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Nerve agents, sometimes also callednerve gases, are a class oforganic chemicals that disrupt the mechanisms by which nerves transfer messages to organs. The disruption is caused by the blocking ofacetylcholinesterase (AChE), anenzyme that catalyzes the breakdown ofacetylcholine, aneurotransmitter. Nerve agents are irreversibleacetylcholinesterase inhibitors used aspoison.
Poisoning by a nerve agent leads to constriction ofpupils, profusesalivation,convulsions, and involuntaryurination anddefecation, with the first symptoms appearing in seconds after exposure. Death byasphyxiation orcardiac arrest may follow in minutes due to the loss of the body's control overrespiratory and other muscles. Some nerve agents are readily vaporized oraerosolized, and the primary portal of entry into the body is therespiratory system. Nerve agents can also be absorbed through the skin, requiring that those likely to be subjected to such agents wear a full body suit in addition to arespirator.
Nerve agents are generally colorless and flavorless liquids. Nerve agents evaporate at varying rates depending on the substance. None are gases in normal environments. The popular term "nerve gas" is inaccurate.[1]
AgentsSarin andVX are odorless;Tabun has a slightly fruity odor andSoman has a slightcamphor odor.[2]
Nerve agents attack thenervous system. All such agents function the same way resulting incholinergic crisis: theyinhibit the enzymeacetylcholinesterase, which is responsible for the breakdown ofacetylcholine (ACh) in thesynapses between nerves that control whether muscle tissues are to relax or contract. If the agent cannot be broken down, muscles are prevented from receiving 'relax' signals and they are effectively paralyzed.[3] It is the compounding of this paralysis throughout the body that quickly leads to more severe complications, including the heart and the muscles used for breathing. Because of this, the first symptoms usually appear within 30 seconds of exposure and death can occur viaasphyxiation orcardiac arrest in a few minutes, depending upon the dose received and the agent used.[2]
Initial symptoms following exposure to nerve agents (likeSarin) are a runny nose, tightness in the chest, andconstriction of the pupils. Soon after, the victim will have difficulty breathing and will experience nausea and salivation. As the victim continues to lose control of bodily functions, involuntarysalivation,lacrimation,urination,defecation,gastrointestinal pain andvomiting will be experienced.Blisters and burning of the eyes and/or lungs may also occur.[4][5] This phase is followed by initiallymyoclonic jerks (muscle jerks) followed bystatus epilepticus–type epileptic seizure. Death then comes via complete respiratory depression, most likely via the excessive peripheral activity at theneuromuscular junction of thediaphragm.[6]
The effects of nerve agents are long lasting and increase with continued exposure. Survivors of nerve agent poisoning almost invariably develop chronic neurological damage and relatedpsychiatric effects.[7] Possible effects that can last at least up to two–three years after exposure include blurred vision,tiredness, declined memory, hoarse voice,palpitations,sleeplessness, shoulder stiffness andeye strain. In people exposed to nerve agents,serum anderythrocyte acetylcholinesterase in the long-term are noticeably lower than normal and tend to be lower the worse the persisting symptoms are.[8][9]
When a normally functioningmotor nerve is stimulated, it releases theneurotransmitteracetylcholine, which transmits the impulse to a muscle or organ. Once the impulse is sent, the enzymeacetylcholinesterase immediately breaks down the acetylcholine in order to allow the muscle or organ to relax.
Nerve agents disrupt the nervous system by inhibiting the function of the enzyme acetylcholinesterase by forming acovalent bond with itsactive site, where acetylcholine would normally be broken down (undergohydrolysis). Acetylcholine thus builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. This same action also occurs at the gland and organ levels, resulting in uncontrolled drooling, tearing of the eyes (lacrimation) and excess production of mucus from the nose (rhinorrhea).
The reaction product of the most important nerve agents, including Soman, Sarin, Tabun and VX, with acetylcholinesterase were solved by the U.S. Army usingX-ray crystallography in the 1990s.[10][11] The reaction products have been confirmed subsequently using different sources of acetylcholinesterase and the closely related target enzyme, butyrylcholinesterase. The X-ray structures clarify important aspects of the reaction mechanism (e.g., stereochemical inversion) at atomic resolution and provide a key tool for antidote development.
