Sulfur mustard toxicity

The mechanism of action of sulfur mustard is multifaceted and complex, and has been reviewed in some detail by Papirmeister et al. (1991), Hurst and Smith (2008), and Smith et al. (2008). Efforts to understand the mechanisms of sulfur mustard toxicity are ongoing. Basically, sulfur mustard disrupts the interface of the epidermis and basement membrane causing blistering between the epidermis and dermis. Both immediate (immediate cell membrane damage) and delayed phases (secondary effects resulting from inflammatory responses, DNA damage, vascular leakage) have been described for sulfur mustard-induced dermal effects (Somani and Babu, 1989). Many of the toxic effects of sulfur mustard can be attributed to oxidative stress. 

Among the most studied mechanisms of sulfur mustard toxicity are thiol depletion resulting in intracellular calcium... 

Petrali, J., Miskena, F., Hamilton, T., Finger, A., Janny, S. (1997). Sulfur mustard toxicity of the rabbit eye an ultrastructural study. J. Toxicol. Cutan. Ocul. Toxicol. 16(4) 221-il. 

Smith, W.J., Gross, C.L., Chan, P., Meier, H.L. (1990). The use of human epidermal keratinocytes in cultures as a model for studying sulfur mustard toxicity. Cell Biol. Toxicol. 6 285-91. 

Debiak, M., Kehe, K., Burkle, A. (2008). Role of poly(ADP-ribose) polymerase in sulfur mustard toxicity. Toxicology (June 18, Epub ahead of print) doi 10.1016/j.tox.2008.06.002. 

Riviere, J.E., Monteiro-Riviere, N.A., Inman, A.O. (1997). The effect of altered media flow and glucose concentration on sulfur mustard toxicity in the isolated perfused porcine skin flap. In Vitro Toxicol. 10 169-81. 

Simbulan-Rosenthal, C.M., Ray, R. et al. (2006). Calmodulin mediates sulfur mustard toxicity in human keratmoc des. 

Medical Countermeasures and Other Therapeutic Strategies for Sulfur Mustard Toxicity... 

Amir, A., Chapman, S., Kadar, T., Gozes, Y., Sahar, R., Allon, N. (2000h). Sulfur mustard toxicity in macrophages effect of dexamethasone. J. Appl Toxicol 20 S51-8. 

Bhattacharya, R., Lakshmana Rao, P.V., Pant, S.C., Pravin Kumar, Tulsawani, R.K., Pathak, U., Kulkami, A., Vijayar-aghavan, R. (2001). Protective effects of amifostine and its analogues on sulfur mustard toxicity in vitro and in vivo. Toxicol. Appl. Pharmacol. 176 24-33. 

Paromov, V., Suntres, Z., Smith, M., Stone, W.L. (2007). Sulfur mustard toxicity following dermal exposure role of oxidative stress, and antioxidant therapy. J. Burns Wounds 1 7. 

Pathak, U., Raza, S.K., Kulkami, A.S., Vijayaraghavan, R., Kumar, P., Jiaswal, D.K. (2004). Novel S-substituted amino-alkylamino ethanethiols potential antidotes against sulfur mustard toxicity. J. Med. Chem 47 3817-22. 

Ray, R., Benton, B.J., Anderson, D.R., Byers, S.L., Petrali, J.P. (2000). Intervention of sulfur mustard toxicity by down-regulation of cell proliferation and metabolic rates. J. Appl. 

Sawyer, T.W. (1998b). Modulation of sulfur mustard toxicity by arginine analogues and related nitric oxide synthase inhibitors in vitro. Toxicol. Sci. 46 112-23. 

Simbulan-Rosenthal, C.M., Ray, R., Benton, B., Soeda, E., Daher, A, Anderson, D., Smith, W.J., Rosenthal, D.S. (2006). Calmodulin mediates sulfur mustard toxicity in human kera-tinocytes. Toxicology 227 21-35. 

The second exception is that while an antidote is available for systemic effects of Lewisite exposure, there are no antidotes for nitrogen mustard or sulfur mustard toxicity, with one minor caveat if given within minutes after exposure, intravenous sodium thiosulfate may prevent death due to sulfur mustard exposure (25). Otherwise, the medical management for skin, ocular, and respiratory exposure is only supportive. One guideline physicians can follow is to keep skin, eye, and airway lesions free from infection. 

Since WWI, a large body of information on sulfur mustard toxicity has been reported from wartime accounts, accidental laboratory and industrial exposures, and animal experiments. Deliberate volunteer exposures of skin to minute amounts of mustard were commonplace in many countries through WWII however, realiza-... 

Petrali JP, Oglesby SB, Mills KR. Ultrastructural correlates of sulfur mustard toxicity. J Toxicol Cutan Ocular Toxicol. 1990 9 193-204. 

Among the most studied mechanisms of sulfur mustard toxicity are thiol depletion, resulting in intracellular calcium imbalance and subsequent cell death alkylation of DNA and other cellular macromolecules lipid peroxidation resulting from sulfur mustard-induced gluthathione depletion and induction of an inflammatory response. The overall mechanism of sulfur mustard toxicity likely involves an interlinking of the aforementioned processes which are briefly described below. 

A key component of sulfur mustard toxicity is the formation of a sulfonium ion and resulting episulfonium intermediate that may react with sulfhydryl-containing macromolecules. Damage may include Ca + translo-cases (Ca +-stimulated, Mg -dependent ATPase), which depend on thiol groups to maintain cellular Ca + homeostasis, and microfilamentous proteins. The resulting increase in intracellular calcium levels ultimately causes a decrease in cellular integrity and induction of apoptosis. Oxidative stress in sulfur mustard toxicity has been reviewed by Smith et al. (2008). 

Within cells, sulfur mustard forms adducts with DNA, primarily those described above. Adducts can also be formed with nucleophilic sites of amino acids and proteins. Byrne etal. (1996) demonstrated that sulfur mustard, with two highly reactive groups was able to form protein crosslinks between cysteine residues and assumed that protein crosslink formation may actually contribute to sulfur mustard toxicity. Contrary to DNA adducts, there is no specific mechanism to reverse protein adduct formation. For this reason, there is a strong forensic interest in the detection of protein adducts of sulfur mustard, as these may provide evidence of sulfur mustard exposure for prolonged periods after an incident. 

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