Nerve agent
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Nerve agents, sometimes also called nerve gases, are a class of organic chemicals that disrupt the mechanisms by which nerves transfer messages to organs. The disruption is caused by the blocking of acetylcholinesterase (AChE), an enzyme that catalyzes the breakdown of acetylcholine, a neurotransmitter. Nerve agents are irreversible acetylcholinesterase inhibitors used as poison.
Poisoning by a nerve agent leads to constriction of
Nerve agents are generally colorless and tasteless 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]
Agents Sarin and VX are odorless; Tabun has a slightly fruity odor and Soman has a slight camphor odor.[2]
Biological effects
Nerve agents attack the nervous system. All such agents function the same way resulting in cholinergic crisis: they inhibit the enzyme acetylcholinesterase, which is responsible for the breakdown of acetylcholine (ACh) in the synapses 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]: 131–139 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 via asphyxiation or cardiac arrest in a few minutes, depending upon the dose received and the agent used.[2]
Initial symptoms following exposure to nerve agents (like
,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 related
Mechanism of action
When a normally functioning motor nerve is stimulated, it releases the neurotransmitter acetylcholine, which transmits the impulse to a muscle or organ. Once the impulse is sent, the enzyme acetylcholinesterase 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 a covalent bond with its active site, where acetylcholine would normally be broken down (undergo hydrolysis). 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 using X-ray crystallography in the 1990s.[9][10] 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.
Treatment
Standard treatment for nerve agent poisoning is a combination of an anticholinergic to manage the symptoms, and an oxime as an antidote.[11] Anticholinergics treat the symptoms by reducing the effects of acetylcholine, while oximes displaces phosphate molecules from the active site of the cholinesterase enzymes, allowing the breakdown of acetylcholine. Military personnel are issued the combination in an autoinjector (e.g. ATNAA), for ease of use in stressful conditions.[12]
Atropine is the standard anticholinergic drug used to manage the symptoms of nerve agent poisoning.[13] It acts as an antagonist to muscarinic acetylcholine receptors, blocking the effects of excess acetylcholine.[12] Some synthetic anticholinergics, such as biperiden,[14] may counteract the central symptoms of nerve agent poisoning more effectively than atropine, since they pass the blood–brain barrier better.[15] 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.[13]
Anticonvulsants, such as diazepam, may be administered to manage seizures, improving long term prognosis and reducing risk of brain damage.[13] This is not usually self-administered as its use is for actively seizing patients.[17]
Countermeasures
Pyridostigmine bromide was used by the US military in the first Gulf War as a pretreatment for Soman as it increased the median lethal dose. It is only effective if taken prior to exposure and in conjunction with Atropine and Pralidoxime, issued in the Mark 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.[18] Evidence suggests that the use of pyridostigmine may be responsible for some of the symptoms of Gulf War syndrome.[19]
Both purified acetylcholinesterase and butyrylcholinesterase have demonstrated success in animal studies as "biological scavengers" (and universal targets) to provide stoichiometric protection against the entire spectrum of organophosphate nerve agents.[21][22] Butyrylcholinesterase currently is the preferred enzyme for development as a pharmaceutical drug primarily because it is a naturally circulating human plasma protein (superior pharmacokinetics) 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.[23]
Classes
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 as Sarin) and a two-character NATO identifier (such as GB).
G-series
The G-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 to World War II, led by Gerhard Schrader (later under the employment of IG Farben).[25]
This series is the first and oldest family of nerve agents. The first nerve agent ever synthesized was GA (
V-series
The V-series is the second family of nerve agents and contains five well known members: VE, VG, VM, VR, and VX, along with several more obscure analogues.[27]
The most studied agent in this family,
Analyzing the structure of thirteen V agents, the standard composition, which makes a compound enter this group, is the absence of halides. 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.[29] The toxicity requirement is waived as the VT agent and its salts (VT-1 and VT-2) are "non-toxic".[30] Replacing the sulfur atom with selenium increases the toxicity of the agent by orders of magnitude.[31]
Novichok agents
The Novichok (Russian: Новичо́к, "newcomer") agents, a series of organophosphate compounds, were developed in the Soviet 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.