Standard treatment for nerve agentpoisoning is a combination of ananticholinergic to manage the symptoms, and anoxime as an antidote.[12] Anticholinergics treat the symptoms by reducing the effects of acetylcholine, while oximes displaces phosphate molecules from theactive site of thecholinesterase enzymes, allowing the breakdown of acetylcholine. Military personnel are issued the combination in anautoinjector (e.g.ATNAA), for ease of use in stressful conditions.[13]
Atropine is the standard anticholinergic drug used to manage the symptoms of nerve agent poisoning.[14] It acts as an antagonist tomuscarinic acetylcholine receptors, blocking the effects of excess acetylcholine.[13] Some synthetic anticholinergics, such asbiperiden,[15] may counteract the central symptoms of nerve agent poisoning more effectively than atropine, since they pass theblood–brain barrier better.[16] While these drugs will save the life of a person affected by nerve agents, that person may be incapacitated briefly or for an extended period, depending on the extent of exposure. The endpoint of atropine administration is the clearing of bronchial secretions.[14]
Pralidoxime chloride (also known as2-PAMCl) is the standard oxime used to treat nerve agent poisoning.[14] Rather than counteracting the initial effects of the nerve agent on the nervous system as does atropine, pralidoxime chloride reactivates the poisoned enzyme (acetylcholinesterase) by scavenging the phosphoryl group attached on the functional hydroxyl group of the enzyme, counteracting the nerve agent itself.[17] Revival of acetylcholinesterase with pralidoxime chloride works more effectively onnicotinic receptors while blocking acetylcholine receptors with atropine is more effective onmuscarinic receptors.[14]
Anticonvulsants, such as diazepam, may be administered to manage seizures, improving long term prognosis and reducing risk of brain damage.[14] This is not usually self-administered as its use is for actively seizing patients.[18]
Pyridostigmine bromide was used by theUS military in thefirst Gulf War as a pretreatment forSoman as it increased themedian lethal dose. It is only effective if taken prior to exposure and in conjunction with Atropine and Pralidoxime, issued in theMark I NAAK autoinjector, and is ineffective against other nerve agents. While it reduces fatality rates, there is an increased risk of brain damage; this can be mitigated by administration of an anticonvulsant.[19] Evidence suggests that the use of pyridostigmine may be responsible for some of the symptoms ofGulf War syndrome.[20]
Butyrylcholinesterase is under development by the U.S. Department of Defense as aprophylacticcountermeasure againstorganophosphate nerve agents. It binds nerve agent in the bloodstream before the poison can exert effects in the nervous system.[21]
Both purifiedacetylcholinesterase and butyrylcholinesterase have demonstrated success in animal studies as "biological scavengers" (and universal targets) to providestoichiometric protection against the entire spectrum of organophosphate nerve agents.[22][23] Butyrylcholinesterase currently is the preferred enzyme for development as a pharmaceutical drug primarily because it is a naturally circulating human plasma protein (superiorpharmacokinetics) and its larger active site compared with acetylcholinesterase may permit greater flexibility for future design and improvement of butyrylcholinesterase to act as a nerve agent scavenger.[24]
There are two main classes of nerve agents. The members of the two classes share similar properties and are given both a common name (such asSarin) and a two-characterNATO identifier (such as GB).
