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

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Medical DiagnosticsChapter 22MEDICAL DIAGNOSTICSBenedict R. Capacio, Phd*; J. Richard Smith † ; Richard K. Gordon, Phd ‡ ; Julian R. Haigh, Phd § ; JohnR. Barr, Phd ¥ ; a n d Gennady E. Platoff Jr, Phd INTRODUCTIONNERVE AGENTSSULFUR MUSTARDLEWISITECYANIDEPHOSGENE3-QUINUCLIDINYL BENZILATESAMPLE CONSIDERATIONSSummary* Chief, Medical Diagnostic and Chemical Branch, Analytical Toxicology Division, US Army Medical Research Institute of Chemical Defense, 3100Rickets Point Road, Aberdeen Proving Ground, Maryland 21010-5400† Chemist, Medical Diagnostic and Chemical Branch, Analytical Toxicology Division, US Army Medical Research Institute of Chemical Defense, 3100Rickets Point Road, Aberdeen Proving Ground, Maryland 21010-5400‡ Chief, Department of Biochemical Pharmacology, Biochemistry Division, Walter Reed Army Institute of Research, 503 Robert Grant Road, Silver Spring,Maryland 20910-7500§Research Scientist, Department of Biochemical Pharmacology, Biochemistry Division, Walter Reed Army Institute of Research, 503 Robert Grant Road,Silver Spring, Maryland 20910-7500¥Lead Research Chemist, Centers for Disease Control and Prevention, 4770 Buford Highway, Mailstop F47, Atlanta, Georgia 30341 Colonel, US Army (Retired); Scientific Advisor, Office of Biodefense Research, National Institute of Allergies and Infectious Disease, National Institutesof Health, 6610 Rockledge Drive, Room 4069, Bethesda, Maryland 20892-6612691
Medical Aspects of Chemical WarfareINTRODUCTIONIn the past, issues associated with chemical warfareagents, including developing and implementingmedical countermeasures, field detection, verificationof human exposures, triage, and treatment, haveprimarily been a concern of the military communitybecause most prior experience with chemical warfareagents was limited to the battlefield. However,chemical agents have been increasingly employedagainst civilian populations, such as in Iraqi attacksagainst the Kurds and the attacks organized by theAum Shinrikyo cult in Matsumoto City and the Tokyosubway. The attacks on the World Trade Center inNew York City and the Pentagon in Washington, DC,in 2001 have increased concern about the potentiallarge-scale use of chemical warfare agents in a civiliansector. Incidents involving large numbers of civilianshave shown that to facilitate appropriate treatment, itis critical to identify not only those exposed, but thosewho have not been exposed, as well. In addition tohealth issues associated with exposure, the politicaland legal ramifications of a chemical warfare attackcan be enormous. It is therefore essential that testingfor exposure be accurate, sensitive, and rapid.For the most part, monitoring for the presence ofchemical warfare agents in humans, or “biomonitoring,”involves examining specimens to determine ifan exposure has occurred. Assays that provide definitiveevidence of agent exposure commonly targetmetabolites, such as hydrolysis products and adductsformed following binding to biomolecular entities.Unlike drug efficacy studies in which blood/plasmalevels usually focus on the parent compounds, assaytechniques for verifying chemical agent exposurerarely target the intact agent because of its limitedlongevity in vivo. Following exposure, many agentsare rapidly converted and appear in the blood as hydrolysisproducts (resulting from reactions with water)and are excreted in urine. Because of rapid formationand subsequent urinary excretion, the use of theseproducts as markers provides a limited window of opportunityto collect a sample with measurable product.More long-lived markers tend to be those that resultfrom agent interactions with large-molecular–weighttargets, such as proteins and DNA. These result fromcovalent binding of the agent or agent moiety to formmacromolecular adducts. As such, the protein acts asa depot for the adducted agent and the residence timeis similar to the half-life of the target molecule.Blood/blood components, urine, and, in rare instances,tissue specimens, termed “sample matrices” or“biomedical samples,” can be used to verify chemicalagent exposure. However, any sample obtained froman exposed individual may be considered as a potentialmatrix (eg, blister fluid from sulfur mustard [NorthAtlantic Treaty Organization (NATO) designation:HD] vesication). Regardless, analyses of these types ofsamples are inherently difficult because of the matrix’scomplex composition and the presence of analyte intrace quantities.Noninvasive urine collection does not require highlytrained medical personnel or specialized equipment.Although biomarkers present in urine are usually shortlived(hours to days) metabolites, they can be presentin relatively high concentrations in samples obtainedshortly after exposure. The collection of blood/plasmashould be performed by trained medical personnel.Blood/plasma samples offer potential benefits becauseboth metabolites and the more long-lived adducts of amacromolecular target can be assayed. The effectivenessof using tissue to verify chemical agent exposure isgenerally limited to postmortem sampling. For example,formalin-fixed brain tissues from fatalities of the Tokyosubway attack were successfully used to verify sarin(NATO designation: GB) as the agent employed in thatattack. 1 Other tissue samples can be obtained from thecarcasses of animals at the incident site.Methods that do not directly analyze cholinesterase(ChE) activity typically involve detection systems likemass spectrometry (MS) combined with either gaschromatography (GC) or liquid chromatography (LC)to separate the analyte from other matrix components.MS detection methods are based upon specific andcharacteristic fragmentation patterns of the parentmolecule, making MS detection desirable because itidentifies the analyte fairly reliably. Other detectionsystems, such as nitrogen-phosphorus detection andflame photometric detection, have also been used.Some analytes can be directly assessed, whereas othersmay require chemical modification (eg, derivatization)to enhance detection or make them more volatile inGC separations. More sophisticated techniques mayemploy GC or LC with tandem MS (MS-MS) detectionsystems, allowing more sensitivity and selectivity.Validating the performance of an analytical techniquesubsequent to initial in-vitro method developmentis usually accomplished with in-vivo animalexposure models. Additional information may begleaned from archived human samples from pastexposure incidents. Samples from humans exposed tosulfur mustard during the Iran-Iraq War and a limitednumber of samples from the Japanese nerve agent attackshave been used to evaluate assay techniques. Inthe case of some agents, background marker levels areknown to exist in nonexposed individuals, making it692
