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

Medical Aspects of Chemical WarfareSarin (GB)OSoman (GD)OCyclosarin (GF)OH 3 C P OCH(CH 3 ) 2H 3 C P OCHC(CH 3 ) 3H 3 CPOFF CH 3FTabun (GA)VXRussian VXOOONC P OCH 2 CH 3H 3 C P OCH 2 CH 3H 3 C P OCH 2 CH(CH 3 ) 2N(CH 3 ) 2SCH 2 CH 2 NCH(CH 3 ) 2CH(CH 3 ) 2SCH 2 CH 2 NCH 3CH 3Fig. 22-1. Chemical structures of nerve agents. The nerve agents sarin (GB), soman (GD), and cyclosarin (GF) lose fluorinesubsequent to binding to cholinesterase. The agents tabun (GA), VX, and Russian VX lose cyanide and the thiol groups.Many of the assays developed for exposure verificationare based on the interaction of nerve agents withChE enzymes. Nerve agents inhibit ChE by forminga covalent bond between the phosphorus atom of theagent and the serine residue of the enzyme active site.That interaction results in the displacement or loss offluorine from sarin, soman, and cyclosarin. The bindingof tabun, VX, and Russian VX is different in that theleaving group is cyanide followed by the thiol groups(see Figure 22-1). 6 Spontaneous reactivation of theenzyme or hydrolysis reactions with water can occurto produce corresponding alkyl methylphosphonicacids (MPAs). Alternatively, the loss of the O-alkylgroup while bound to the enzyme produces a highlystable organophosphoryl-ChE bond, a process referredto as “aging.” Once aging has occurred, the enzyme isconsidered resistant to reactivation by oximes or othernucleophilic reagents. 4 The spontaneous reactivationand aging rates of the agents vary depending on the O-alkyl group. For example, VX-inhibited red blood cell(RBC) ChE reactivates at an approximate rate of 0.5%to 1% per hour for the first 48 hours, with minimal aging.On the other hand, soman-inhibited ChE does notspontaneously reactivate and has a very rapid agingrate, with a half-time of approximately 2 minutes. 4General Clinical TestsWith the exception of ChE analysis, there are nostandard clinical assays that specifically test for nerveagent exposure. However, over the years numerouslab-based, non-ChE analytical methods have beendeveloped, and several successfully utilized, to verifynerve agent exposure. For the most part, these employMS with GC or LC separations. The tests are relativelylabor intensive, requiring trained personnel and sophisticatedinstrumentation not usually available inclinical settings. Most experience using these techniqueshas come from animal exposure models. Theseassessments allow for determination of test sensitivityand biomarker longevity in experimental models. Inhumans, there is limited experience from accidentaland terror-related exposures. This chapter will reviewassays for chemical warfare agent exposure that havebeen published in the literature and how they havebeen applied in potential exposure situationsAssay of Parent CompoundsAnalyzing for parent nerve agents from biomedicalmatrices, such as blood or urine, is not a viablediagnostic technique for retrospective detection ofexposure. 7 Parent agents are relatively short-lived becauseof rapid hydrolysis and binding to plasma andtissue proteins, imposing unrealistic time restraintson sample collection. The short residence time is especiallyprofound with the G agents (relative to VX).Following the intravenous administration of soman at2 times the median lethal dose (LD 50) results in parentagent detection at toxicologically relevant levels for104 and 49 minutes in guinea pigs and marmosets, respectively;rapid elimination was reflected in terminal694