N-Acetyl-L-Cysteine as Prophylaxis against Sulfur Mustard

Military Medicine, Jan 2005 by Bobb, Andrew J, Arfsten, Darryl P, Jederberg, Warren W

Sulfur mustard (HD) is a blister agent targeting the eyes, respiratory system, skin, and possibly other organs. Extensive exposure can destroy the immune system by destruction of bone marrow cells. There is no antidote for HD or effective treatment other than rapid decontamination. Clinical trials have demonstrated activity for N-acetyl-L-cysteine (NAC) against a number of significant human pathologies involving free radicals, and animal and tissue studies have suggested efficacy for NAC as a chemoprotectant against many toxic chemicals. Among these are studies demonstrating that NAC significantly reduces the effects of HD and HD simulants, both in cultured cells and animals. Given the historical effectiveness of HD, the lack of any effective treatment, the demonstrated chemoprotective properties of NAC, its low toxicity, the lack of regulatory controls, and the data supporting efficacy against HD effects, we suggest daily oral administration of the maximum safe dose of NAC to personnel entering combat zones.

The Threat

Sulfur Mustard: History of Use on the Battlefield

Sulfur mustard (bis-(2-chloroethyl) sulfide; CAS 505-60-2) is often referred to by the acronym HD; although HD technically refers to a highly purified form of sulfur mustard generally produced after World War I, in this communication it will be used, for brevity's sake, to refer to any sulfur mustard formulation. HD was first used in war near Ypres, Belgium on July 12, 1917; although it was only used for 1 year, HD was responsible for approximately 80% of the chemical casualties in World War I. Italy used mustard on the Abyssinians (Ethiopians) in its 1935-1936 conquest of that country, and Japan used it in China starting in 1939.1 Mustard was inadvertently released from the SS John Harvey in 1943 by German bombing.2 HD, probably of Soviet make, was used by Egypt in the 1963-1967 Yemen War.3 Iraq used mustard (probably HD) extensively in the Iran-Iraq war,4 causing as many as 45,000 casualties.5

Mustard Effects

HD is a vesicant, i.e., a blister agent. It is an oily liquid of low volatility that causes extensive damage to all contacted tissues. The skin develops erythema typically 4 to 8 hours after exposure. Vesication appears 2 to 18 hours later;6 this delay of effects promotes the spreading of the agent beyond the original deployment site. These blisters will generally coalesce over time to produce large bulk 0.5 to 5 cm in diameter. Liquid mustard may produce a full-thickness (third-degree) burn. Severe skin lesions may require months to heal.7 Inhaled mustard vapor can produce acute airway injury 4 to 6 hours after exposure, including hoarseness, pharyngeal and laryngeal erythema, wheezing and dyspnea, and epithelial sloughing with pseudomembrane formation in severe exposures.6 Initial nonbacterial bronchitis is followed by bacterial superinfection in 4 to 6 days. Ocular exposure to even small amounts of mustard vapor results in irritation; more severe exposures bring on pain, severe conjunctivitis, and corneal damage.6 HD-induced photophobia lasts for weeks. Most deaths result from pulmonary damage complicated by infection and occur several days following exposure. A study of the disease and mortality rate for persons exposed to HD in Saradasht, Iran, in 1987, found that of the 108 deaths that have occurred among severely exposed individuals, 93 died within the first month of HD exposure.8 A majority (85 of 108) of these deaths occurred within the first 2 weeks of exposure and resulted entirely from respiratory failure caused by pulmonary injury or sepsis secondary to infection of the lungs or other tissues. Most who died of respiratory failure died within 2 days of HD exposure. Persons who died of infection and sepsis often developed acute respiratory distress syndrome which resulted in death despite antibiotic therapy.

Two hypotheses exist for the biochemical effects of mustard exposure. HD is a DNA alkylating agent,9 causing strand breaks which are irreparable to cellular machinery.6 The normal response to irreparable DNA damage is apoptosis, sometimes called programmed cell death, in which the cell actively destroys itself through a series of metabolic processes including DNA segmentation, proteolysis of cellular enzymes, and disruption of the cell membrane.10 This is consistent with reports that many HD effects appear to be mediated through apoptotic mechanisms.11-16 Second, because HD reacts rapidly with glutathione (GSH), an intracellular reducing agent involved in many detoxification reactions,17 a second hypothesis for HD effects is the profound depletion of intracellular GSH, leaving the cell susceptible to naturally-produced reactive oxygen species.6 Damage from reactive oxygen species also results in apoptosis.18 It therefore appears that whatever the mechanism, (1) apoptosis is induced as the mechanism of tissue destruction and (2) GSH is a sink for HD damage, reducing the effective dose received by the cell and subsequent cell damage.