Nerve agents are chemicals which interfere with the action of the nervous system. Their primary mode of action is inhibition of acetylcholinesterase, resulting in acetycholine accumulation in synaptic junctions, and producing an initial stimulation followed by prevention of cholinergic neurotransmission. Other important effects may be produced by direct binding of some nerve agents to cardiac muscarinic receptors and nicotinic receptors, stimulation of NMDA receptors, and interference with GABA neurotransmission.

The majority of nerve agents belong to a class of compounds known as the organophosphates. In addition there is a class of compounds known as the carbamates which include compounds which act in a similar manner to the organophosphate nerve agents.

Most nerve agents are colorless to brown (depending on purity) liquids with vapors that are heavier than air. Evaporation rates for nerve agents range from roughly equal to those for water to that of motor oil. A variety of odors have been reported for nerve agents, but this appears to be highly subjective and dependent on the presence of impurities, and should not be used to identify agents.

Response to Incidents

Nerve agents have the potential to rapidly affect large numbers of people. There are two types of releases, unintentional and intentional.

In an unintentional release, which would most likely occur as a result of a transportation accident or at a storage or disposal facility, emergency responders would most probably be aware of the nature of the agent, including its specific identity, fairly early on (hopefully when dispatched. The response might well also include specialized units trained to deal with such accidental releases. In such cases, the information pages for the specific agent involved should be consulted and the recommendations provided there followed.

In the case of an intentional release, such as might occur in the case of terrorist use of a chemical agent, the specific identity of the agent may not be known to responders or medical personnel for some time.

The following information is intended for the situation in which the identity of the agent is not immediately known.

DETECTION

Nerve agent sensitive chemical agent detectors (e.g., CAM, M18A2, M256, etc.) and papers (e.g., M8, M9) may be used for detection.

Detection of nerve agents may also result from the observation of symptoms associated with nerve agent intoxication.

SYMPTOMS AND EFFECTS

Miosis is a very characteristic symptom of nerve agent intoxication. Victims will often report difficulty in seeing (blurred vision, things seem dim). Other commonly experienced symptoms are rhinorrhea and difficulty breathing. Onset is usually very rapid, occurring within seconds to minutes of exposure to vapors, within half an hour of exposure to liquid agents.

Lowered acetylcholinesterase levels are indicators of nerve agent intoxication in victims. Rapid assays exist for cholinesterase activity. However, note that treatment should be based on observed symptoms, rather than cholinesterase levels, especially in mild or moderate intoxication, where depending on the agent, red blood cell (RBC) or plasma cholinesterase levels are affected differently depending on the agents. It is possible for a victim to be moderately intoxicated while still exhibiting cholinesterase levels in the normal range. The change in cholinesterase levels is a better indicator of the severity of intoxication, however baseline levels for victims are unlikely to be available.

Depending on the degree of intoxication, symptoms may include:

MEDICAL COUNTERMEASURES

Useful Drugs	Atropine sulfate	Oximes	Diazepam

Initial care should include terminating the exposure to the agent by removal of the victim from the contaminated area followed by decontamination. Only rescuers provided with LEVEL A chemical protective ensembles should enter a contaminated area to attempt rescue of individuals unable to assist themselves. Supportive care will involve ensuring an airway, and early intubation may be required for victims with large exposures.

! Use of succinylcholine to assist intubation is contraindicated due to possible interactions with nerve agents.

The immediate treatment for nerve agent intoxication is intravenous injection of 2 mg atropine sulfate (pediatric dose calculate based on 0.02 mg/kg with a minimum dose of 0.1 mg) (intramuscular injection should be considered if the patient is hypoxic and ventilation can not be initiated, as there is a risk of ventricular fibrillation). An initial dose of 5 mg atropine sulfate (pediatric dose calculate based on 0.05 mg/kg) should be used for severe intoxication This should be followed by additional injections of atropine at 10-15 minute intervals, continuing until bronchoconstriction has been eliminated and secretions dried. (At this point, bradycardia, if it was present, should also have been reversed; miosis will not be reversed by systemic atropine) If breathing has stopped, a mechanical respirator should be used to ventilate the patient. DO NOT ATTEMPT MOUTH-TO-MOUTH RESUCITATION. If possible, oxygen or oxygen-enriched air should be used for ventilation. If possible, monitor cardiac activity.

