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

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Medical DiagnosticsTable 22-9 continuedCl: chemical ionizationDNA: deoxyribonucleic acidGC: gas chromatographyLC: liquid chromatographyLOD: limit of detectionMS: mass spectrometryMSMTESE: 1-methylsulfinyl-2-[2-(methylthio)ethylsulfonyl]ethaneRNase: ribonucleaseSBMSE: 1,1’-sulfonylbis[2-(methylsulfinyl)ethane]SBMTE: 1,1’-sulfonylbis[2-(methylthio)ethane]SPE: solid phase extractionTDG: thiodiglycolTiCl 3: titanium trichlorideWBC: white blood cellData sources: (1) Black RM, Read RW. Detection of trace levels of thiodiglycol in blood, plasma and urine using gas chromatography-electroncapturenegative-ion chemical ionisation mass spectrometry. J Chromatogr. 1988;449:261–270. (2) Jakubowski EM, Woodard CL, MershonMM, Dolzine TW. Quantification of thiodiglycol in urine by electron ionization gas chromatography-mass spectrometry. J Chromatogr.1990;528:184–190. (3) Black RM, Read RW. Improved methodology for the detection and quantitation of urinary metabolites of sulphurmustard using gas chromatography-tandem mass spectrometry. J Chromatogr B Biomed Appl. 1995;665:97–105. (4) Boyer AE, Ash D, Barr DB, etal. Quantitation of the sulfur mustard metabolites 1,1’-sulfonylbis[2-(methylthio)ethane] and thiodiglycol in urine using isotope-dilution gaschromatography-tandem mass spectrometry. J Anal Toxicol. 2004;28:327–332. (5) Black RM, Read RW. Methods for the analysis of thiodiglycolsulphoxide, a metabolite of sulphur mustard, in urine using gas chromatography-mass spectrometry. J Chromatogr. 1991;558:393–404. (6)Black RM, Clarke RJ, Read RW. Analysis of 1,1’-sulphonylbis[2-(methylsulphinyl)ethane] and 1-methylsulphinyl-2-[2-(methylthio)ethylsulphonyl]ethane,metabolites of sulphur mustard, in urine using gas chromatography-mass spectrometry. J Chromatogr. 1991;558:405–414. (7)Young CL, Ash D, Driskell WJ, et al. A rapid, sensitive method for the quantitation of specific metabolites of sulfur mustard in human urineusing isotope-dilution gas chromatography-tandem mass spectrometry. J Anal Toxicol. 2004;28:339–345. (8) Read RW, Black RM. Analysisof beta-lyase metabolites of sulfur mustard in urine by electrospray liquid chromatography-tandem mass spectrometry. J Anal Toxicol.2004;28:346–351. (9) Read RW, Black RM. Analysis of the sulfur mustard metabolite 1,1’-sulfonylbis[2-S-(N-acetylcysteinyl)ethane] in urineby negative ion electrospray liquid chromatography-tandem mass spectrometry. J Anal Toxicol. 2004;28:352–356. (10) Fidder A, Noort D, deJong AL, Trap HC, de Jong LPA, Benschop HP. Monitoring of in vitro and in vivo exposure to sulfur mustard by GC/MS determination ofthe N-terminal valine adduct in hemoglobin after a modified Edman degradation. Chem Res Toxicol. 1996;9:788–792. (11) Noort D, Fidder A,Benschop HP, de Jong LP, Smith JR. Procedure for monitoring exposure to sulfur mustard based on modified Edman degradation of globin. JAnal Toxicol. 2004;28:311–315. (12) Black RM, Clarke RJ, Harrison JM, Read RW. Biological fate of sulphur mustard: identification of valine andhistidine adducts in haemoglobin from casualties of sulphur mustard poisoning. Xenobiotica. 1997;27:499–512. (13) Noort D, Hulst AG, TrapHC, de Jong LPA, Benschop HP. Synthesis and mass spectrometric identification of the major amino acid adducts formed between sulphurmustard and haemoglobin in human blood. Arch Toxicol. 1997;71:171–178. (14) Noort D, Hulst AG, de Jong LP, Benschop HP. Alkylation ofhuman serum albumin by sulfur mustard in vitro and in vivo: mass spectrometric analysis of a cysteine adduct as a sensitive biomarkerof exposure. Chem Res Toxicol. 1999;12:715–721. (15) Noort D, Fidder A, Hulst AG, Woolfitt AR, Ash D, Barr JR. Retrospective detection ofexposure to sulfur mustard: improvements on an assay for liquid chromatography-tandem mass spectrometry analysis of albumin-sulfurmustard adducts. J Anal Toxicol. 2004;28:333–338. (16) Capacio BR, Smith JR, DeLion MT, et al. Monitoring sulfur mustard exposure by gaschromatography-mass spectrometry analysis of thiodiglycol cleaved from blood proteins. J Anal Toxicol. 