Carbamates
Contrary to some claims,[32] not all nerve agents are organophosphates. The starting compound studied by the United States was the carbamate EA-1464, of notorious toxicity.[33] Compounds similar in structure and effect to EA-1464 formed a large group, including compounds such as EA-3990 and EA-4056.[33] The Family Practice Notebook claims carbamate-based nerve agents can be three times as toxic as VX.[34] Both the United States[27] and the Soviet Union[35] developed carbamate-based nerve agents during the Cold 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,[36] despite their significant differences in chemical makeup and mechanisms of action.[37] Carbamate-based nerve agents have been identified as Schedule 1 Nerve Agents,[37] the highest classification possible under the CWC, reserved for agents with no identified alternate use, and those that can cause the most harm.[38]
Insecticides
Some
Methods of dissemination
Many methods exist for spreading nerve agents such as:[40]
- uncontrolled aerosol munitions
- smoke generation
- explosive dissemination
- atomizers, humidifiers and foggers
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.[40]
History
This section needs additional citations for verification. (March 2009) |
Discovery
This first class of nerve agents, the G-series, was accidentally discovered in Germany on December 23, 1936, by a research team headed by Gerhard Schrader working for IG Farben. Since 1934, Schrader had been working in a laboratory in Leverkusen to develop new types of insecticides for IG Farben. While working toward his goal of improved insecticide, Schrader experimented with numerous compounds, eventually leading to the preparation of Tabun.
In experiments, Tabun was extremely potent against insects: as little as 5
In 1935 the
Sarin was discovered by Schrader and his team in 1938 and named in honor of its discoverers: Gerhard Schrader, Otto Ambros, Gerhard Ritter , and Hans-Jürgen von der Linde.[41] It was codenamed T-144 or Trilon-46. It was found to be more than ten times as potent as Tabun.
Soman was discovered by Richard Kuhn in 1944 as he worked with the existing compounds; the name is derived from either the Greek 'to sleep' or the Latin '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.
During World War II
In 1939, a pilot
.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 (now
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 with
- Four pipe fitters had liquid Tabun drain onto them and died before their rubber suits could be removed.
- A worker had two liters of Tabun pour down the neck of his rubber suit. He died within two minutes.
- Seven workers were hit in the face with a stream of Tabun of such force that the liquid was forced behind their respirators. Only two survived despite resuscitation measures.
The plant produced between 10 000 and 30 000 tons of Tabun before its capture by the Soviet Army[citation needed] and moved, probably to Dzerzhinsk, USSR.[43][44]
In 1940 the
During that time, German
This is detailed in Joseph Borkin's book The Crime and Punishment of IG Farben:[46]
Tabun, flew Otto 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 to ethylene, probably had a greater capacity to produce mustard 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 and I.G. had patented 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., The Crime and Punishment of IG Farben
Post–World War II
Since World War II, Iraq's use of mustard gas against Iranian troops and
Operatives of the Aum Shinrikyo religious group made and used Sarin several times on other Japanese, most notably the Tokyo subway sarin attack.[48][49]
In the Gulf War, no nerve agents (nor other chemical weapons) were used, but a number of U.S. and UK personnel were exposed to them when the Khamisiyah 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 of Gulf War syndrome.[50]
On 13 February 2017, the nerve agent
On 4 March 2018, a former Russian agent (who was convicted of high treason but allowed to live in the
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.[57][58][59] 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.[60]
Ocean disposal
In 1972, the United States Congress banned the practice of disposing chemical weapons into the ocean. Thirty-two thousand tons 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 of Operation 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.[61]
There is currently a lack of scientific data regarding the ecological and health effects of this dumping. In the event of leakage, many nerve agents are soluble in water and would dissolve in a few days, while other substances like
Detection
Detection of gaseous nerve agents
The methods of detecting gaseous nerve agents include but are not limited to the following.
Laser photoacoustic spectroscopy
This
The following nerve agent simulants have been identified with this multiwavelength LPAS:[63]
- dimethyl methyl phosphonate (DMMP)
- diethyl methyl phosphonate (DEMP)
- diisopropyl methyl phosphonate (DIMP)
- dimethylpolysiloxane(DIME), triethyl phosphate (TEP)
- tributyl phosphate (TBP)
- two volatile organic compounds (VOCs)
- acetone (ACE)
- isopropanol (ISO), used to construct Sarin
Other gases and air contaminants identified with LPAS include:[65][67]
- CO2 Carbon dioxide
- Benzene
- Formaldehyde
- Acetaldehyde
- Ammonia
- NOx Nitrogen oxide
- SO2 Sulphur oxide
- Ethylene Glycol
- TATP
- TNT
Non-dispersive infrared
Non-dispersive infrared techniques have been reported to be used for gaseous nerve agent detection.[68][65]
IR absorption
Traditional IR absorption has been reported to detect gaseous nerve agents.[65]
Fourier transform infrared spectroscopy
Fourier transform infrared (FTIR) spectroscopy has been reported to detect gaseous nerve agents.[65]
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{{cite journal}}
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External links
- ATSDR Case Studies in Environmental Medicine: Cholinesterase Inhibitors, Including Pesticides and Chemical Warfare Nerve Agents U.S. Department of Health and Human Services
- Nervegas: America's Fifteen-year Struggle for Modern Chemical Weapons Army Chemical Review
- History Note: The CWS Effort to Obtain German Chemical Weapons for Retaliation Against Japan CBIAC Newsletter
- AChE inhibitors and substrates – 2wfz, 2wg0, 2wg1, 1som in Proteopedia