Nerve agent

This article is about the chemical. For the band, see The Nerve Agents.

This article forms part of the series Chemical agents
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Nerve agents are a class of phosphorus-containing organic chemicals (organophosphates) that disrupt the mechanism by which nerves transfer messages to organs. The disruption is caused by blocking acetylcholinesterase, an enzyme that normally relaxes the activity of acetylcholine, a neurotransmitter.

As chemical weapons, they are classified as weapons of mass destruction by the United Nations according to UN Resolution 687 (passed in April 1991) and their production and stockpiling was outlawed by the Chemical Weapons Convention of 1993; the Chemical Weapons Convention officially took effect on April 29, 1997.

Poisoning by a nerve agent leads to contraction of pupils, profuse salivation, convulsions, involuntary urination and defecation, and eventual death by asphyxiation as control is lost over respiratory muscles. Some nerve agents are readily vaporized or aerosolized and the primary portal of entry into the body is the respiratory 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 a respirator.

Biological effects

As their name suggests, nerve agents attack the nervous system of the human body. All such agents function the same way: by inhibiting the enzyme acetylcholinesterase which is responsible for the breakdown of acetylcholine (ACh) in the synapse. ACh gives the signal for muscles to contract, preventing them from relaxing.^[1]

Initial symptoms following exposure to nerve agents (like sarin) are a runny nose, tightness in the chest, and constriction of the pupils. Soon after, the victim will then have difficulty breathing and will experience nausea and drooling. As the victim continues to lose control of his or her bodily functions, he or she will involuntarily salivate, lacrimate, urinate, defecate, and experience gastrointestinal pain and vomiting. Blisters and burning of the eyes and/or lungs may also occur.^[2][3] This phase is followed by initially myoclonic jerks followed by status epilepticus. Death then comes via complete respiratory depression, most likely via the excessive peripheral activity at the neuromuscular junction of the diaphragm.^[4]

The effects of nerve agents are very long lasting and cumulative (increased by successive exposures) and survivors of nerve agent poisoning almost invariably suffer chronic neurological damage. This neurological damage can also lead to continuing psychiatric effects.^[5]

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 acetylcholinesterase by forming a covalent bond with the site of the enzyme where acetylcholine normally undergoes hydrolysis (breaks down). The structures of the complexes of soman (one of the most toxic nerve agents) with acetylcholinesterase from Torpedo californica have been solved by X-ray crystallography (PDB codes: 2wfz, 2wg0, 2wg1, and 1som). The mechanism of action of soman could be seen on example of 2wfz. The result is that acetylcholine 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).

Antidotes

Atropine and related anticholinergic drugs act as antidotes to nerve agent poisoning because they block acetylcholine receptors, but they are poisonous in their own right. (Some synthetic anticholinergics, such as biperiden may counteract the central symptoms of nerve agent poisoning better than atropine, since they pass the blood-brain barrier better than atropine.) While these drugs will save the life of a person affected with nerve agents, that person may be incapacitated briefly or for an extended period, depending on the amount of exposure. The endpoint of atropine administration is the clearing of bronchial secretions. Atropine for field use by military personnel is often loaded in an autoinjector, for ease of use in stressful conditions. The limitation of atropine is that it is only indicated for use against soman.

Pralidoxime chloride, also known as 2-PAM chloride, is also used as an antidote. Rather than counteracting the initial effects of the nerve agent on the nervous system like atropine, pralidoxime chloride reactivates the poisoned enzyme (acetylcholinesterase) by scavenging the phosphoryl rest attached on the functional hydroxyl group of the enzyme. Though safer to use, it takes longer to act.

Revival of acetylcholinesterase with pralidoxime chloride works more effectively on nicotinic receptors while blocking acetylcholine with atropine is more effective on muscarinic receptors. Often, severe cases of the poisoning are treated with both drugs.^[6][7]

Countermeasures in Development

Butyrylcholinesterase is a prophylactic countermeasure against organo-phosphorus nerve agents. It acts as a scavenger by binding nerve agent in the blood stream before it can exert effects in the nervous system. Because it is a biological scavenger (and universal target) it is currently the only therapeutic agent effective in providing complete stoichiometric protection against the entire spectrum of organo-phosphorus nerve agents.^[8]

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, whilst V series are persistent. All of the compounds in this class were discovered and synthesized during or soon after World War II, led by Dr. Gerhard Schrader (later under the employment of IG Farben).

