Sulfur mustard in humans

The toxic effects of sulfur mustard in humans and animals have been extensively reviewed by ATSDR (2003), Sidell and Hurst (1992), Somani (1992), Watson and Griffin (1992), lOM (1993), NRC (2003), and Romano et al. (2008). 

Mol, M., de Vries, R., Kluivers, A. (1991). Effects of nicotinamide on biochemical changes and microblistering induced by sulfur mustard in human skin organ cultures. Toxicol. Appl. Pharmacol. 107 439-49. 

Papirmeister, B., Gross, C., Petrali, J., Hixson, C. (1984). Pathology produced by sulfur mustard in human skin grafts on athymic nude mice, I Gross and light microscopic changes. J. Toxicol. Cutan. Ocul. Toxicol. 3 371-91. 

R. A. Martinez, L. A. Silks, and J. R. Barr. 2004. A rapid, sensitive method for the quantitation of specific metabolites of sulfur mustard in human urine using isotope-dilution gas chromatography-tandem mass spectrometry. J. Anal. Toxicol. 28(5) 339-45. 

Human Data. lARC (1975), Waters et al. (1983), Watson et al. (1989a), and the Institute of Medicine (1993) have summarized the epidemiological evidence concerning the potential carcinogenicity of sulfur mustard in humans. Much of this information has come from studies of soldiers exposed during World War I as well as from studies of workers at chemical agent manufacturing facilities. 

Human volunteers have been exposed in a controlled way to sulfur mustard liquid and vapor in order to observe the adverse effects on the exposed skin (see overview by Papirmeister et al., 1991 ), whereas the effects on the respiratory tract do not appear to have been studied. Furthermore, no reports can be found that describe the toxicokinetics of sulfur mustard in humans. 

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). 

J.L. Hambrook, D.J. Howells and C. Schock, Biological fate of sulfur mustard (l,l -thiobis(2-chloroethane)) uptake, distribution and retention of 35S in skin and in blood after cutaneous application of 35S-sulfur mustard in rat and comparison with human blood in vitro, Xenobiotica, 23, 537-561 (1993). 

Distribution studies of 35S-sulfur mustard in rats after cutaneous exposure to sulfur mustard, and human blood treated in vitro, showed that a small percentage of radioactivity remained associated with the hemoglobin and persisted for the lifetime of the... 

R.M. Black, J.M. Harrison and R.W. Read, Biological fate of sulfur mustard in vitro alkylation of human haemoglobin by sulfur mustard, Xenobiotica, 27, 11-32 (1997). 

More recent in vitro experiments, using human skin, have confirmed the presence of unhydrolyzed sulfur mustard in the lipophilic stratum comeum and the upper epidermis. Twenty-four hours post-exposure, the distribution ratio between the epidermis and the dermis has been determined at 62 to 38%. Ctulcott and colleagues (2000) also suggested that efforts to remove or neutralize the agent from these deposits might have a clinical benefit for the patient. 

Martens, M. E. (1994). Hexose monophosphate shunt activity in human epidermal keratinocytes exposed to sulfur mustard. In Proceedings of the Meeting of Research Study Group-3 on Prophylaxis and Therapy Against Chemical Agents (NATO Technical Proceedings AC/243(Panel 8)TP/9, pp. 6.1-6.4). Brussels, Belgium NATO. 

Barr JR, Young CL, Woolfit AR, et al. Comprehensive quantitative tandem MS analysis of urinary metabolites and albumin adducts following an accidental human exposure to sulfur mustard. In Proceedings ofthe 53rd Conference ofthe American Society of Mass Spectrometry, San Antonio, TX, June 2005. 

Gerasimo et al. (2000) compared the abihty of soapy water, physiological saline, and Diphoterine to decontaminate sulfur mustard. They exposed human skin obtained from elective abdominoplasty to C14 labeled sulfur mustard in vitro for 5 min. They added the lavage to the test tube and removed the skin after 3 min, 10 min, or 3 successive 10 min washes. In each case, Diphoterine significantly removed more sulfur mustard than the other two treatments. For the 3 successive washes, Diphoterine removed 50% of the applied agent compared to 37% for soapy water and 32% for physiological saline. 

Gerasimo, P., Blomet, J., Mathieu, L., and Hall, A., Diphoterine decontamination of C14—sulfur mustard contaminated human skin fragments in vitro. Toxicologist, 54(1), 152, 2000. 

Figure 2. Day-to-day variability in N7-HETE-dG detection in sulfur mustard-exposed human blood. Frozen blood in 300 pi aliquots was analyzed with the immunoslotblot assay on 6 different days. The data presented are the averages of 6 duplicate analyses with standard deviations.

Agent HD (Sulfur Mustard). RfDe = 7 x 10 mg kg d. A LOiAEL was identified in a two-generation reproductive toxicity study conducted in rats. A total uncertainty factor of 3000 was applied to account for protection of sensitive subpopulations (10), animal-to-human extrapolation (10), LOAEL-to-NOAEL extrapolation (3), and extrapolation from a subchronic to chronic exposure (10). A LOAEL-to-NOAEL UF of 3, instead of the default value of 10, was used because the critical effect (stomach lesions) was considered to be mild in severity and may have been enhanced by the vehicle used (sesame oil in which sulfur mustard is fully soluble) and the route of administration (gavage), which is more likely to result in localized irritant effects. The key study did identify a toxic effect that is consistent with the vesicant properties of sulfur mustard. In none of the other available studies was there any indication of a different effect occurring at a lower exposure level. 

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