2004;28:306–310. (17) Van der SchansGP, Mars-Groenendijk R, de Jong LP, Benschop HP, Noort D. Standard operating procedure for immunoslotblot assay for analysis of DNA/sulfur mustard adducts in human blood and skin. J Anal Toxicol. 2004;28:316–319. (18) Noort D, Fidder A, Hulst AG, de Jong LP, BenschopHP. Diagnosis and dosimetry of exposure to sulfur mustard: development of a standard operating procedure for mass spectrometric analysisof haemoglobin adducts: exploratory research on albumin and keratin adducts. J Appl Toxicol. 2000;20(suppl 1):S187–S192.were the first collected following hospital admission5 to 10 days after the suspected exposure. Willemsdetailed the patients’ medical histories. 101 Briefly, theinjuries were described as moderate to severe andwere consistent with sulfur mustard injury, includingerythema and fluid-filled vesicles. Urine sampleswere initially analyzed for intact sulfur mustard, butwere found to be negative. Following treatment ofthe urine samples with a strong acid to convert TDGto sulfur mustard, the samples were analyzed usingGC-MS. The TDG concentrations found in the first setof samples collected at the hospital ranged between5 to 100 ng/mL for the majority of the samples. Thehighest observed TDG concentration was 330 ng/mLfrom a casualty who died 1 day after admission. Duringthe hospitalization, 18 to19 days after the exposure,a second set of urine samples was collected from onegroup. TDG levels in that set of samples were similarto observed background levels in control samples.TDG background levels were determined from urinesamples obtained from nonexposed individuals andwere generally less than 12 ng/mL, although two of thecontrol samples had levels of 21 ng/mL and 55 ng/mL.Elevated background levels in control samples mayindicate that this method also converts TDG-sulfoxideor some other analytes into sulfur mustard.Drasch et al examined urine samples obtainedduring an autopsy of a sulfur mustard casualty for715
Medical Aspects of Chemical Warfareunmetabolized sulfur mustard. 85 The victim was anIranian soldier, age 24, who died of complications frompneumonia 7 days after the suspected exposure. Thepatient had been transferred to an intensive care unitin Munich, Germany. Samples were taken during theautopsy and stored at – 20°C for 1 year prior to analysis.Despite very high concentrations of sulfur mustardfound in autopsy tissue specimens, sulfur mustard wasnot detected in the urine samples.In 1990 Jakubowski et al received urine samples froman accidental laboratory exposure to sulfur mustard. 102A liquid flashpoint tester overheated, vaporized amixture that was thought to contain only a deconnedsolution, and exposed a chemist who had attempted toshut down the reaction. Nine hours after the incident,the individual felt a burning sensation on his arms,hands, neck, and face. Medical care was sought themorning after blisters appeared on his hands and arms.The erythematous and vesicated areas were estimatedto be less than 5% and 1% of the total body surfacearea, respectively. The patient collected his total urineoutput for a 2-week period. For the first 3 days, thepatient’s total urine output was only about a third tohalf that of the average adult daily output of 1.5 liters,but the patient had a normal output level over the next10 days. The assay method used measured both freeand conjugated TDG. 87 The maximum TDG urinaryexcretion rate was 20 µg/day on the third day. TDGconcentrations of 10 ng/mL or greater were observedin some samples for up to 1 week after the exposure.A rate constant was calculated for TDG concentrationfrom days 4 through 10 and the half-life was foundto be 1.2 days. A great deal of intraday variabilitywas noted for the TDG urine concentrations. Consequently,the collection of several urine samples perday is recommended. An attempt was also made toestimate the total amount of sulfur mustard on thepatient’s skin. The estimate was based on two assumptions:1) the