TheG-series is thus named because German scientists first synthesized them. G series agents are known as non-persistent, meaning that they evaporate shortly after release, and do not remain active in the dispersal area for very long. All of the compounds in this class were discovered and synthesized during or prior toWorld War II, by scientists working atIG Farben - a company which played an instrumental role inThe Holocaust.[26]
This series is the first and oldest family of nerve agents. The first nerve agent ever synthesized was GA (Tabun) in 1936. GB (Sarin) was discovered next in 1939, followed by GD (Soman) in 1944, and finally the more obscure GF (Cyclosarin) in 1949. GB was the only G agent that was fielded by the US as a munition, in rockets,aerial bombs, andartillery shells.[27]
G agents are characterized by being almost industrially insoluble, as they are difficult to produce on a large scale at the same time in high purity and stability. The most problematic component is DF and the fluoride ion, with the United States being the only country capable of producing this precursor on a large scale and in a pure and stabilized form. Another component, which has fallen into disuse, is dimethylphosphoramido dicyanidate, which is equally problematic.[28][29]
Replacing the fluorine in methylphosphonofluoridates causes a sharp drop in toxicity, as does dimethylphosphoramidocyanidates.[30] The stabilization of these compounds was focused on finding leaving groups that would replace the fluorine and cyanide ions - with the exception of phosphocholine-derived V agents -, this led to the development of some V agents, when the output group was bulky.[29]
TheV-series is the second family of nerve agents and contains five well known members:VE,VG,VM,VR, andVX, along with several more obscure analogues.[31]
The most studied agent in this family,VX (it is thought that the "X" in its name comes from its overlapping isopropyl radicals), was invented in the 1950s atPorton Down inWiltshire, England. Ranajit Ghosh, a chemist at the Plant Protection Laboratories ofImperial Chemical Industries (ICI) was investigating a class of organophosphate compounds (organophosphate esters of substituted aminoethanethiols). Like Schrader, Ghosh found that they were quite effective pesticides. In 1953 and 1954, ICI conductedfield trials, intending to market the material as anacaricide with the common nameamiton. Development was halted, as it was too toxic for safe use.[32] The toxicity did not escape military notice and some of the more toxic materials had been sent to Porton Down for evaluation. After the evaluation was complete, several members of this class of compounds became a new group of nerve agents, the V agents (depending on the source, the V stands for Victory, Venomous, or Viscous). The best known of these is probablyVX, withVR ("Russian V-gas") coming a close second (amiton is largely forgotten as VG, with G probably coming from "G"hosh). All of the V-agents are persistent agents, meaning that these agents do not degrade or wash away easily and can therefore remain on clothes and other surfaces for long periods. In use, this allows the V-agents to be used to blanket terrain to guide or curtail the movement of enemy ground forces. The consistency of these agents is similar to oil; as a result, the contact hazard for V-agents is primarily – but not exclusively – dermal. VX was the only V-series agent that was fielded by the US as a munition, in rockets,artillery shells, airplane spray tanks, andlandmines.[27][33]
Analyzing the structure of thirteen V agents, the standard composition, which makes a compound enter this group, is the absence ofhalides. It is clear that many agricultural pesticides can be considered as V agents if they are notoriously toxic. The agent is not required to be a phosphonate and presents a dialkylaminoethyl group.[34] The toxicity requirement is waived as the VT agent and its salts (VT-1 and VT-2) are "non-toxic".[35] Replacing the sulfur atom with selenium increases the toxicity of the agent by orders of magnitude.[36]
The Novichok (Russian:Новичо́к, "newcomer") agents, a series oforganophosphate compounds, were developed in theSoviet Union and in Russia from the mid-1960s to the 1990s. The Novichok program aimed to develop and manufacture highly deadly chemical weapons that were unknown to the West. The new agents were designed to be undetectable by standard NATO chemical-detection equipment and overcome contemporary chemical-protective equipment.
In addition to the newly developed "third generation" weapons, binary versions of several Soviet agents were developed and were designated as "Novichok" agents.
