Sarin is a volatile, colorless and odorless liquid. Exposure can be lethal even at very low concentrations, and death can occur within one to ten minutes after direct inhalation of a lethal dose[5][6] due to suffocation fromrespiratory paralysis, unless antidotes are quickly administered.[4] People who absorb a non-lethal dose and do not receive immediate medical treatment may suffer permanent neurological damage.[citation needed][7]
Like some other nerve agents that affect theneurotransmitteracetylcholine, sarin attacks thenervous system by interfering with the degradation of the neurotransmitter acetylcholine atneuromuscular junctions. Death usually occurs as a result ofasphyxia due to the inability to control the muscles involved in breathing.[8]
Initial symptoms following exposure to sarin are arunny nose, tightness in the chest, andconstriction of the pupils (miotic action). Soon after, the person will have difficulty breathing and experiencenausea and drooling. This progresses to losing control of bodily functions, which may cause the person to vomit, defecate, and urinate. This phase is followed bytwitching and jerking. Ultimately, the person becomes comatose and suffocates in a series of convulsivespasms. Common mnemonics for the symptomatology of organophosphate poisoning, including sarin, are the "killer Bs" ofbronchorrhea andbronchospasm because they are the leading cause of death,[9] andSLUDGE – salivation,lacrimation, urination, defecation, gastrointestinal distress, and emesis (vomiting). Death may follow in one to ten minutes after direct inhalation, but may also occur after a delay ranging from hours to several weeks, in cases where exposure is limited but no antidote is applied.[8]
Sarin has a highvolatility (ease with which a liquid can turn into vapour) relative to similar nerve agents, making inhalation very easy, and may even absorb through 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]
Sarin is a potentinhibitor of acetylcholinesterase,[12] an enzyme that degrades theneurotransmitteracetylcholine after it is released into thesynaptic cleft. In vertebrates, acetylcholine is the neurotransmitter used at the neuromuscular junction, where signals are transmitted betweenneurons from theperipheral nervous system to muscle fibres. Normally, acetylcholine is released from the neuron to stimulate the muscle, after which it is degraded byacetylcholinesterase, allowing the muscle to relax. A build-up of acetylcholine in thesynaptic 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 eitherin vivo orin vitro. Its primary inactivemetabolites havein vivo serum half-lives of approximately 24 hours. The serum level of unbound isopropyl methylphosphonic acid (IMPA), a sarinhydrolysis 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 liquidchromatography, while acetylcholinesterase activity is usually measured by enzymatic methods.[15]
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.[16][17]
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 28–35 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, lower 28 mg/m3 value is for general population).[20] This number represents the estimated lethal concentration for 50% of exposed victims, theLCt50 value. TheLCt95 orLCt100 value is estimated to be 40–83 mg per cubic meter for exposure time of two minutes.[21][22] Calculating effects for different exposure times and concentrations requires following specific toxic load models. In general, brief exposures to higher concentrations are more lethal than comparable long time exposures to low concentrations.[23] 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 almost always manufactured as aracemic mixture (a 1:1 mixture of its enantiomeric forms) as this involves a much simplersynthesis while providing an adequate weapon.[27][28]
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 analcoholysis withisopropyl alcohol. Two variants of this final step are common. One is the reaction ofmethylphosphonyl difluoride with isopropyl alcohol, which produces a racemic mixture of sarin enantiomers withhydrofluoric acid as a byproduct:[29]
The second process, known as the "Di-Di" process, uses equimolar quantities ofmethylphosphonyl difluoride (Difluoro) andmethylphosphonyl dichloride (Dichloro). This reaction gives sarin,hydrochloric acid and other minor byproducts. The Di-Di process was used by the United States for the production of its unitary sarin stockpile.[29]
The scheme below shows a generic example that employs the Di-Di method as the final esterification step; in reality, the selection of reagents and reaction conditions dictate both product structure and yield. The choice of enantiomer of the mixed chloro fluoro intermediate displayed in the diagram is arbitrary, but the final substitution is selective for chloro over fluoro as theleaving group. Inert atmosphere and anhydrous conditions (Schlenk techniques) are used for synthesis of sarin and other organophosphates.[29]
An example of "di-di" process using arbitrary reagents.