assay for the free and conjugated TDGrepresents approximately 5% of the total amount ofsulfur-mustard–related products in the blood, and 2)the bioavailability factor from skin to blood is 10 (ie,10% of the sulfur mustard on the skin penetrated intothe blood). A total of 0.243 mg of TDG was recoveredover a 2-week period. This represents 4.86 mg in theblood, or 48.6 mg on the skin.There are currently four instances of human exposureto sulfur mustard in which urine samples weresubjected to several different assays in order to targetmultiple urinary metabolites. The first report describeda small subset of urine samples previously analyzedby Wils et al 83 and were later reanalyzed by Black andRead 88 after storage at – 20°C for a 5-year period. Willemsprovided clinical information on the five individualsand coded them C1 through C5. 101 This groupof individuals was reportedly exposed to explodingbombs that generated black dust and rain. Decontaminationefforts consisted only of clothing removal,although some victims may have also showered. Earlysymptomatology included eye and throat irritationalong with respiration difficulties. Within 1 to 2 days,victims developed erythema and small blisters on theskin, edema of the eyelids, photophobia, coughing,dyspnea, and hemoptysis. The patients were admittedto a hospital 10 days after the suspected sulfur mustardexposure. Urine samples were obtained at that time.Four of the five patients were discharged 26 to 37days after hospitalization. Patient C1 developed adultrespiratory distress syndrome and was given ventilatorysupport, but died in cardiovascular shock 15 daysafter the original exposure event (5 days after hospitaladmission). Wils et al coded the urine sample set fromindividuals C1 to C5 as G1 to G5 in their report and,using the GC-MS assay described above, found concentrationsof TDG at 90 ng/mL, 45 ng/mL, 40 ng/mL,40 ng/mL, and 15 ng/mL for individuals 1 through5, respectively. 83 Using a different method measuringTDG and TDG-sulfoxide as a single analyte followedby GC-MS-MS analysis, Black and Read found TDGand TDG-sulfoxide levels of 69 ng/mL, 28 ng/mL, and33 ng/mL for individuals C1, C2, and C5, respectively.C3 and C4 were not assayed because their sampleswere insufficient. Control urine samples analyzed byBlack and Read produced a background level of 11ng/mL. 88 Urine samples from all five casualties wereanalyzed for β-lyase concentrations, with the highestconcentration found in patient C1. The concentrationsfound in the urine from four of the casualties rangedbetween 0.5 to 5 ng/mL, while the individual who diedhad a β-lyase concentration of 220 ng/mL. 88Once again using the GC-MS-MS method thatmeasures both TDG and TDG-sulfoxide as a singleanalyte, Black and Read analyzed urine samples fromtwo casualties of an alleged sulfur mustard attack onthe Kurdish town of Halabja in 1988. 88 The patientshad been transferred to London for medical treatmentand urine samples were collected 13 days afterthe alleged incident. Black and Read found combinedTDG plus TDG-sulfoxide levels of 11 ng/mL for bothpatients, but also found similar concentration levelsin control samples. Urine samples were also analyzedfor β-lyase concentrations using GC-MS-MS. Althoughthe concentration of the β-lyase metabolites found inboth patients was near the limit of detection for theassay, the analytes were clearly detectable and rangedbetween 0.1 and 0.3 ng/mL. 88 The urine samples werelater analyzed using the LC-MS-MS assay that candistinguish the individual β-lyase metabolites. 96 The716
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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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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 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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Abbreviations and AcronymsAbBreviat
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Abbreviations and AcronymsPADPRP: p
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