degrades after a period of several weeks to several months. The shelf life can be shortened by impurities in precursor materials. According to the CIA, some Iraqi sarin had a shelf life of only a few weeks, owing mostly to impure precursors.
Along with nerve agents such as tabun and VX, sarin can have a short shelf life. Therefore, it is usually stored as two separate precursors that produce sarin when combined. Sarin's shelf life can be extended by increasing the purity of the precursor and intermediates and incorporating stabilizers such as tributylamine. In some formulations, tributylamine is replaced by diisopropylcarbodiimide (DIC), allowing sarin to be stored in aluminium casings. In binary chemical weapons, the two precursors are stored separately in the same shell and mixed to form the agent immediately before or when the shell is in flight. This approach has the dual benefit of solving the stability issue and increasing the safety of sarin munitions.
Sarin was discovered in 1938 in Wuppertal-Elberfeld in Germany by scientists at IG Farben who were attempting to create stronger pesticides; it is the most toxic of the four G-Series nerve agents made by Germany. The compound, which followed the discovery of the nerve agenttabun, was named in honor of its discoverers: Schrader, Ambros, Gerhard Ritter, and von der Linde.
Use as a weapon
In mid-1939, the formula for the agent was passed to the chemical warfare section of the German Army Weapons Office, which ordered that it be brought into mass production for wartime use. Pilot plants were built, and a high-production facility was under construction (but was not finished) by the end of World War II. Estimates for total sarin production by Nazi Germany range from 500 kg to 10 tons. Though sarin, tabun and soman were incorporated into artillery shells, Germany did not use nerve agents against Allied targets.
Sarin gas used against animals in a weapons experiment.
1950s (early): NATO adopted sarin as a standard chemical weapon, and both the USSR and the United States produced sarin for military purposes.
1953: 20-year-old Ronald Maddison, a Royal Air Force engineer from Consett, County Durham, died in human testing of sarin at the Porton Down chemical warfare testing facility in Wiltshire, England. Ten days after his death an inquest was held in secret which returned a verdict of misadventure. In 2004, the inquest was reopened and, after a 64-day inquest hearing, the jury ruled that Maddison had been unlawfully killed by the "application of a nerve agent in a non-therapeutic experiment".
1957: Regular production of sarin chemical weapons ceased in the United States, though existing stocks of bulk sarin were re-distilled until 1970.
1976: Chile's intelligence service, DINA, assigned biochemist Eugenio Berríos to develop Sarin gas within its program Proyecto Andrea, to be used as a weapon against its opponents. One of DINA's goals was to package it in spray cans for easy use, which, according to testimony by former DINA agent Michael Townley, was one of the planned procedures in the 1976 assassination of Orlando Letelier. Berríos later testified that it was used in a number of assassinations.
1993: The United Nations Chemical Weapons Convention was signed by 162 member countries, banning the production and stockpiling of many chemical weapons, including sarin. It went into effect on April 29, 1997, and called for the complete destruction of all specified stockpiles of chemical weapons by April 2007. When the convention entered force, the parties declared worldwide stockpiles of 15,047 tonnes of sarin. As of December 2015, 89% of the stockpiles had been destroyed.
May 2004: Iraqi insurgents detonated a 155 mm shell containing binary precursors for sarin near a U.S. convoy in Iraq. The shell was designed to mix the chemicals as it spun during flight. The detonated shell released only a small amount of sarin gas, either because the explosion failed to mix the binary agents properly or because the chemicals inside the shell had degraded with age. Two United States soldiers were treated after displaying the early symptoms of exposure to sarin.
April 2018: Douma chemical attack victims reported to have symptoms consistent with exposure to sarin and other agents. On 6 July 2018, the Fact-Finding Mission (FFM) of the OPCW published their interim report. The report stated that, "The results show that no organophosphorus (sarin) nerve agents or their degradation products were detected in the environmental samples or in the plasma samples taken from alleged casualties".
2019: Sarin was reportedly detected in mail sent to the headquarters of Facebook in Menlo Park, CA, but cleared as a false alarm upon further investigation by authorities.
^"Nearly half a million litres of chemical warfare agents destroyed in two-year operation". UN Chronicle. 31 (3). September 1, 1994. p. 36. Retrieved 2015. The two-year operation managed to destroy ... the nerve agents sarin and tabun .... The UN Special Commission on Iraqi disarmament, set up under Security Council resolution 687 (1991) concerning the disposal of Iraq's weapons of mass destruction, reported that it had completed in June an important part of its mandate--the elimination of that country's declared chemical weapons stockpile.
^Millard CB, Kryger G, Ordentlich A, et al. (June 1999). "Crystal structures of aged phosphonylated acetylcholinesterase: nerve agent reaction products at the atomic level". Biochemistry. 38 (22): 7032-9. doi:10.1021/bi982678l. PMID10353814.. See Proteopedia1cfj.
^Hörnberg, Andreas; Tunemalm, Anna-Karin; Ekström, Fredrik (2007). "Crystal Structures of Acetylcholinesterase in Complex with Organophosphorus Compounds Suggest that the Acyl Pocket Modulates the Aging Reaction by Precluding the Formation of the Trigonal Bipyramidal Transition State+,?". Biochemistry. 46 (16): 4815-4825. doi:10.1021/bi0621361. PMID17402711.
^Baselt, Randall C.; Cravey, Robert H. (2017). Disposition of Toxic Drugs and Chemicals in Man. Seal Beach, California: Biomedical Publications. pp. 1926-1928. ISBN978-0815105473.