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

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Medical Diagnosticsplus the parent agent (isopropyl methylphosphonofluoridate).Following isolation from the matrix withsolid phase extraction techniques, the agent was thenanalyzed using GC with MS or other appropriatedetection systems. Other research has demonstratedconceptually similar approaches for detecting tabun 28and VX. 33 In the case of tabun, the cyanide group,which is initially lost upon binding to the enzyme,is replaced with fluorine, leading to the formation ofO-ethyl N,N-dimethyl-phosphoramidofluoridate, afluorinated analog of tabun. 28 Similarly, the thiol groupin VX, which is initially lost upon binding to the enzyme,is replaced by fluorine, resulting in a fluorinatedanalog of VX (ethyl methyl-phosphonofluoridate;VX-G). 33 Variations and improvements of the fluorideregeneration procedure have evolved to enhance testsensitivity by optimizing agent extraction, increasinginjection volumes (thermal desorption and large volumeinjector), and using alternate detection formats(eg, flame photometric detection, positive ion chemicalionization, and high-resolution electron impact MS). 6,33Additionally, Jakubowski et al 34 have successfully appliedthe procedure to RBCs.With regard to the ability of a fluoride ion to regeneratesoman bound to BChE, it is well known thatthe process of aging would preclude release from theenzyme. However, studies have indicated that the fluorideion regeneration process, as applied to soman-poisonedanimals, has produced contrary results. 35 Thesestudies suggest that soman can be displaced from siteswhere aging does not play a significant role. Black etal 36 have demonstrated that both sarin and soman bindto tyrosine residues of human serum albumin. Theobservation that the alkyl group remained intact, inparticular for soman, argues that binding to this sitedoes not result in aging as seen with ChEs. 36 Similarly,carboxylesterase, known to exist in high quantities inrats and mice, has been shown to form adducts withsoman. 37–41 Moreover, soman formation has beendemonstrated via fluoride-induced regeneration ofsoman-inhibited carboxylesterase in rat plasma 37 andpurified human albumin. 35 Although the presence ofcarboxylesterase in significant amounts is questionablein humans, the albumin provides a potential source ofthe protein from which the agent can be regenerated.Currently the utility of fluoride regeneration in humanexposures involving soman is unclear. More studies areneeded to clarify the utility of fluoride regeneration inhumans with soman exposure following confirmedevents.Nagao et al 42,43 employed a different approach,exploiting sarin bound to AChE, using blood as thematrix. This procedure detected IMPA, following itsrelease from the sarin-AChE complex, using an alkalinephosphatase digestion process. The analyticaltechnique used is similar to numerous other GC-MSassays for hydrolysis products.Another approach based on OP binding to BChEhas been reported by Fidder et al. 44 This methodinvolves digesting BChE to produce nonapeptidefragments containing the serine-198 residue to whichnerve agents bind. Analyzing nonapeptides employsLC-MS-MS techniques. The utility of this method wasdemonstrated by analyzing two archived samplesfrom the Tokyo subway terrorist attack. The authorsreported results similar to a previous analysis of thosesamples, in this case using the fluoride regenerationprocedure. 44 A reported advantage of this techniqueis that aged or nonaged OPs can be successfullyidentified. In the case of sarin-inhibited enzyme, theserine-198 is conjugated to IMPA; for soman followingloss of the pinacolyl alkyl group (ie, aging), MPA wasfound bound to the serine residue. In addition, theprocedure was useful for detecting BChE adductedto OP pesticides as well as non-OP anti-ChEs, suchas pyridostigmine. 44 A limitation of the assay is thatagent identity is needed for MS analysis. 45 For thisreason, an extension of this procedure was developedthat uses a generic approach. 45 The method employeda chemical modification of the phosphyl group on theserine residue to a common nonapeptide, regardlessof the specific agent involved. 45 Because a commonnonapeptide is the outcome, a single MS method wasemployed in the analysis (Table 22-3). 45Application to Human ExposuresThe fluoride ion regeneration procedure 29 was usedto analyze serum from exposed individuals in the AumShinrikyo terrorist attacks at Matsumoto and in theTokyo subway. As previously indicated, this procedureis based upon the use of fluoride ion to regenerate theparent agent and free BChE. The amount of regeneratedsarin from serum ranged from 1.8 to 2.7 ng/mLin the Matsumoto incident and 0.2 to 4.1 ng/mL in theTokyo attacks. 29Although unable to detect MPA or IMPA directlyfrom the blood of victims of the Tokyo subway attack,Nagao et al 42,43 detected these compounds after alkalinephosphatase digestion of the sarin-AChE complex.However, the authors did not report MPA or IMPAconcentrations. Although not directly relevant to diagnostictesting, a conceptually similar approach wasalso applied to formalin-fixed brain tissues (GB-boundAChE) from victims of the Tokyo subway attack. 1 Theassays conducted on frozen cerebral cortex did not detectMPA or IMPA. Similar studies with formalin-fixedcerebellum tissue resulted in detecting only MPA. The699
