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formerly the Center for Biosecurity of UPMC Nerve Agents
Background
1984.4 Toward the end of that war, the Iraqi military reportedly Nerve agents are a class of chemicals grouped together based on deployed a cocktail of chemical weapons—possibly including their common mechanism of action, which is interruption of GB, GA, and VX—against its own Kurdish population living vital nerve transmissions to various organs.1,2 Nerve agents are usually organophosphates (OP)—esters of phosphoric acid— Aum Shinrikyo, the Japanese cult/terrorist organization is also which, as a group, can range in toxicity from relatively harmless known for use of nerve agents. In 1994, the group released to lethal at certain dosages.2 Indeed, many commonly used sarin gas in a failed attempt to assassinate local judges in insecticides in the United States contain organophosphates.2 Matsumoto, Japan; that action resulted in 8 civilian deaths.8 Military nerve agents can be extremely lethal even at small The following year, Aum released sarin gas into the Tokyo doses.3 The most well-known of these are tabun, sarin, soman, subway system, killing 13 people and sending more than 6,000 GF, and VX. Like other organophosphates, the military nerve agents are manmade compounds; none are found in nature.2 In December 2012, during the ongoing civil war in Syria, there were reports of a release of nerve agents against Syrian Use as a Chemical Warfare Agent
civilians in the town of Aleppo.9 The Assad government and the The first nerve agent of military relevance was inadvertently opposition forces have since both claimed that it was the other discovered in 1937 by the German chemist Gerhard Schrader who released the nerve agents.9 While details about the alleged while he was conducting research on ethyl-N-dimethyl- release remain unclear, both Britain and France have said that phosphoroamidocyanate, now more commonly known as there is credible evidence indicating that Syria’s government has tabun (GA). After his discovery of GA’s toxicity and lethality, released chemical weapons multiple times during the civil war.10 Dr. Schrader reported his findings to the German War The US continues to investigate the claim.10 Ministry, which went on to weaponize GA, sarin (GB), and soman (GD)—known collectively as the G-series.2 In the Mechanism of Action & Physical Properties
late 1940s, researchers in England produced a group of nerve At room temperature, nerve agents are primarily liquid.2 The agents known as the V-series, which includes the chemical G-series agents are clear, colorless, and tasteless.11 Sarin is the weapon VX, or O-ethyl S-[2-(diisopropylamino)ethyl] most volatile nerve agent.11 VX, is the least volatile, is odorless, Despite the 1925 Geneva Protocol, “For the Prohibition of These agents act primarily by interfering with the nervous the Use in War of Asphyxiating, Poisonous or other Gases, system, generating an overstimulation of muscles.2 The primary and of Bacteriological Methods of Warfare,” many countries mechanism of toxicity results from the inhibition of the enzyme have developed and maintained their own stores of chemical acetylcholinesterase (AChE) at the neuromuscular junction,1,12 weapons.4 The United States and the Soviet Union both which causes overstimulation of the muscles through the built stockpiles of chemical weapons, including nerve agents, excessive accumulation of the neurotransmitter acetylcholine during the Cold War.2 The Chemical Weapons Convention (ACh).12 This over stimulation results in muscle paralysis.
