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

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Medical DiagnosticsTable 22-8Target Analytes for Analysis Methods Outlined in Table 22-7TDGTDG-SulfoxideGlucuronide-bound Acid-labile Glucuronide-bound Acid-labileFree conjugates esters Free conjugates estersYes yes no no no no 1Yes yes no no no no 2Yes no yes yes no yes 3Yes yes yes yes yes yes 4TDG: thiodiglycolData 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,et al. Quantitation of the sulfur mustard metabolites 1,1’-sulfonylbis[2-(methylthio)ethane] and thiodiglycol in urine using isotope-dilutiongas chromatography-tandem mass spectrometry. J Anal Toxicol. 2004;28:327–332.levels were reanalyzed without the reduction step,the TDG level in all the samples was less than 2.5ng/mL. This indicates that the free and bound formsof the TDG-sulfoxide, rather than the free and boundforms of TDG, are responsible for a larger portion ofthe observed background levels in the nonexposed humanurine samples. These results are consistent withthose found in other, smaller studies of backgroundlevels. 86,87,90,91 Boyer et al discovered that storage conditionof urine samples must also be considered whenanalyzing samples for TDG and TDG-sulfoxide. 89 In astudy of urine samples stored at – 20 o C for an 8-monthperiod, they found that all free and conjugated TDG inthe samples had oxidized to free and conjugated TDGsulfoxide.Consequently, the use of a reducing agentwas shown to be critical for the analysis of samplesthat had been frozen for any length of time.Black et al identified a series of metabolites formedfrom sulfur mustard’s reaction with GSH, a smallmolecular–weighttripeptide that acts as a free radicalscavenger (Figure 22-7). 91–93 While a large number ofmetabolites were identified in animal experiments,there are three verified reaction products in urinesamples obtained from individuals exposed to sulfurmustard. One set of reaction products is believed toresult from metabolism of the sulfur-mustard–GSHconjugate by the β-lyase enzyme (see Figure 22-7d).Two β-lyase metabolites have been identified in theurine from exposed individuals:• 1-methylsulfinyl-2-[2-(methylthio)ethylsulfonyl]ethane(MSMTESE) and• 1,1’-sulfonylbis[2-(methylsulfinyl)ethane](SBMSE).MSMTESE and SBMSE can be reduced using titaniumchloride and analyzed by GC-MS-MS as asingle analyte: 1,1’-sulfonylbis[2-(methylthio)ethane](SBMTE; Exhibit 22-1). 94,95 Black et al reported a limit ofdetection of 0.1 ng/mL, 94 while Young et al extendedthe lower limit of detection to 0.038 ng/mL. 95 To date,no background levels have been found in the urine ofunexposed individuals, including studies where urinesamples from over 100 individuals were analyzedusing two different assay methods. 89,95 Alternatively,MSMTESE and SBMSE can be analyzed individuallywithout reducing the two analytes to single analyte usingelectrospray LC-MS-MS. 96 Lower limits of detectionwere 0.1 to 0.5 ng/mL for each of the analytes.The final urinary biomarker to be discussed is alsoa reaction product of sulfur mustard with GSH: 1,1’-sulfonylbis[2-S-(N-acetylcysteinyl)ethane] (see Figure22-7e; Table 22-9). Using solid phase extraction forsample cleanup and analyte concentration, followedby analysis with negative ion electrospray LC-MS-MS,Read and Black were able to achieve detection limitsof 0.5 to 1.0 ng/mL. 97Assays for several other potential urinary analyteshave been developed, but these analytes have yet tobe confirmed in human-exposed samples. N7-(2-hydroxyethylthioethyl)guanine is a breakdown productfrom alkylated DNA that has been observed in animalstudies. Fidder et al developed both a GC-MS methodthat requires derivatization of the analyte and an711
Medical Aspects of Chemical Warfareaglutathione (tripeptide)OOH 2N CH CH 2 CH 2 C NH CH C NH CH 2 COOHCOOHCH2SHglutamic acid cysteine glycineglutamic acidNHObCH 2CH 2ClCH 2CH 2SCH2CH C glycineS+ 2 glutathioneSCH 2CH 2ClCH 2CH 2SCH2CH C glycineNHOglutamic acidc(O) nSCH 2CH 2 S CH 2CHNH 2CH 2CH 2 S CH 2CHCOOHCOOHNH 2β-lyasedO 2SCH 2CH 2SOCH 3CH 2CH 2SCH 3eO 2SCH 2CH 2CH 2CH 2SSHNCH 2CHCH 2CHCOOH 3COOHCOOHHNCOOH 3O 2SCH 2CH 2SOCH 3CH 2CH 2SOCH 3Fig. 22-7. Reaction pathway proposed by Black et al (1992). (a) Structure of glutathione. (b) Reaction of sulfur mustard andglutathione. (c) Intermediate product. (d) β-lyase metabolites 1-methylsulfinyl-2-[2-(methylthio)ethylsulfonyl]ethane (MSM-TESE) and 1,1’-sulfonylbis[2-(methylsulfinyl)ethane] (SBMSE). (e) Bis-mercapturic acid conjugate of mustard sulfone.Data source: Black RM, Brewster K, Clarke RJ, Hambrook JL, Harrison JM, Howells DJ. Biological fate of sulphur mustard,1,1’-thiobis(2-chloroethane): isolation and identification of urinary metabolites following intraperitoneal administration torat. Xenobiotica. 1992;22:405–418.712
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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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Abbreviations and AcronymsAbBreviat
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Abbreviations and AcronymsPADPRP: p
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