Oximes (pralidoxime salts, obidoxime) may be of use in restoring acetylcholinesterase activity. Their effectiveness varies with the agent involved in the intoxication. Obidoxime is the most generally useful oxime; however, it may cause liver damage. In general, absent specific information on the agent, use of pralidoxime salts should be considered, with a slow intravenous infusion of pralidoxime chloride of 500 mg to 2 g (pediatric dose calculate based on 15-25 mg/kg) being given initially. An intramuscular dose of 1 mg in 3 mL sterile saline may be used if IV access can not be established. Consider repeat doses at hourly intervals if the clinical condition does not change or if it worsens.

Diazepam should be administered to control convulsions. It also has value in controlling fear on the part of the patient. An initial dose of 5 mg may be followed by additional doses at 15 minute intervals up to a total of 15 mg.

More information on therapy may be found on the pages covering specific agents.

The categories above are based on on categories in the Textbook of Military Medicine, Part 1, Medical Aspects of Chemical and Biological Warfare. Categories may be briefly defined as follows:

• Immediate:Victim requires immediate life-saving care when that care is available and of short duration.
• Delayed:Victim requires major/prolonged care, but delay of care will not adversely affect the outcome of the injury.
• Minimal:Victim has relatively minor injuries that can be helped by nonphysicians.
• Expectant:Victim has severe injuries which will not be survivable even given optimal care with available resources.

Level A protective equipment (self-contained breathing equipment or gas mask, barrier suit) must be used. Medical personnel treating casualties should avoid direct (skin-to skin) contact; protective gear including breathing protection should be worn when treating casualties prior to decontamination. Latex gloves are not adequate protection. Victims should be decontaminated as rapidly as possible (see the section on decontamination). Remove casualties from exposure as rapidly as possible. Victims must not be moved into clean treatment areas where unmasked/ungloved personnel are working until decontamination is complete.

The combustion products produced by burning nerve agents are generally less toxic than the agents. If nerve agents are burning and other considerations permit it, the fire should not be extinguished.

Agents absorbed by cloth (clothing, blankets, etc.) may be released as a vapor by the cloth for for a significant period after exposure.

Also refer to 2004 Emergency Response Guidebook (ERG2004) Guide 153.

DECONTAMINATION

Victims

• Remove victim from contaminated zone
• Remove contaminated clothing, personal jewelry, etc.
• Wash with copious amounts of water at a comfortable ("tepid") temperature
• Wash with 0.5% hypochlorite solution (e.g., prepd. by mixing 1 part household bleach with 9 parts water) or, alternately, soap and water.
• Rinse with copious amounts of tepid water.

In general, you will encounter only small amounts of residual liquid contamination among survivors, since exposure to large amounts of liquid nerve agent is rapidly fatal.

Property

Surface decontamination may be accomplished using hypochlorite bleach slurries, dilute alkalis, or DS2 decontaminating solution. Note that some agents will generate toxic reaction products when treated with decontaminants. If possible, decontamination of facilities and equipment should be deferred until the specific agent has been identified.

Adsorbant powders may be used to contain liquid agents.

COMMON PRECURSORS

Ammonium bifluoride Diethylaminoethanol Diethyl N,N-dimethylphosphoramidate Diethyl ethylphosphonate Diethyl methylphosphonite Diethyl phosphite Diisopropylamine N,N-Diisopropyl-(beta)-aminoethyl chloride N,N-Diisopropylaminoethanethiol N,N-Diisopropyl-(beta)-aminoethanol Dimethylamine Dimethylamine hydrochloride Dimethyl ethylphosphonate Dimethyl methylphosphonate Dimethylphosphite Ethylphosphonous dichloride Ethylphosphonous difluoride Ethylphosphonyl dichloride Ethylphosphonyl difluoride Hydrogen fluoride Methylphosphonous dichloride

Methylphosphonous difluoride Methylphosphonyl dichloride Methylphosphonyl difluoride O-ethyl-2-(diisopropylamino)ethyl methylphosphonate Phosphorus oxychloride Phosphorus pentachloride Phosphorus pentasulfide Phosphorus trichloride Pinacolone Pinacolyl alcohol Potassium bifluoride Potassium cyanide Potassium fluoride Sodium bifluoride Sodium cyanide Sodium fluoride Thionyl chloride Triethyl phosphite Trimethyl phosphite

COMMENTS

All declared military nerve agents belong to the organophosphate family of compounds. The carbamates have not, at least according to the open literature, been militarized.