Medical Aspects of Chemical WarfareTable 22-3Analytical Methods Using Adducts to BiomoleculesSample Matrix Product Identified Analytical MethodPlasma/serum GA, GB GC-NPD 1,2Red blood cell impa, MPA GC-MS 3,4Brain (cerebellum) mpa GC-MS 5Plasma/serum VX-G GC-FPD/GC-MS 6Plasma/serum phosphylated nonapeptides from BChe lc-MS-MS 7Plasma/serum GA, GB, GF, VX-G GC-MS/GC-MS(HR) 8Plasma/serum/red blood cell GB GC-MS 9Plasma/serum phosphylated nonapeptides from BChE- derivatized LC-MS-MS 10BChE: butyrylcholinesteraseFPD: flame photometric detectionGA: tabunGB: sarinGC: gas chromatographyGF: cyclosarinHR: high resolutionIMPA: isopropyl methylphosphonic acidLC: liquid chromatographyMPA: methylphosphonic acidMS: mass spectrometryNPD: nitrogen-phosphorus detectorVX-G : ethyl methylphosphonofluoridateData sources: (1) Polhuijs M, Langenberg JP, Benschop HP. New method for retrospective detection of exposure to organophosphorus anticholinesterases:application to alleged sarin victims of Japanese terrorists. Toxicol Appl Pharmacol. 1997;146:156–161. (2) Polhuijs M, Langenberg JP,Noort D, Hulst AG, Benschop HP. Retrospective detection of exposure to organophosphates: analyses in blood of human beings and rhesusmonkeys. In: Sohns T, Voicu VA, eds. NBC Risks: Current Capabilities and Future Perspectives for Protection. Dordrecht, Holland, Netherlands:Kluwer Academic Publishers; 1999:513–21. (3) Nagao M, Takatori T, Matsuda Y, et al. Detection of sarin hydrolysis products from sarin-likeorganophosphorus agent-exposed human erythrocytes. J Chromatogr B Biomed Sci Appl. 1997;701:9–17. (4) Nagao M, Takatori T, Matsuda Y,Nakajima M, Iwase H, Iwadate K. Definitive evidence for the acute sarin poisoning diagnosis in the Tokyo subway. Toxicol Appl Pharmacol.1997;144:198–203. (5) Matsuda Y, Nagao M, Takatori T, et al. Detection of the sarin hydrolysis product in formalin-fixed brain tissues of victimsof the Tokyo subway terrorist attack. Toxicol Appl Pharmacol. 1998;150:310–320. (6) Jakubowski EM, Heykamp LS, Durst HD, ThompsonSA. Preliminary studies in the formation of ethyl methylphosphonofluoridate from rat and human serum exposed to VX and treated withfluoride ion. Anal Lett. 2001;34:727–737. (7) Fidder A, Hulst AG, Noort D, et al. Retrospective detection of exposure to organophosphorusanti-cholinesterases: mass spectrometric analysis of phosphylated human butyrylcholinesterase. Chem Res Toxicol. 2002;15:582–590. (8)Degenhardt CE, Pleijsier K, van der Schans MJ, et al. Improvements of the fluoride reactivation method for the verification of nerve agentexposure. J Anal Toxicol. 2004;28:364–371. (9) Jakubowski EM, McGuire JM, Evans RA, et al. Quantitation of fluoride ion released sarin inred blood cell samples by gas chromatography-chemical ionization mass spectrometry using isoptope dilution and large-volume injection.J Anal Toxicol. 2004;28:357–363. (10) Noort D, Fidder A, van der Schans MJ, Hulst AG. Verification of exposure to organophosphates: genericmass spectrometric method for detection of human butyrylcholinesterase adducts. Anal Chem. 2006;78:6640–6644.inability to detect IMPA was due to hydrolysis duringthe 2-year storage period. The inability to detect hydrolysisproducts in the cerebral cortex as opposed tothe cerebellum was reportedly consistent with the relativeAChE activity detected in each tissue. The studyauthors state that this is the first verification of nerveagent exposure using formalin-fixed brains. 1Due to the limited number of human exposures tonerve agents, it is difficult to fully ascertain the advantagesand disadvantages of various definitive testingmethodologies. Numerous assays to detect hydrolysisproducts in blood or urine have been developed; somehave been employed in exposure incidents. The disadvantageof these methods stems from the relativelyrapid agent elimination and resultant limited opportunityto obtain specimens. The advantage of usingadducts formed with large-molecular–weight targets(AChE or BChE) is a longer time frame (relative tothat of hydrolysis products) to verify exposures. Someinvestigations have indicated that methods employingBChE provide benefits over those with AChE becauseBChE is more abundant in blood. 44 Assays involvingBChE digestion with subsequent assay of nonapeptidefragments facilitate identification of aged or nonagedadduct at the phosphylated serine-198 residue; thereforethey are potentially useful in detecting agents such700
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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 721: Medical Aspects of Chemical Warfare
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Abbreviations and AcronymsAbBreviat
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Abbreviations and AcronymsPADPRP: p
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