Sulfur mustard (dichlorethylsulphide) and nitrogen mustard are blistering agents, or vesicants, that have been used in chemical warfare dating to before the nineteenth century. Their historical use is most often remembered in the first and second world wars.[1] The harbinger of sulfur mustard exposure is a subtle smell of onions, horseradish, or garlic. When exposed to sulfur mustard, skin and mucous membranes blister, causing painful and disfiguring burns and airway and pulmonary injury and edema. Systemic manifestations can occur with the higher dose or longer duration of exposure. Treatment is mostly supportive and requires definitive care at burn specialty centers for optimal wound management and skin grafting, as needed.

Sulfur mustard exposures occur when the skin or mucous membranes come into contact with the aerosolized, semi-solid, or liquid chemical. The severity of an injury is related to duration and route of exposure, a dose of exposure, and ambient and exposed surface temperature and humidity.[2]

Cutaneous Exposure

Sulfur mustard is lipophilic, and thus causes most severe injury in areas of the skin rich with eccrine and sebaceous glands. The face, axillae, and groin are particularly sensitive to sulfur mustard exposure.[3] Patients usually present with delayed onset of cutaneous burn from 30 minutes after exposure to up to 48 hours later. Sulfur mustard exposure causes blisters and bullae when skin or mucous membranes are exposed, resulting in partial and full thickness burns.

Sulfur mustard exposure causes degeneration of the basement membrane of the skin and mucous membranes and induces inflammatory changes. Apoptosis of cells and basement membrane degeneration cause the characteristic bullae to form. These bullae are filled with a yellow fluid, which itself can cause burns when healthcare workers come into contact with it without appropriate protection.[2]

Respiratory Exposure

Respiratory tract injury occurs when the chemical is inhaled, but an evident injury is usually delayed 12 to 48 hours after exposure. The warm, moist environment of the upper airway contributes to increased absorption and severe injury in significant respiratory tract exposures. Sulfur mustard damages the respiratory epithelium causing inflammation and necrosis. Tracheobronchial tree edema ensues, and injury is localized predominantly to the upper airway and large bronchi. This structural damage leads to clinical signs of a cough, hoarseness, excess sputum production, dyspnea and, in more severe high concentration exposures, pulmonary edema, bronchopneumonia and acute respiratory distress syndrome (ARDS). In sulfur mustard exposures, death can occur from acute pulmonary edema or secondary pulmonary infection. Chronic low-level exposures result in chronic bronchitis, decreased lung volumes and chronic cough.[3]

Ocular Exposure

The corneal epithelium is particularly sensitive to sulfur mustard exposure due to the moist and warm environment created by the thin layer of tears over the cornea. Acute manifestations of ocular exposure include acute conjunctivitis, eyelid inflammation, and photophobia. A low dose or short exposure time may cause chemical conjunctivitis; whereas, a high dose or longer exposure time may cause temporary blindness. After an ocular injury, patients may go on to have chronic corneal ulcerations and chemical keratitis.[4]

Gastrointestinal Exposure

A gastrointestinal injury is mostly localized to the upper tract, including oropharyngeal, esophageal, and gastric edema, inflammation, and necrosis. Patients with significant gastrointestinal injury can develop nausea and vomiting, abdominal pain, and diarrhea which may be bloody. Sequelae of gastrointestinal exposure described include the development of Barrett’s esophagus and some malignancies.[4][2]

Hematological Effects

Large cutaneous exposures or multi-system exposures can affect the hematopoietic system resulting in an initial leukocytosis followed by leukopenia, occasionally pancytopenia. Delayed mortality has been attributed to leukopenia in some cases.[4]

Although in the United States, the manufacture of sulfur mustard in the has ceased, stockpiles of sulfur mustard are located in several storage sites across the country. After the First and Second World Wars, sulfur mustard-containing shells, and other undetonated artillery shells were disposed of in vast chemical dumping off the coast of New Jersey. To this day, periodic exposures occur when fisherman inadvertently dredge up unused shells containing sulfur mustard. There is also the potential for exposure at U.S. stockpile sites. Although none reported recently, chemical agents still have the potential to be employed in modern warfare and were last used against American troops in the Gulf War.[5][1]

Sulfur mustard is proposed to exert its effects on the cell through a number of pathways. Its absorption leads to increase in free radicals and lipid peroxidation, ultimately causing oxidative cellular injury and apoptosis. In one proposed mechanism, sulfur mustard alkylates deoxyribonucleic acid (DNA) leading to activation of the intracellular repair enzyme poly(adenosine diphosphate-ribose) polymerase (PARP). This exhausts intracellular nicotinamide adenine dinucleotide (NAD+) leading to decreased glycolysis, protease release, and cell injury. Upon cell death, proteases are released from the cell, causing dermal-epidermal separation as blisters. In another proposed mechanism, sulfur mustard inactivates glutathione, which leaves the cell vulnerable to oxidative injury and leads to increased intracellular accumulation of calcium and ultimately cell death. The etiology of acute and delayed toxicity of sulfur mustard exposure is not fully elucidated.[2]