Sulfur mustard biomarker

D. Noort, A.G. Hulst, L.P.A. De Jong and H.P. Benschop, Alkylation of human serum albumin by sulfur mustard in vitro and in vivo mass spectrometric analysis of a cysteine adduct as a sensitive biomarker of exposure, Chem. Res. Toxicol, 12, 715-721 (1999). 

Recent work has focused on the identification of possible biomarkers of sulfur mustard exposure and injury (Buxton et al., 2000, 2001 Danne et al., 2000). More recently, the role of metalloproteinases and collagen degradation (Gerecke et al., 2005), platelet activating factor (Clark et al., 2005, 2006), and interaction with cytochrome P450... 

Arroyo, C.M., Burman, D.L., Kahler, D.W., Nelson, M.R., Corun, C.M., Guzman, J.J., Smith, M.A., Purcell, E.D., Hackley, B.E., Soni, S.D., Broomfield, C.A. (2004). TNF-alpha expression patterns as potential molecular biomarker for human skin cells exposed to vesicant chemical warfare agents sulfur mustard (HD) and Lewisite (L). Cell Biol. Toxicol. 20 345-59. 

Smith, J.R., Capacio, B.R., Korte, W.D., Woolfitt, A.R., Barr, J.R. (2008). Analysis for plasma protein biomarkers following an accidental human exposure to sulfur mustard. J. Anal. Toxicol. 32 17-24. 

Analytical Methods for Urine. Efforts to analyze for specific biomarkers in urine of sulfur mustard exposure prior to 1995 targeted either unmetabolized sulfur mustard or TDG. Vycudihk (1985) prepared urine samples using organic extraction with diethylether and analyzed them using GC-MS. The method was later modified (Vycudihk, 1987) by the addition of a strong acid to the urine samples to isolate possible conjugates of sulfur mustard. Vycudihk indicated that the methods could not distinguish between sulftir mustard and its hydroxyethyl metabohtes that were present in the urine samples. 

The final sulfur mustard urinary biomarker to be discussed is also a reaction product of sulfur mustard with glutathione 1,1 -sulfonyl-bis-[2-S-(V-acetylcystein T)ethane. Using solid-phase extraction for sample cleanup and analyte concentration followed by analysis with negative ion electrospray LC-MS-MS, Read and Black (2004b) were able to achieve detection limits of 0.5-1.0 ng/mL. Methods for the analysis of urine samples for sulfur mustard verification are summarized in Table 19.5. 

Analysis of Blood Samples. Urinary metabolites undergo relatively rapid elimination from the body, whereas blood components offer biomarkers that have the potential to be used for verification of sulfur mustard exposure long after the exposure incident. Three different approaches have been used for blood biomarker analysis. The intact macromolecule such as protein or DNA with the sulfur mustard adducts still attached can be analyzed. To date, this approach has only been demonstrated for hemoglobin using in vitro experiments. For proteins, an alternate approach is to enzymatically digest them to produce a smaller peptide with the sulfur mustard adduct still attached. Methods of this type have been developed for both hemoglobin and albumin. A third approach has been to cleave the sulfur mustard adduct from the macromolecule and analyze in a fashion similar to that used for free metabolites found in the urine. The later two approaches have both been successfully used to verify human exposure of sulfur mustard. 

Tewari-Singh, N., Rana, S., Gu, M., et al., 2009. Inflammatory biomarkers of sulfur mustard analog 2-chIoroethyl ethyl sulfide (CEES)-induced skin injury in SKH-1 hairless mice. Toxicol. Sci. 108, 194—206. 

There is a variety of biomarkers that can verify an exposure to sulfur mustard. Table 61.2 shows an overview of these biomarkers. Analogous to the nerve agents, biomarkers can be distinguished in metabolites that are excreted in urine and adducts to proteins. A disadvantage of the major metabolite, thiodiglycol, is that this compoimd is also present in subjects not exposed to sulfur mustard (Black and Read, 1995 Boyer et al., 2004). In that respect, the protein adducts are more reliable biomarkers for sulfur mustard exposure because these biomarkers point unambiguously to an exposure to sulfur mustard. The sulfur mustard adduct to the N-terminal valine of globin can be analyzed after a... 

TABLE 61.2 CONCLUDING REMARKS AND FUTURE DIRECTIONS Biomarkers for Sulfur Mustard Exposure 921... 

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