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The Coat of Arms1818Medical Departm
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Textbooks of Military MedicinePubli
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MEDICAL ASPECTS o fCHEMICAL WARFARE
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ContentsContributorsForeword by The
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ContributorsMICHAEL ADLER, PhDResea
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DONALD M. MAXWELL, MSResearch Chemi
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ForewordThe US military has been co
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PrefaceA significant concern for th
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PrologueThe original edition of Med
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xxii
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Medical Aspects of Chemical Warfare
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Nerve AgentsChapter 5NERVE AGENTSFR
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Nerve AgentsAbout 10,000 to 30,000
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Nerve Agentsphorofluoridate (DFP) w
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Nerve AgentsFig. 5-2. This schemati
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Nerve AgentsExhibit 5-1 continuedis
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Nerve Agentsactivity but only 15% t
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Nerve AgentsTABLE 5-3CHEMICAL, PHYS
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Nerve AgentsTABLE 5-4EFFECTS OF EXP
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Nerve Agentsaffecting the other eye
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Nerve Agentsmay cause severe rhinor
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Nerve Agentsof jerks and tremor.Cen
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Nerve Agentsand they were decreased
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Nerve Agentsnerve agent toxicity on
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Nerve Agentspatient. Decontaminatio
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Nerve AgentsFig. 5-5. The Mark I ki
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Nerve Agentsadministered intramuscu
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Nerve Agentsthat hydroxamine reacti
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Nerve AgentsOral administration may
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Nerve AgentsTABLE 5-7RECOMMENDED TH
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Nerve Agentsimpairment such as whee
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Nerve Agentssuboptimal, manner. The
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Nerve Agentsthan those who did not.
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Nerve Agentssible for binding nerve
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Nerve Agentsfor comparison was not
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Nerve AgentsTABLE 5-11EFFECTS OF PY
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Nerve Agentstivity of smooth muscle
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Nerve Agents38. Grob D, Lilienthal
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Nerve Agents77. McDonough JH, Shih
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Nerve Agents117. McLeod CG Jr, Sing
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Nerve Agents154. Tryphonas l, Veino
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Nerve Agents193. Funckes AJ. Treatm
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Nerve Agents235. Suzuki T, Morita H
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Nerve Agents274. Pellegrini JE, Bak
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PROCESSMedical Aspects of Chemical
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Triage of Chemical CasualtiesChapte
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Triage of Chemical Casualtiesreceiv
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Triage of Chemical Casualtiesentran
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Triage of Chemical Casualtiescatego
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Triage of Chemical CasualtiesIn a f
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Triage of Chemical Casualtiesnose)
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Triage of Chemical CasualtiesWith n
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Triage of Chemical Casualties14. Sa
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Decontamination of Chemical Casualt
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Page 713: Medical Aspects of Chemical Warfare
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Abbreviations and AcronymsAbBreviat
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Abbreviations and AcronymsPADPRP: p
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