(CWC), which became effective in April 1997, effectively bans development, stockpiling, or use of all chemical weapons.5 Signs & Symptoms
As signatories to the CWC, the US and Russia, as well as the other 163 signatories, are compelled to reduce and ultimately Nerve agents can enter the body through inhalation or through eliminate their stockpiles of chemical weapons, including nerve the skin.2 G-series agents are significantly more toxic when inhaled.2 Symptoms from exposure to nerve agents will vary depending on the type of agent and the type and extent of Despite the large stores of these nerve agents around the world, exposure, though generally, symptoms will include miosis the actual use of military nerve agents has been limited.2 The (constriction of the pupils), rhinorrhea (runny nose), dyspnea Iran-Iraq War (1980-1988) saw the first use of nerve agents in (shortness of breath), convulsions, and a loss of muscle control, modern warfare, when Iraq released GA on Iranian troops in with an onset of symptoms potentially occurring within seconds UPMC Center for Health Security, www.UPMCHealthSecurity.org Table 1: Nerve Agents Overview
State at Room
Chemical Name
Range of Toxicity
Temperature
Tabun (GA)
exposure can be lethal within colorless vapor Sarin (GB)
methylphosphoro- drop on skin can cause death temperature or when aerosolized by an explosion Soman (GD) Trimethyl-
Cyclosarin
temperature or when aerosolized by an explosion or minutes.13 Nerve agents are lethal at certain levels of exposure,2 nausea and vomiting, rhinorrhea, increased salivation, tightness with death resulting from respiratory failure, depression of the central nervous system, and excessive secretions.3 Transdermal exposure to nerve agents generally results in a Inhalation exposure at a large enough dose, depending on vapor slower onset of systemic symptoms, as the toxins are gradually concentration and duration of exposure, can result in an onset diffused through the skin. The latency and severity of of symptoms within 30 seconds to 2 minutes.1 Symptoms may symptoms are affected by the temperature of the surrounding include loss of consciousness, convulsions, flaccid paralysis, and area, the dose, and the anatomical area of exposure.1 With respiratory failure.3,14 Symptoms after an inhalation exposure to exposure on parts of the body where the dermal layers are thin, a more limited quantity of vapor will still begin quite soon after such as the ears and eyelids, the toxins will be absorbed more exposure, though are generally not as severe. Symptoms may rapidly.1 Effects may begin within 30 minutes, or as long as 18 include miosis, red conjunctiva, dimmed or blurry vision, pain, UPMC Center for Health Security, www.UPMCHealthSecurity.org Table 2: Onset and Symptoms of Nerve Agent Exposure
Inhalation
Transdermal
Onset: Seconds to minutes following exposure
Onset: Up to 18 hours after exposure
Exposure
Symptoms: Miosis, rhinorrhea, dyspnea
Symptoms: Sweating, twitching at site of exposure; possibly
nausea, vomiting, diarrhea
Onset: Seconds to minutes following exposure
Onset: Within 30 minutes of exposure
Exposure
Symptoms: Loss of consciousness, seizures, apnea,
Symptoms: Loss of consciousness, seizures, apnea, flaccid paralysis
flaccid paralysis; miosis, nose and mouth secretions With an exposure that is limited to a very small drop, Atropine1 works by counteracting the effects of the excessive symptoms may include sweating and twitching at the site amount of acetyl choline while the body works to clear the of exposure.14 Slightly greater exposure can result in nausea, nerve agent.1,2 Pralidoxime chloride works by reversing the vomiting, and diarrhea.14 Following exposure to a full drop, agent’s mechanism of action, and reactivating AChE.1,2 symptoms may include loss of consciousness, convulsions, and Early treatment with pralidoxime can prevent the otherwise irreversible nerve damage associated with exposure.1 Pralidoxime should continue to be administered for a period of Diagnosis
For clinical diagnosis, the most reliable indicator of exposure to a chemical nerve agent is generally miosis, though it will not Control Measures & Prophylaxis
always occur in victims who have come in contact with nerve Exposure to organophosphate pesticides is relatively common.13 agents through transdermal exposure.1,14 Following inhalation In the US, where these pesticides are widely used, many exposure to nerve agents in vapor form, however, nearly all emergency medical teams are familiar with the diagnosis victims will present with miosis, usually in both eyes.14 Indeed, and treatment of exposure and have access to atropine and after the Tokyo subway sarin release, more than 90% of victims pralidoxime.13 However, in widespread exposure to military who were exposed to the vapor presented with miosis.1 nerve agents, which would likely result in multiple victims, local supplies of these drugs would be quickly depleted.13 Treatment
