Medical Aspects of Chemical Warfare (2008) - The Black Vault

Medical Aspects of Chemical WarfareINTRODUCTIONNerve agents are highly lethal chemical agentthreats to the US population. Chemically, they belongto the organophosphorus (OP) compound groupand are among the most toxic substances identified.OP compounds were originally developed for useas insecticides, but their extreme toxicity and rapideffects on higher vertebrates have led to their adoptionas weapons of warfare. The OP compounds mostcommonly used as chemical weapons (referred toas “nerve agents”) are O-ethyl N,N-dimethyl phosphoramidocyanidate(tabun; North Atlantic TreatyOrganization [NATO] designation: GA), diisopropylphosphonofluoridate (sarin; NATO designation: GB),pinacoloxymethyl-fluorophosphonate (soman; NATOdesignation: GD), cyclohexylmethyl phosphonofluoridate(cyclosarin; NATO designation: GF), and ethyl-S-diisopropylaminoethyl methylphosphonothiolate(VX). Newer, nontraditional nerve agents pose evengreater dangers than these traditional ones.Nerve agents in aerosol or liquid form can enter thebody by inhalation or by absorption through the skin.Poisoning may also occur through the consumptionof liquids or foods contaminated with nerve agents.Nerve agents are lethal at extremely low levels; exposureto a high concentration of nerve agent can result indeath within minutes. Poisoning takes longer when thenerve agent is absorbed through the skin. The valuesfor the median lethal dose (LD 50) in mammals, includingestimates for humans, are in the mg/kg dose rangefor all routes of exposure except skin, in which LD 50values are in the mg/kg range. 1 Personnel may also beeffected through secondary contact with contaminatedvictims. Survivors may have long-term central nervoussystem dysfunction following intoxication. 2The acute toxicity of OPs is attributed to their bindingto and irreversible inhibition of acetylcholinesterase(AChE). The resulting increase in acetylcholineconcentration manifests at the cholinergic synapsesof both the peripheral and central nervous systemsby over-stimulation at the neuromuscular junctionsas well as alteration in the function of the respiratorycenter. 3–5 This precipitates a cholinergic crisis characterizedby miosis, increased tracheobronchial andsalivary secretions, bronchoconstriction, bradycardia,fasciculation, behavioral incapacitation, muscularweakness, and convulsions, culminating in death byrespiratory failure. 3Nerve agents are stable, easily dispersed, and can bemanufactured by readily available industrial chemicalprocesses, including OP pesticide production facilities,which can easily be converted to produce nerveagents. Even the most dangerous forms of nerve agentsare within the technical capability of sophisticatedterrorist networks. Nerve agents possessed by roguestates and other potential US adversaries have longbeen known to pose a serious threat to US forces. AumShinrikyo’s 1995 sarin attack in the Tokyo subway systemdemonstrated that nerve agents are also a real andpotent terrorist threat to civilian populations. Nerveagents are attractive chemical weapons for terroristuse because small quantities are fast-acting and cancause death or harm by multiple routes. Some types ofnerve agents are highly persistent, enabling terroriststo construct long-lasting hazards to target populations.For example, the administration of highly persistentnerve agents to frequently used public facilities, likesubway trains, can effect mass disruption by causingcitizens to fear using those facilities important toeveryday life. The use of nerve agents in combinationwith other weapons may also make differentiatingcausalities challenging and place first responders andlaw enforcement personnel at risk when entering acontaminated area.Current antidotal regimens for OP poisoning consistof a combination of pretreatment with a spontaneouslyreactivating AChE inhibitor, such as pyridostigminebromide, and postexposure therapy with an anticholinergicdrug, such as atropine sulfate, and an oxime,such as 2-pralidoxime chloride 6 and an anticonvulsantsuch as diazepam, 7 if needed. Although these antidotalregimens effectively prevent lethality and, inbest cases, reverse toxicity following exposure, theydo not prevent the exposed individual from becominga casualty. Moreover, no current therapies for nerveagent exposure can provide sustained protection toan individual; they have to be readministered withinminutes or hours and are therefore limited by practicaland logistical issues. Treated patients often show signsof postexposure incapacitation, convulsions, and performancedeficits or, in the case of recurring seizures,permanent brain damage. 8–10 Some nerve agents, suchas soman, present an additional challenge because ofthe rapid dealkylation of soman-inhibited AChE thatis resistant to therapeutic reversal by an oxime.An urgent need exists for new medical countermeasuresto nerve agent exposure that provide highersurvival rates, eliminate or reduce enduring adverse effectsto survivors, and significantly reduce or eliminatethe need for repeated administration of therapeuticdrugs. Ideally, medical treatment should be administeredwithin approximately 1 minute after exposureand should be effective for all OP compounds. Thesechallenges stimulated the development of enzymebioscavengers as a pretreatment therapy to sequester244