Principal Organophosphate Nerve Agents Investigated for Military Use
CODE	CAS Index Name	CAS Registry Number	Other
GA	Phosphoramidocyanidic acid, dimethyl-, ethyl ester	77-81-6	Tabun
GB	Phosphonofluoridic acid, methyl-, 1-methylethyl ester	107-44-8	Sarin
GD	Phosphonofluoridic acid, methyl-, 1,2,2-trimethylpropyl ester	96-64-0	Soman
GE	Phosphonofluoridic acid, ethyl-, 1-methylethyl ester	1189-87-3
GF	Phosphonofluoridic acid, methyl-, cyclohexyl ester	329-99-7	cyclosarin
GV	Phosphoramidofluoridic acid, dimethyl-, 2-(dimethylamino)ethyl ester	141102-74-1	also GP
VE	Phosphonothioic acid, ethyl-, S-[2-(diethylamino)ethyl] O-ethyl ester	21738-25-0
VG	Phosphorothioic acid, S-[2-(diethylamino)ethyl] O,O-diethyl ester	78-53-5	Amiton (sold as pesticide)
VM	Phosphonothioic acid, methyl-, S-[2-(diethylamino)ethyl] O-ethyl ester	21770-86-5
VR	Phosphonothioic acid, methyl-, S-[2-(diethylamino)ethyl] O-(2-methylpropyl) ester	159939-87-4	also RVX, Russian VX
VS	Phosphonothioic acid, ethyl-, S-[2-[bis(1-methylethyl)amino]ethyl] O-ethyl ester	73835-17-3
VX	Phosphonothioic acid, methyl-, S-[2-[bis(1-methylethyl)amino]ethyl] O-ethyl ester	50782-69-9

Structures of Selected Nerve Agents

Historical Notes

Toxic organophosphate compounds had been investigated extensively as pesticides during the 1920's and 1930's, but it was not until 1937 that their potential as chemical warfare agents was recognized.

Tabun (GA), which was to become the first military nerve agent, was first examined for use as an insecticide shortly before Christmas, 1936 in a program under the direction of Dr. Gerhard Schrader at the Bayer facility at Elberfield. In short order, an accidental exposure of Dr. Schrader and a laboratory assistant to Tabun vapors made it quite clear that this compound had potential military applications. This was reported to the German government, which subsequently undertook the production of Tabun and the filling of munitions at at Dyhernfurth (now Bzerg Dolny, Poland). Over the course of the Second World War, the Germans produced over 12,000 tons of this agent.

The Germans also investigated a series of related organophosphate compounds for military utility (both as weapons and as insecticides), and at the end of the war had begun to produce a second nerve agent, Sarin (GB) and were investigating the utility of a third, Soman (GD).

Intelligence reports on organophosphate insecticides identified by the various German programs were declassified (some reports, notably an account by Dr. Schrader, were issued in an unclassified version that detailed only the insecticide work and a classified version that also detailed the war gas work). This both stimulated interest in organophosphates in the insecticide industry and (because the work had been done for the German military) made the compounds the Germans had identified available for anyone to use without the need to obtain licenses or pay royalties.

After the end of the war, the victors assimilated the work done by the Germans. The British and the Americans would decide to make Sarin their nerve agent of choice, while the Soviet Union, after flirting with Tabun (they had, after all, captured the manufacturing plant), would decide on both Sarin and Soman.

In the 1950's, organophosphates continued to attract interest as pesticides (as well as as chemical warfare agents). In 1952, Dr. Ranajit Ghosh, a chemist at the Plant Protection Laboratories of the British firm Imperial Chemical Industries was investigating a class of organophosphate compounds (organophosphate esters of substituted aminoethanethiols). Like the earlier investigators 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 seen to the British 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 who you talk to, 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.

Nerve agent research continued. One direction was in the development of even more toxic agents. The greatest strides in this direction Vil Mirzayanov, who has related details of the Soviet chemical warfare program, has stated that the Soviets achieved considerable success with this in the period 1985, developing several highly toxic agents, currently known in the open literature only as "Foliant" agents (for the program name) and by various code designations, such as A-230 and A-232.