Further protective measures against nerve agents include The effectiveness of treatments for exposure to a nerve agent gas masks and protective clothing.4 Soldiers who are at risk depends on the dose, type of exposure, and the specific agents of exposure to nerve agents will often carry atropine and involved.2 Some nerve agents can produce irreversible effects pralidoxime injectors in an antidote kit, so as to be able to within just a few minutes of exposure, though others take have quick access to treatment if they are exposed.2,4 Iranian much longer.2 Exposure to soman, for example, must be treated troops were known to carry atropine injectors during the Iran- within minutes of exposure for treatment to be effective.2 Iraq War,4 and US troops carried both of these drugs in their Exposure to tabun, by comparison, can be treated several hours antidote kits during the Persian Gulf War.2 Some drugs, such as pyridostigmine bromide, can serve as Atropine and pralidoxime chloride are the 2 drugs used to prophylaxis. Prophylactic treatment with pyridostigmine treat nerve agent exposure.2 Diazepam (valium) or similar bromide may allow for a longer treatment window after benzodiazepines can be used to mitigate the convulsions exposure to nerve agents,2 and may improve survival rates.1 References
3. Sifton DW, Kelly GL. PDR guide to biological and 1. Geoghegan J, Tong JL. Chemical warfare agents. chemical warfare response. 1st ed. Montvale, NJ: Thomson/ Continuing Education in Anaesthesia, Critical Care & Pain. 4. Ali J. Chemical Weapons and the Iran-Iraq War: A Case 2. Shea DA. Chemical Weapons: A Summary Report of Study in Noncompliance. The Nonproliferation Review. Characteristics and Effects: CRS Report for Congress; 2001;Spring:43-58. http://cns.miis.edu/npr/pdfs/81ali.pdf. December 13, 2012: http://www.fas.org/sgp/crs/nuke/ R42862.pdf. Accessed April 18, 2013.
UPMC Center for Health Security, www.UPMCHealthSecurity.org 5. Convention on the Prohibition of the Development, 11. CDC. Nerve Agents (GA, GB, GD, VX). Toxic Substances Production, Stockpiling and Use of Chemical Weapons and Portal 2011; March 3, 2011 Available at: http://www.atsdr.
cdc.gov/substances/toxsubstance.asp?toxid=93. Accessed 6. CDC. Chemical Weapons Elimination - Closing U.S. Chemical Warfare Agent Disposal Facilities. 2012; July 18, 12. Golomb BA, Marshall GN, Harley NH, et al. A review 2012 Available at: http://www.cdc.gov/nceh/demil/closing_ of the scientific literature as it pertains to Gulf War illnesses. facilities.htm. Accessed April 18, 2013.
7. Pan PP. Plant to Destroy Chemical Weapons Opens in 13. Institute of Medicine (U.S.). Committee on R & D Needs Russia. The Washington Post. May 30, 2009. http://articles.
for Improving Civilian Medical Response to Chemical and washingtonpost.com/2009-05-30/world/36772555_1_ Biological Terrorism Incidents., National Research Council shells-and-warheads-nerve-agents-chemical-safety. Accessed (U.S.). Board on Environmental Studies and Toxicology. Chemical and biological terrorism : research and development 8. Richard Danzig MS, Terrance Leighton, Lloyd Hough, to improve civilian medical response. Washington, D.C.: Hidemi Yuki, Rui Kotani, Zachary M. Hosford. Aum Shinrikyo: Insights Into How Terrorists Develop Biological 14. Sidell FR, Patrick WC, Dashiell TR. Jane’s chem-bio and Chemical Weapons: Center for a New American handbook. Alexandria, Va.: Jane’s Information Group; 1998.
9. DeYoung K. Britain, France claim Syria used chemical This fact sheet may be reproduced and distributed ONLY as is. weapons. The Washington Post. April 18, 2013. http:// Requests for permission to change or alter the content or appearance www.washingtonpost.com/world/national-security/britain- in any way should be directed to the webmaster at: france-claim-syria-used-chemical-weapons/2013/04/18/ f17a2e7c-a82f-11e2-a8e2-5b98cb59187f_story_1.html. Accessed April 19, 2013.
10. Gladstone R, Schmitt E. Syria Faces New Claim on Chemical Arms. The New York Times. April 18, 2013. http://www.nytimes.com/2013/04/19/world/middleeast/Syria.html?_r=0. Accessed April 19, 2013.
UPMC Center for Health Security, www.UPMCHealthSecurity.org

Source: http://www.upmchealthsecurity.org/website/our_work/biological-threats-and-epidemics/fact_sheets/nerve_agents.pdf