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

Medical Diagnosticsas soman. Few methods have been published that usethe assay of adducts to biomolecules to verify chemicalwarfare agent exposure in humans (Table 22-4).Cholinesterase AnalysisOP chemical warfare agents are potent and irreversibleinhibitors. Exposure results in excessiveaccumulation of acetylcholine that hyperstimulatescholinergic tissues and organs and ultimately leadsto life-threatening cholinergic crises in humans. 3 Themechanism of OP toxicity is the inhibition of AChEand BChE involved in the termination of neurotransmissionin cholinergic synapses and neuromuscularjunctions of the central nervous system. 46 SynapticAChE is not amenable to direct measurement, butbecause of functional similarities between synapticand erythrocyte AChE, the activity of AChE in wholeblood can be used as a reliable surrogate biomarkerof central and peripheral nervous system activity. 47Exposure to OP nerve agents, carbamates, pesticides,anesthetics, and drugs (such as cocaine) selectivelyreduces AChE and BChE activity. 3 Thus, it is crucial todiagnose OP exposure or intoxication early, and bloodChE activity (usually RBC-AChE) can be exploited as atool for confirming exposure to these agents and commencingantidotal (oxime) therapy. 48,49 Because theseChE inhibitors comprise a group of structurally diversecompounds with a wide range of relative specificitiesfor RBC-AChE and plasma BChE, a complete profileof inhibition is probably more accurately reflected ifboth ChEs are measured.Exposure to OP nerve agents or pesticides thatresults in inhibition of less than about 20% AChEor BChE (especially if clinical symptoms are absent)may not easily be detected because of considerableinter- and intraindividual variations in AChE and(especially) BChE activities. 50 Moderate clinical symptomsof poisoning will be apparent at 50% to 70%AChE inhibition, with severe toxicity seen at greaterthan 90% inhibition. 51 While general measurement ofChE activity in blood is not specific for exposure toany OP nerve agent, carbamate, or pesticide, laboratorymeasurements by MS techniques can positivelyTable 22-4Methods Used to Confirm Human Exposures to Nerve Agent Adducts toBiomoleculesAgent/Incident Sample Matrix Product Identified Concentration Reported Analytical MethodGB, Matsumoto and Serum GB matsumoto (1.8–2.7 ng/mL) GC-NPD 1,2Tokyo, Japan T tokyo (0.2–4.1 ng/mL)GB, Tokyo, Japan Red Blood Cell IMPA, mpa nR GC-MS 3,4GB, Tokyo, Japan Brain (cerebellum) mpa nR GC-MS 5GB, Tokyo, Japan Plasma/Serum Phosphylated nona- 10–20 pmol inhibited BChE/mL LC-MS-MS 6(selected samples)peptides from BChEBChE: butyrylcholinesteraseGB: sarinGC: gas chromatographyIMPA: isopropyl methylphosphonic acidLC: liquid chromatographyMPA: methylphosphonic acidMS: mass spectrometricNPD: nitrogen-phosphorus detectorNR: not reportedData 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, LangenbergJP, Noort D, Hulst AG, Benschop HP. Retrospective detection of exposure to organophosphates: analyses in blood of human beings andrhesus monkeys. In: Sohns T, Voicu VA, eds. NBC Risks: Current Capabilities and Future Perspectives for Protection. Dordrecht, Holland, theNetherlands: Kluwer Academic Publishers; 1999:513–521. (3) Nagao M, Takatori T, Matsuda Y, et al. Detection of sarin hydrolysis productsfrom sarin-like organophosphorus agent-exposed human erythrocytes. J Chromatogr B Biomed Sci Appl. 1997;701:9–17. (4) Nagao M, TakatoriT, Matsuda Y, Nakajima M, Iwase H, Iwadate K. Definitive evidence for the acute sarin poisoning diagnosis in the Tokyo subway. ToxicolAppl Pharmacol. 1997;144:198–203. (5) Matsuda Y, Nagao M, Takatori T, et al. Detection of the sarin hydrolysis product in formalin-fixedbrain tissues of victims of the Tokyo subway terrorist attack. Toxicol Appl Pharmacol. 1998;150:310–320. (6) Fidder A, Hulst AG, Noort D,et al. Retrospective detection of exposure to organophosphorus anti-cholinesterases: mass spectrometric analysis of phosphylated humanbutyrylcholinesterase. Chem Res Toxicol. 2002;15:582–590.701