As both reactions leave considerable acid in the product, sarin produced in bulk by these methods has a short half-life without further processing, and would be corrosive to containers and damaging to weapons systems. Various methods have been tried to resolve these problems. In addition to industrialrefining techniques to purify the chemical itself, various additives have been tried to combat the effects of the acid, such as:
Ammonia gas was used byNazi Germany as a non-additive stabilizer at RVIII Raubkammer, with success. Recovered artillery munitions filled with sarin from RVIII Raubkammer, inMunster, abandoned for half a century, showed a sarin concentration of over 80%.[34]
Isopropylamine was included as part of theM687 155 mm field artillery shell, which was abinary sarin weapon system developed by the US Army.[36]
Another byproduct of these two chemical processes isdiisopropyl methylphosphonate, formed when a second isopropyl alcohol reacts with the sarin itself and from disproportionation of sarin, when distilled incorrectly. The factor of its formation in esterification is that as the concentration of DF-DCl decreases, the concentration of sarin increases, the probability of DIMP formation is greater. DIMP is a natural impurity of sarin, that is almost impossible to be eliminated, mathematically, when the reaction is a 1 mol-1 mol "one-stream".[37]
Rabbit used to check for leaks at former sarin production plant (Rocky Mountain Arsenal), 1970
Degradation of phosphoryl halides begins with hydrolysis of the bond between phosphorus and the fluorine atom. This P-F bond is easily broken by nucleophilic agents through aSN2 mechanism, such as water andhydroxide.[38] At highpH, sarin decomposes rapidly to relatively nontoxicphosphonic acid derivatives.[39][40] The initial breakdown of sarin is into isopropyl methylphosphonic acid (IMPA)[41], 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 intomethylphosphonic acid (MPA), which can also be produced by other organophosphates.[42]
Sarin with residual acid degrades after a period of several weeks to several months. The shelf life can be shortened by impurities inprecursor materials. According to theCIA, someIraqi sarin had a shelf life of only a few weeks, owing mostly to impure precursors.[43]
Along with nerve agents such astabun andVX, sarin can have a short shelf life. Therefore, it is usually stored as two separate precursors that produce sarin when combined.[44] Sarin's shelf life can be extended by increasing the purity of the precursor and intermediates and incorporatingstabilizers such astributylamine. In some formulations, tributylamine is replaced bydiisopropylcarbodiimide (DIC), allowing sarin to be stored inaluminium casings. Inbinary chemical weapons, the two precursors are stored separately in the sameshell 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.
In mid-1939, the formula for the agent was passed to thechemical warfare section of theGerman Army Weapons Office, which ordered that it be brought into mass production for wartime use. Pilot plants were built, and a production facility was under construction (but was not finished) by the end ofWorld War II. Estimates for total sarin production byNazi Germany range from 500 kg to 10 tons.[46]
Though sarin,tabun, andsoman were incorporated intoartillery shells, Germany did not use nerve agents againstAllied targets.Adolf Hitler refused to initiate the use of gases such as sarin as weapons.[47]
U.S.Honest John missile warhead cutaway, showingM134 Sarin bomblets (c. 1960)Sarin gas used against animals in a weapons experiment
1950s (early):NATO adopted sarin as a standard chemical weapon. The USSR and the United States produced sarin for military purposes.
1953: 20-year-oldRonald Maddison, aRoyal Air Force engineer fromConsett,County Durham, died in human testing of sarin at thePorton Down chemical warfare testing facility inWiltshire, England. Ten days after his death aninquest was held in secret which returned a verdict ofmisadventure. 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".[48]
1957: Regular production of sarin chemical weapons ceased in the United States, though existing stocks of bulk sarin were re-distilled until 1970.[30]
1970: DuringOperation Tailwind, America may have deployed Sarin gas against the Communist Pathet Lao, alongside American defectors to the Laotian Communists.[49]
1976: Chile's intelligence service,DINA, assigned biochemistEugenio Berríos to develop Sarin gas within its programProyecto Andrea, to be used as a weapon against its opponents.[50] One of DINA's goals was to package it in spray cans for easy use, which, according to testimony by former DINA agentMichael Townley, was one of the planned procedures in the 1976assassination of Orlando Letelier.[50] Berríos later testified that it was used in a number of assassinations and it was planned to be used to kill inhabitants, through poisoning the water supply ofArgentine capitalBuenos Aires, in caseOperation Soberanía took place.[51][52]
1993: The United NationsChemical 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.[54] When the convention entered force, the parties declared worldwide stockpiles of 15,047 tonnes of sarin. As of November 28, 2019, 98% of the stockpiles have been destroyed.[55]
May 2004:Iraqi insurgents detonated a 155 mm shell containing binary precursors for sarin near a U.S. convoy inIraq. 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.[60]
April 2018: Victims of theDouma chemical attack in Syria reported to have symptoms consistent with exposure to sarin and other agents. On July 6, 2018, the Fact-Finding Mission (FFM) of the OPCW published their interim report. The report stated that, "The results show that no organophosphorous [sarin] nerve agents or their degradation products were detected in the environmental samples or in the plasma samples taken from alleged casualties". The chemical agent used in the attack was later identified as elementalchlorine.[68]
July 2023: The U.S. destroyed the last of its declared chemical weapons, a sarin nerve agent-filledM55 rocket, on July 7, 2023.[69]
^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.S2CID11744952.. SeeProteopedia1cfj.
^Hörnberg A, Tunemalm AK, Ekström F (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.
^Bide RW, Armour SJ, Yee E (2005). "GB toxicity reassessed using newer techniques for estimation of human toxicity from animal inhalation toxicity data: new method for estimating acute human toxicity (GB)".Journal of Applied Toxicology.25 (5):393–409.doi:10.1002/jat.1074.ISSN0260-437X.PMID16092087.S2CID8769521.
^J. B. Kremer; S. Kremer; M. Banke; K. Kranich. Analytical Investigations on World War II Sarin GB. Wehrwissenschaftliches Institut fUr Schutztechnologien ABC-Schutz (WIS). umboldtstraBe 29633 Munster, Germany. 1995
^Organisation for the Prohibition of Chemical Weapons (November 30, 2016)."Annex 3". Report of the OPCW on the Implementation of the Convention on the Prohibition of the Development, Production, Stockpiling and Use of Chemical Weapons and on Their Destruction in 2015 (Report). p. 42. RetrievedMarch 8, 2017.