Contrary to some claims,[37] not all nerve agents areorganophosphates. The starting compound studied by the United States was thecarbamate EA-1464, of notorious toxicity.[38] Compounds similar in structure and effect to EA-1464 formed a large group, including compounds such asEA-3990 andEA-4056.[38] The Family Practice Notebook claims carbamate-based nerve agents can be three times as toxic as VX.[39] Both the United States[31] and the Soviet Union[40]developed carbamate-based nerve agents during theCold War. Carbamate-based nerve agents are sometimes grouped in academic literature with Fourth Generation Novichok agents, as they were added to the CWC schedule on banned agents at the same time,[41] despite their significant differences in chemical makeup and mechanisms of action.[42] Carbamate-based nerve agents have been identified as Schedule 1 Nerve Agents,[42] the highest classification possible under the CWC, reserved for agents with no identified alternate use, and those that can cause the most harm.[43]
Someinsecticides, includingcarbamates andorganophosphates such asdichlorvos,carbofuran andparathion, are nerve agents. The metabolism ofinsects is sufficiently different frommammals that these compounds have little effect onhumans and othermammals at proper doses, but there is considerable concern about the effects of long-term exposure to these chemicals byfarm workers andanimals alike. At high enough doses,acute toxicity and death can occur through the same mechanism as other nerve agents. Some insecticides such asdemeton,dimefox andparaoxon are sufficiently toxic to humans that they have been withdrawn from agricultural use, and were at one stage investigated for potential military applications.[citation needed]Paraoxon was allegedly used as anassassination weapon by theapartheid South African government as part ofProject Coast. Organophosphatepesticide poisoning is a major cause of disability in many developing countries and is often the preferred method of suicide.[44]
Several pesticides were investigated as candidate chemical warfare agents, only when they demonstrated high activity in mammals. Paraoxon, mevinphos, and armine were the first agents investigated as chemical warfare agents, candidates G.[29]
Many methods exist for spreading nerve agents such as:[45]
The method chosen will depend on the physical properties of the nerve agent(s) used, the nature of the target, and the achievable level of sophistication.[45]
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This first class of nerve agents, the G-series, was accidentally discovered in Germany on 23 December 1936, by a research team headed byGerhard Schrader working forIG Farben. Since 1934, Schrader had been working in a laboratory inLeverkusen to develop new types ofinsecticides forIG Farben. While working toward his goal of improved insecticide, Schrader experimented with numerous compounds, eventually leading to the preparation ofTabun.
In experiments, Tabun was extremely potent against insects: as little as 5ppm of Tabun killed all theleaf lice he used in his initial experiment. In January 1937, Schrader observed the effects of nerve agents on human beings first-hand when a drop of Tabun spilled onto a lab bench. Within minutes he and his laboratory assistant began to experiencemiosis (constriction of the pupils of the eyes), dizziness and severe shortness of breath. It took them three weeks to recover fully.
In 1935 theNazi government had passed a decree that required all inventions of possible military significance to be reported to theMinistry of War, so in May 1937 Schrader sent a sample of Tabun to thechemical warfare (CW) section of theArmy Weapons Office inBerlin-Spandau. Schrader was summoned to the Wehrmacht chemical lab in Berlin to give a demonstration, after which Schrader'spatent application and all related research was classified as secret. Colonel Rüdiger, head of the CW section, ordered the construction of new laboratories for the further investigation of Tabun and other organophosphate compounds and Schrader soon moved to a new laboratory atWuppertal-Elberfeld in theRuhr valley to continue his research in secret throughoutWorld War II. The compound was initially codenamed Le-100 and later Trilon-83.
Sarin was discovered by Schrader and his team in 1938 and named in honor of its discoverers:GerhardSchrader,OttoAmbros,GerhardRitter [de], and Hans-Jürgen von der Linde.[46] It was codenamed T-144 or Trilon-46. It was found to be more than ten times as potent as Tabun.
Soman was discovered byRichard Kuhn in 1944 as he worked with the existing compounds; the name is derived from either theGreek 'to sleep' or theLatin 'to bludgeon'. It was codenamed T-300.
Cyclosarin was also discovered during WWII but the details were lost and it was rediscovered in 1949.
The G-series naming system was created by the United States when it uncovered the German activities, labeling Tabun as GA (German Agent A), Sarin as GB and Soman as GD. Ethyl Sarin was tagged GE and Cyclosarin as GF.
In 1939, a pilotplant for Tabun production was set up atMunster-Lager, onLüneburg Heath near the German Army proving grounds atRaubkammer [de]. In January 1940, construction began on a secret plant, code named "Hochwerk" (High factory), for the production of Tabun atDyhernfurth an der Oder (nowBrzeg Dolny inPoland), on theOder River 40 km (25 mi) fromBreslau (nowWrocław) inSilesia.
The plant was large, covering an area of 2.4 by 0.8 km (1.49 by 0.50 mi) and was completely self-contained, synthesizing all intermediates as well as the final product, Tabun. The factory even had an underground plant for filling munitions, which were then stored at Krappitz (nowKrapkowice) in Upper Silesia. The plant was operated byAnorgana GmbH [de], a subsidiary ofIG Farben, as were all otherchemical weapon agent production plants in Germany at the time.