This series is the first and oldest family of nerve agents. The first nerve agent ever synthesised 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 USA as a munition, specifically in rockets, aerial bombs, howitzer rounds and gun rounds.^[9]

V-Series

Chemical form of the nerve agent VX

Dr. Ranajit Ghosh, a chemist at the Plant Protection Laboratories of Imperial Chemical Industries was investigating a class of organophosphate compounds (organophosphate esters of substituted aminoethanethiols). Like Dr. Schrader, an earlier investigator of organophosphates, Dr. Ghosh found that they were quite effective pesticides. In 1954, ICI put one of them on the market under the trade name Amiton. It was subsequently withdrawn, as it was too toxic for safe use. The toxicity did not go unnoticed and some of the more toxic materials had in fact been sent to the British Armed Forces research facility at Porton Down for evaluation. After the evaluation was complete, several members of this class of compounds would become 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 probably VX, with the Russian V-gas coming a close second (Amiton is largely forgotten as VG). This class of compounds is also sometimes known as Tammelin's esters, after Lars-Erik Tammelin of the Swedish Institute of Defense Research. Dr. Tammelin was also conducting research on this class of compounds in 1952, but for obvious reasons he did not publicize his work widely.^{[citation needed][clarification needed]}

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. The most studied agent in this family, VX, was invented in the 1950s at Porton Down in the United Kingdom. The other agents in this series have not been studied extensively and information about them is limited. It is known, however, that the V-series agents are about 10 times more toxic than the G-agent sarin (GB)^{[citation needed]}.

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 USA as a munition, consisting of rockets, artillery shells, airplane spray tanks and landmines.^[9][10]

Novichok agents

Main article: Novichok agent

The Novichok (Russian for "newcomer") agents are a series of organophosphate compounds that were developed in the Soviet Union from the mid 1960s to the 1990s. The goal of this program was to develop and manufacture highly deadly chemical weapons that were unknown to the West. These new agents were designed to be undetectable by standard NATO chemical detection equipment and to defeat chemical protective gear.

In addition to the newly developed "third generation" weapons, binary versions of several Soviet agents were developed and are designated as "Novichok" agents.

Insecticides

A number of insecticides, the phenothiazines, organophosphates such as dichlorvos, malathion and parathion, are nerve agents. The metabolism of insects is sufficiently different from mammals that these compounds have little effect on humans and other mammals at proper doses; but there is considerable concern about the effects of long-term exposure to these chemicals by farm workers and animals alike. At high enough doses, however, acute toxicity and death can occur through the same mechanism as other nerve agents. Organophosphate pesticide poisoning is a major cause of disability in many developing countries and is often the preferred method of suicide.^[11]

Dissemination

Several methods exist for disseminating nerve agents on the battlefield. These include:

• Uncontrolled Aerosol Munitions
• Smoke Generation
• Explosive Dissemination
• Atomizers, Humidifiers and Foggers

The method chosen will depend upon the physical nature of the nerve agent(s) used, the nature of the target, and the achievable level of sophistication.^[12]

History

The discovery of nerve agents

This first class of nerve agents, the G-Series, was accidentally discovered in Germany on December 23, 1936 by a research team headed by Dr. 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 ppm of tabun killed all the leaf 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 experience miosis (constriction of the pupils of the eyes), dizziness and severe shortness of breath. It took them three weeks to recover fully.

In 1935 the Nazi government had passed a decree that required all inventions of possible military significance to be reported to the Ministry of War, so in May 1937 Schrader sent a sample of tabun to the chemical warfare (CW) section of the Army Weapons Office in Berlin-Spandau. Dr. Schrader was summoned to the Wehrmacht chemical lab in Berlin to give a demonstration, after which Schrader's patent application and all related research was classified. 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 at Wuppertal-Elberfeld in the Ruhr valley to continue his research in secret throughout World 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 after their initials: Schrader, Ambrose, Rudriger and van der Linde. 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 Dr. 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 'discovered' again 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.^[13] Ethyl sarin was tagged GE and cyclosarin as GF.