Another direction was intended to develop ways of making it safer for the users. This lead to the development of the so-called binary weapons, in which precursors for the nerve agents are mixed in a munition to produce the agent just prior to its use. As the precursors are often significantly less hazardous than the agents, this makes handling and transporting the munitions much simpler. In addition, the precursors may be more simple to stabilize than the agent they produce. Binary systems are known to have been developed for sarin, soman, and VX - they are coded with the code of the agent produced followed by a -2 (respectively GB-2, GD-2, and VX-2). Vil Mirzayanov has indicated that binary versions of the Russian V gas and some of the Foliant agents have also been developed, and are designated as "Novichok" (newcomer) agents. In this instance, an additional motivation is to make the identification of these agents harder, as the compounds are supposed to be related to agricultural chemicals.

Use in War

Despite their monopoly on nerve agents in the Second World War, the Germans never used them. The reasons for this are not totally clear, but certainly owe much to the following factors:

• the tactical situation was rarely appropriate for the use of chemical weapons during the Second World War,
• the Germans had reason to fear any chemical retaliation, since they depended on horse-drawn transport to a greater extent than the Allies, and
• the Germans believed that the Allies also possessed nerve agents (diisopropylfluorophosphate, a pesticide, had been studied under the code name PF-3, but was ultimately rejected by the Americans).

Terrorist Use

As knowledge of the toxic properties of nerve agents spread in the wake of the Second World War and the rise of the Cold War, there were a number a number of incidents of attempts to acquire and threats to use nerve agents by non-state actors. Prior to the 1990s, they were generally not taken too seriously, although occasional threats, such as those made by the so-called Alphabet Bomber in 1974, seemed to display sufficient knowledge to make them credible. It was generally felt, however, that the combination of technical obstacles and a reluctance to cross the threshold to the use of weapons of mass destruction in pursuit of political goals (in part due to a fear of the backlash that would be generated) would restrain terrorists from the use of chemical weapons.

However, in the 1990s, the threshold would be crossed by a new type of terrorist group, the apocalyptic cult. On June 27th, 1994, the Aum Shinrikyo organization released sarin (GB) in Matsumoto, Japan, killing 7 people and injuring at least 500. As the group did not claim responsibility, and as the intentional use of nerve agents was deemed unlikely, the police at first looked the wrong way, suspecting an accident by a local man attempting to produce a pesticide. As time went on and the evidence mounted that it was, in fact, a deliberate release, the police began to turn their attention to Aum, but were hampered by Japan's stringent laws regarding the protection of religions. On March 22, 1995, however, Aum Shinrikyo acted in a manner that would force action, releasing sarin in several subway trains in Tokyo. There were 12 deaths, and more than 6000 injured.

While the police moved very rapidly after the Tokyo subway incident, it was widely seen as a case of locking the barn door after the horse was gone. It did not help that they were unable to secure all of Aum's facilities, as abortive attacks with other agents were made even after the police had moved in on the facility where there sarin had been produced. And, in the course of the subsequent investigation, it was learned that sarin was not the only nerve agent the cult had investigated - they had also produced small quantities of VX, and used it in at least one murder.

Related International Classification of Diseases Codes

Heading	ICD-9-CM
Toxic effect of organophosphate & carbamate	989.3
Accidental poisoning by other specified gases and vapors	E869.8
Suicide and self-inflicted poisoning using other specified gases and vapors	E952.8
Assault by poisoning using other gases and vapors	E962.2
Injury due to terrorism involving chemical weapons	E979.7
Injury due to war operations by gases, fumes, and chemicals	E997.2
Death due to terrorism involving chemical weapons	U01.7
Heading	ICD-10
Accidental poisoning by and exposure to other and unspecified chemicals and noxious substances	X49
Intentional self-poisoning (suicide) by and exposure to other gases and vapors	X67
Assault (homicide) by gases and vapors	X88
Assault (homicide) by other specified chemicals and noxious substances	X89
Assault (homicide) by unspecified chemical or noxious substance	X90
War operations involving chemical weapons and other forms of unconventional warfare	Y36.7

Selected References and Resources

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