Because of the plant's deep secrecy and the difficult nature of the production process, it took from January 1940 until June 1942 for the plant to become fully operational. Many of Tabun's chemical precursors were so corrosive that reaction chambers not lined with quartz or silver soon became useless. Tabun itself was so hazardous that the final processes had to be performed while enclosed in double glass-lined chambers with a stream of pressurized air circulating between the walls.
Three thousand German nationals were employed at Hochwerk, all equipped withrespirators andclothing constructed of a poly-layered rubber/cloth/rubber sandwich that was destroyed after the tenth wearing. Despite all precautions, there were over 300 accidents before production even began and at least ten workers died during the two and a half years of operation. Some incidents cited inA Higher Form of Killing: The Secret History of Chemical and Biological Warfare are as follows:[47]
The plant produced between 10 000 and 30 000 tons of Tabun before its capture by the Soviet Army[citation needed] and moved, probably toDzerzhinsk,USSR.[48][49]
In 1940 theGerman Army Weapons Office ordered the mass production of Sarin for wartime use. A number of pilot plants were built and a high-production facility was under construction (but was not finished) by the end ofWorld War II. Estimates for total Sarin production by Nazi Germany range from 500 kg to 10tons.
During that time, Germanintelligence believed that theAllies also knew of these compounds, assuming that because these compounds were not discussed in the Allies' scientific journals information about them was being suppressed. Though Sarin, Tabun and Soman were incorporated intoartillery shells, the German government ultimately decided not to use nerve agents against Allied targets. The Allies did not learn of these agents until shells filled with them were captured towards the end of the war. German forces used chemical warfare against partisans during theBattle of the Kerch Peninsula in 1942, but did not use any nerve agent.[50]
This is detailed in Joseph Borkin's bookThe Crime and Punishment of IG Farben:[51]
Speer, who was strongly opposed to the introduction ofTabun, flewOtto Ambros,I.G.'s authority on poison gas as well as synthetic rubber, to the meeting. Hitler asked Ambros, "What is the other side doing about poison gas?" Ambros explained that the enemy, because of its greater access toethylene, probably had a greater capacity to producemustard gas than Germany did. Hitler interrupted to explain that he was not referring to traditional poison gases: "I understand that the countries with petroleum are in a position to make more [mustard gas], but Germany has a special gas, Tabun. In this we have a monopoly in Germany." He specifically wanted to know whether the enemy had access to such a gas and what it was doing in this area. To Hitler's disappointment Ambros replied, "I have justified reasons to assume that Tabun, too, is known abroad. I know that Tabun was publicized as early as 1902, that Sarin was patented and that these substances appeared in patents. " (...)Ambros was informing Hitler of an extraordinary fact about one of Germany's most secret weapons. The essential nature of Tabun and Sarin had already been disclosed in the technical journals as far back as 1902 andI.G. hadpatented both products in 1937 and 1938. Ambros then warned Hitler that if Germany used Tabun, it must face the possibility that the Allies could produce this gas in much larger quantities. Upon receiving this discouraging report, Hitler abruptly left the meeting. The nerve gases would not be used, for the time being at least, although they would continue to be produced and tested.
— Joseph Borkin, The Crime and Punishment of IG Farben
Since World War II, Iraq's use of mustard gas against Iranian troops andKurds (Iran–Iraq War of 1980–1988) has been the only large-scale use of any chemical weapons. On the scale of the single Kurdish village ofHalabja within its own territory, Iraqi forces did expose the populace to some kind of chemical weapons, possibly mustard gas and most likely nerve agents.[52]
Operatives of theAum Shinrikyo religious group made and usedSarin several times on Japanese citizens, most notably in theTokyo subway sarin attack.[53][54]
In theGulf War, no nerve agents (nor other chemical weapons) were used, but a number of U.S. and UK personnel were exposed to them when theKhamisiyah chemical depot was destroyed. This and the widespread use of anticholinergic drugs as a protective treatment against any possible nerve gas attack have been proposed as a possible cause ofGulf War syndrome.[55]
Sarin gas was deployed ina 2013 attack onGhouta during theSyrian Civil War, killing several hundred people. Most governments contend that forces loyal to PresidentBashar al-Assad deployed the gas;[56] however, theSyrian Government has denied responsibility.