During World War II

In 1939, a pilot plant for tabun production was set up at Munster-Lager, on Luneberg heath near the German Army proving grounds at Raubkammer. In January 1940, construction began on a secret plant, code named "Hochwerk" (High factory), for the production of tabun at Dyherrnfurth an der Oder (now Brzeg Dolny in Poland), on the Oder River 40 km (25 mi) from Breslau (now Wrocław) in Silesia.

The plant was large, covering an area of 2.4 by 0.8 km (1.5 by 0.5 miles) 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 Krapkowice) in Upper Silesia. The plant was operated by Anorgana GmbH, a subsidiary of IG Farben, as were all other chemical 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.

3,000 German nationals were employed at Hochwerk, all equipped with respirators and clothing 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 in A Higher Form of Killing: The Secret History of Chemical and Biological Warfare are as follows:

• 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.^[13]

In 1940 the German 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 of World War II. Estimates for total sarin production by Nazi Germany range from 500 kg to 10 tons.

During that time, German intelligence believed that the Allies 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 into artillery 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.

This is detailed in Joseph Borkin's book The Crime and Punishment of IG Farben:

Speer, who was strongly opposed to the introduction of 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.

— Joseph Borkin, The Crime and Punishment of IG Farben

The secret gets out

Towards the end of World War II and during the occupation of Germany, the Allies recovered weapons containing the three German nerve agents of the day, prompting further research into nerve agents by the former Allies. The Red Army captured a factory producing tabun at Dyhernfurth in early 1945, they dismantled the entire site and took it back to Russia. Stocks of tabun, sarin and soman were discovered by all the Allies within Germany; the Anglo-American advance seizing around 250,000 tons of chemical weapons, the subset of nerve agents (totaling around 30,000 tons) was split with the British taking 14,000 tons of tabun-filled bombs and the Americans taking the balance of sarin-filled devices. The British-held bombs were eventually dumped at sea over 1955-56 as Operation Sandcastle.

The fourth G-series nerve agent, cyclosarin, although discovered by German scientists studying organophosphates during WWII was seemingly not found by the Allies, but independently rediscovered in 1949.

In 1952, researchers in Porton Down, England invented the VX nerve agent, inspired by the commercial pesticide Amiton, later reclassified as VG. The UK soon unilaterally abandoned the chemical weapons and chemical weapons research. In 1958 the British government traded their VX technology with the United States of America in exchange for information on thermonuclear weapons; by 1961 the US was producing large amounts of VX and performed its own nerve agent research. The four agents (VE, VG, VM, VX) are collectively known as the "V-Series" class of nerve agents.

Since World War II

Victims of the Halabja chemical weapons attack.

Since World War II, Iraq's use of mustard gas against Iranian troops and Kurds (Iran-Iraq war of 1981–1988) has been the only large-scale use of any chemical weapons. On the scale of the single Kurdish village of Halabja within its own territory, Iraqi forces did expose the populace to some kind of chemical weapons, possibly mustard gas and most likely nerve agents.^[14]

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. One of the most widely publicised uses of nerve agents was the 1995 terrorist attack in which operatives of the Aum Shinrikyo religious group released sarin into the Tokyo subway system.

Ocean disposal of chemical weapons

In 1972, The United States Congress banned the practice of disposing chemical weapons into the ocean. However 32,000 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 created 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. Additionally, due to poor records, they currently only know the rough whereabouts of half of them.

It is unknown how these dumps of chemical weapons have affected the ocean ecology. The steel containers they are contained within face a variable rate of decay and no one is really certain where or how deep they were dumped. If a nerve agent leaks into the ocean, it is unlikely to negatively affect any living organisms before it breaks down into its nonlethal chemical components. This is because nerve agents are not very stable, so even remaining in their containers, they are likely not very active any more. Then, if they were to be exposed to salt water, the salt water would likely break them down very quickly before they did any significant damage to animal life^{[citation needed]}.

