Sulfur mustard action mechanism

Field First Aid Decontaminate At Once for All Exposed Victims Although sulfur mustards cause cellular changes within minutes of contact, the onset of pain and other clinical effects are delayed for one to twenty-four hours. Sulfur mustards are alkylating agents that may cause bone marrow suppression and neurologic and gastrointestinal toxicity. However, the biochemical mechanisms of action are not clearly understood by anyone. The death rate from exposure to sulfur mustard during World War I was 2-3 percent,... 

T. A. Connors, "Mechanism of Action of 2-Chloroethyl Derivatives, Sulfur Mustards, Epoxides and Aziridines" in "Antineoplastic and Immunosuppresive Agents" Part II, A. C. Sartorelli and D. J. Johns Eds., Springer-Verlag Berlin-Heidelberg New York, 1975, p. 18. 

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. 

Casillas and Babin, unpublished). Finally, inflammatory cell infiltration, which may occur about a day after exposure, may also play a role in delaying SM wound healing (Maumenee and Schloz, 1948). The sheer number of potential target areas in a multilayered, multicell organ that may be affected by sulfur mustard make the task of determining SM s exact mechanism of action quite difficult. 

FIGURE 50.4. Sulfur mustard, its structure, mechanism of action, and targets of adduct formation. A Mechanism of reaction of sulfur mustard and nucleotide guanine. B Sites of alkylation hy sulfur mustard. Arrows mark identified targets in nucleotides and amino acid histidine. 

Smith, K.J., Hurst, C.G., Moeller, R.B., Skelton, H.G., Sidell, F.R. (1995). Sulfur mustard its continuing threat as a chemical warfare agent, the cutaneous lesions induced, progress in understanding its mechanism of action, its long-term health effects, and new developments for protection and therapy. J. Am. Acad. Dermatol. 32 16S-16. 

Sulfur mustards are vesicants and alkylating agents however, the biochemical mechanisms of action are not clearly understood. They are highly reactive and combine rapidly with proteins, DNA, or other molecules. Therefore, within minutes following exposure, intact mustard or its reactive metabolites are not found in tissue or biological fluids. Sulfur mustards also have cholinergic activity, stimulating both muscarinic and nicotinic receptors. The onset of clinical symptoms and their time of onset depend on the severity of exposure. The death rate... 

DNA alkylation may not completely account for sulfur mustard s toxicity, however. Sulfur mustard may also affect intracellular enzymes and the structural components of cell membranes, causing dissolution of intracellular attachments and a cleft in the basal epidermal layer. In turn, inflammation develops, followed by edema and blisters (3). Although nitrogen mustard is less potent than sulfur, its mechanism of action is similar. 

Karnofsky DA, Graef I, Smith HW. Studies on the mechanism of action of the nitrogen and sulfur mustards in vivo. Am J Pathol. 1948 24 275-291. 

The effects of time, temperature, and humidity on the vapor penetration of HNl and HNS into the forearm skin of human male volunteers were reported by NDRC (1945). Results of this research showed similar effects of temperature and humidity as observed for sulfur mustard (e.g., greater absorption with increased temperature and humidity). The penetration of HNl and HNS was found to be linear with time (5-20 min for HNl and 30-60min for HNS). At 71-72°F and 50-52% relative humidity, the HNl penetration rate was 2.8pg/cm / min and for HNS, it was 0.18 pg/cm /min at 72-73°F and 45 8% relative humidity. At 86-87°F and 47-49% relative humidity, the HNl penetration rate increased to 5.2 pg/cm /min, and the HNS penetration rate increased to 0.3 pg/cm /min at 85°F and 47 8% relative humidity. Excretion via the urine is likely a major route of elimination, especially due to the water solubility of the immo-nium ion (see "Mechanism of Action" section). 

Sulfur mustard is a bifunctional alkylating agent. The mechanism of action of sulfur mustard is multifaceted... 

Shakarjian, M.P., Heck, D.E., Gray, J.P., et al., 2010. Mechanisms mediating the vesicant actions of sulfur mustard after cutaneous exposure. Toxicol. Sci. 114, 5-19. 

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