On 13 February 2017, the nerve agentVX was used in theassassination of Kim Jong-nam, half-brother of the North Korean leaderKim Jong-un, atKuala Lumpur International Airport inMalaysia.[57]
On 4 March 2018, a former Russian agent (who was convicted of high treason but allowed to live in theUnited Kingdom via aspy swap agreement),Sergei Skripal, and his daughter, who was visiting from Moscow,were both poisoned by a Novichok nerve agent in the English city ofSalisbury. They survived, and were subsequently released from hospital.[58] In addition, aWiltshire Police officer, Nick Bailey, was exposed to the substance. He was one of the first to respond to the incident. Twenty-one members of the public received medical treatment following exposure to the nerve agent. Despite this, only Bailey and the Skripals remained in critical condition.[59] On 11 March 2018,Public Health England issued advice for the other people believed to have been in the Mill pub (the location where the attack is believed to have been carried out) or the nearbyZizzi Restaurant.[60] On 12 March 2018, British Prime MinisterTheresa May stated that the substance used was a Novichok nerve agent.[61]
On 30 June 2018, two British nationals, Charlie Rowley and Dawn Sturgess,were poisoned by a Novichok nerve agent of the same kind that was used in the Skripal poisoning, which Rowley had found in a discarded perfume bottle and gifted to Sturgess.[62][63][64] Whilst Rowley survived, Sturgess died on 8 July.Metropolitan Police believe that the poisoning was not a targeted attack, but a result of the way the nerve agent was disposed of after the poisoning in Salisbury.[65]
In 1972, the United States Congress banned the practice of disposing chemical weapons into the ocean. Thirty-two thousandtons of nerve and mustard agents had already been dumped into the ocean waters off the United States by the U.S. Army, primarily as part ofOperation CHASE. According to a 1998 report by William Brankowitz, a deputy project manager in the U.S. Army Chemical Materials Agency, the Army created at least 26 chemical weapons dump sites in the ocean off at least 11 states on both the west and east coasts. Due to poor records, they currently only know the rough whereabouts of half of them.[66]
There is currently a lack of scientific data regarding the ecological and health effects of this dumping, but there have been a few incidents of chemical weapons washing ashore or being accidentally retrieved, for example during dredging ortrawl fishing operations.[67]
The methods of detecting gaseous nerve agents include but are not limited to the following.
Laserphotoacoustic spectroscopy (LPAS) is a method that has been used to detect nerve agents in the air. In this method, laser light is absorbed bygaseousmatter. This causes a heating/cooling cycle and changes inpressure. Sensitivemicrophones conveysound waves that result from the pressure changes. Scientists at theU.S. Army Research Laboratory engineered an LPAS system that can detect multiple trace amounts of toxic gases in one air sample.[68]
Thistechnology contained three lasersmodulated to differentfrequency, each producing a different sound wave tone. The different wavelengths of light were directed into a sensor referred to as the photoacoustic cell. Within the cell were the vapors of different nerve agents. The traces of each nerve agent had a signature effect on the "loudness" of the lasers' sound wave tones.[69] Some overlap of nerve agents' effects did occur in the acoustic results. However, it was predicted that specificity would increase as additional lasers with unique wavelengths were added.[68] Yet, too many lasers set to differentwavelengths could result in overlap ofabsorption spectra. Citation LPAS technology can identifygases inparts per billion (ppb) concentrations.[70][69][71]
The following nerve agent simulants have been identified with this multiwavelength LPAS:[68]
Other gases and air contaminants identified with LPAS include:[70][72]
Non-dispersive infrared techniques have been reported to be used for gaseous nerve agent detection.[73][70]
TraditionalIR absorption has been reported to detect gaseous nerve agents.[70]
Fourier transform infrared (FTIR) spectroscopy has been reported to detect gaseous nerve agents.[70]
{{citation}}:ISBN / Date incompatibility (help)On February 22, 2018, the United States determined under the Chemical and Biological Weapons Control and Warfare Elimination Act of 1991 (CBW Act) that the Government of North Korea used the chemical warfare agent VX to assassinate Kim Jong Nam, in the Kuala Lumpur airport.