Footnotes

1. ^ Sidell, Frederick R.; Ernest T. Takafuji, David R. Franz (D.V.M.) (1997). Medical aspects of chemical and biological warfare. Borden Institute, Walter Reed Army Medical Center. pp. 131–139. 
2. ^ A Tutorial to Chemical and Biological Agents
3. ^ Effects of Chemical Agents
4. ^ Sidell, Frederick R.; Ernest T. Takafuji, David R. Franz (D.V.M.) (1997). Medical aspects of chemical and biological warfare. Borden Institute, Walter Reed Army Medical Center. pp. 147–149. 
5. ^ Sidell, F. R (1974). "Soman and sarin: clinical manifestations and treatment of accidental poisoning by organophosphates". Clinical toxicology 7 (1): 1–17. doi:10.3109/15563657408987971. PMID 4838227. 
6. ^ http://ocw.core.org.cn/CORE/medicine/veterinary-pharmacology/lecture_notes_files/notes_17.Chapter_Fifteen__Detoxicants.pdf
7. ^ http://www.fas.org/nuke/guide/usa/doctrine/army/mmcch/NervAgnt.htm
8. ^ http://www.jpeocbd.osd.mil/packs/Default.aspx?pg=1207
9. ^ ^{a b} FM 3-8 Chemical Reference handbook; US Army; 1967
10. ^ "U.S. Army Destroys Entire Stockpile of VX Spray Tanks" http://www.cma.army.mil/fndocumentviewer.aspx?docid=003677713, U.S. Army Chemical Materials Agency, December 26, 2007, accessed January 4, 2007
11. ^ "Overcoming apathy in research on organophosphate poisoning", BMJ (former British Medical Journal) 2004;329:1231-1233 (20 November)
12. ^ Ledgard, Jared (2006). A Laboratory History of Chemical Warfare Agents. 
13. ^ ^{a b} https://ccc.apgea.army.mil/sarea/products/textbook/Web_Version/chapters/chapter_5.htm#history, Frederick Sidell
14. ^ Susan, Kinsley. "Whatever Happened To The Iraqi Kurds?". Human Rights Watch in Iraq. Human Rights Watch. http://www.hrw.org/legacy/reports/1991/IRAQ913.htm. Retrieved 20 July 2011. 

References

• Borkin, Joseph (1978). The Crime and Punishment of IG Farben. New York: Free Press. 1978. ISBN 0-02-904630-0, available for download in Australia (as it is out-of-print) see this link.
• Clarke, Robin (1969). We all fall down: the prospects of biological and chemical warfare. Penguin. ISBN 0-14-021121-7. 
• E-Medicine. (June 29, 2004). CBRNE – Nerve Agents, V-series: Ve, Vg, Vm, Vx. Retrieved Oct. 23, 2004.
• E-Medicine. (June 30, 2004). CBRNE – Nerve Agents, G-series: Tabun, Sarin, Soman. Retrieved Oct. 23, 2004.
• Mitretek Systems. (May 2004). Short History of the Development of Nerve Gases. Retrieved Oct. 23, 2004.
• Paxman, J.; Harris, R. (2002). A Higher Form of Killing: The Secret History of Chemical and Biological Warfare (2002 Rando edition). Random House Press. ISBN 0-8129-6653-8.
• United States Senate, 103d Congress, 2d Session. (May 25, 1994). The Riegle Report. Retrieved Nov. 6, 2004.
• Organisation for the Prohibition of Chemical Weapons – Nerve Agents [1]
• History of fluorophosphates as related to the development of nerve agents in Germany, Great Britain and the U.S.A.
• C. H. Gunderson, C. R. Lehmann, F. R. Sidell, B. Jabbari (1992). "Nerve agents: a review". Neurology 42 (5): 946–950. PMID 1315942. http://neurology.org/cgi/content/abstract/42/5/946. 
• Buckley NA, Roberts D, Eddleston M. Overcoming apathy in research on organophosphate poisoning. BMJ. 2004 Nov 20;329(7476):1231–3. Review. PMID 15550429

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
• Goats' Milk Used in Production of Anti-nerve Gas Agents
• AChE inhibitors and substrates – 2wfz, 2wg0, 2wg1, 1som in Proteopedia