eMedicine Specialties > Emergency Medicine > Warfare - Chemical, Biological, Radiological, Nuclear and Explosives

CBRNE - Vesicants, Mustard: Hd, Hn1-3, H

Author: Daniel J Dire, MD, FACEP, FAAP, FAAEM, Clinical Associate Professor, Department of Emergency Medicine, University of Texas-Houston
Contributor Information and Disclosures

Updated: Dec 21, 2007

Introduction

Background

Mustard agents are vesicants (blister agents) used in warfare to produce casualties, degrade fighting efficiency, and force opposing troops to wear full protective equipment. Mustard agents are cytotoxic alkylating compounds and include nitrogen mustards (HN-1, HN-2, HN-3), sulfur mustards (H, HD, HT), and mustard-lewisite (HL). Mustard agents are oily liquids ranging from colorless (in pure state) to pale yellow to dark brown, depending on the type and purity. They have a faint odor of mustard, onion, garlic, or horseradish, but because of olfactory fatigue, do not rely on odor for detection. Volatility varies with the particular compound. Mustard agents are only slightly soluble in water and may persist for long periods. HN-1 is more volatile and less persistent than HD, but it is only one fifth as potent a vesicant to the skin. HN-3 is less volatile and more persistent than HD and has equal vesicant effects.

Mustard agents rapidly penetrate clothing and skin. Chemical protective mask with charcoal filters, chemical protective overgarments with charcoal, and butyl rubber chemical protective gloves and boots afford full protection against mustard agents.

More than 2 dozen nations may have the capability to manufacture offensive chemical weapons. Mustard agents are simple to manufacture and therefore can be a first choice for countries or terrorists who decide to have a capacity for chemical warfare agents. Mustard agents may be delivered by artillery shell, mortar shell, rockets, bombs, or aircraft spray. Since World War I, mustard use in at least 12 conflicts has been supported by evidence or allegations. Historically, mustard agents are the most widely used type of chemical warfare agent.

Mustard agents constitute both a vapor and a liquid threat. Mustard agents cause tissue damage within several minutes of contact. No immediate symptomatic or local reaction occurs to mustard vapor or liquid. Decontamination must be performed immediately after contact to prevent injury. A latent period occurs, ranging from 4-12 hours after mild exposure and 1-3 hours after severe exposure, prior to the onset of symptoms. More than 80% of mustard casualties are from vapor exposure, but more severe injuries are caused after contact with liquid mustard agents.

Mustards first were produced in 1822, but their harmful effects were not discovered until 1860. On July 12, 1917, the Germans delivered artillery shells containing HD on a World War I battlefield near Ypres, Belgium. More than 20,000 casualties resulted from this first use of mustard as a chemical warfare agent. Subsequently, mustard agents accounted for 80% of chemical casualties in World War I. Among 6980 cases of mustard burns during World War I, the location of the lesions were as follows: eyes, 86%; respiratory, 75%; scrotum, 42%; face, 27%; anus, 24%; legs, 11%; buttocks, 10%; hands, 4%; and feet, 1.5%. Fewer than 5% of casualties from mustard who reached medical treatment died. Mustard injuries were slow to heal and necessitated an average convalescent period of more than 6 weeks.

Italy allegedly used mustard against Abyssinia in the 1930s. Japan allegedly used mustard agents against the Chinese from 1937-1944.

Nitrogen mustard agents were synthesized in the late 1930s. Mechlorethamine (HN-2) became the prototypical mustard agent used as a cancer chemotherapeutic agent. Germans and Americans started the military production of nitrogen mustard agents in 1941 and 1943, respectively. They have not been used on the battlefield.

Toward the end of World War II, a German air attack on the Italian port of Bari struck a US ship loaded with mustard agent munitions. Large amounts of mustard agents were released to the atmosphere and into the harbor water. Many soldiers and sailors were exposed to the mustard-contaminated water. Of 617 US mustard casualties, 83 died.

During the Yemen War of 1963-1967, Egypt reportedly used mustard bombs against the royalist troops in North Yemen.

During the Iran-Iraq war from 1979-1988, approximately 5000 Iranian soldiers were reported killed by Iraqi chemical agents, 10-20% by mustard agents. Additionally, 40,000-50,000 individuals were injured resulting in many chronic medical problems.

After the February 1991 cease-fire ending the Persian Gulf War, United Nations inspection teams discovered mustard agents at Al Muthanna, Iraq.

In Sweden, recurring incidents of mustard agent exposures involve fisherman who encounter discarded chemical weapons that were dumped in the waters off the coast after World War II.

Developing nations and terrorist groups can easily obtain HD because of its low cost and availability. The US stockpile of mustard chemical warfare agents currently is undergoing destruction.

Pathophysiology

Mustard agents are lipophilic and are absorbed readily across intact skin and mucous membranes. The rapid penetration is enhanced by moisture, heat, and thin skin. The physical properties (low volatility and a freezing point of 14^o C) of sulfur mustard (H, HD, HT) make it a better weapon for use in warm or hot environments due to a greater risk of vapor inhalation. Approximately 20% of HD is absorbed by the skin, the remainder evaporates. Of the absorbed HD, 10-50% of the mustard dose binds to the skin as reacted (fixed) mustard, and the remaining 50-90% is distributed in the circulation as unreacted (free) mustard to almost all organs and tissues. Because of dilutional effects, systemic effects are observed only at high doses. Mustard is eliminated from the body in the urine as a by-product of alkylation.

No single mechanism or clear understanding exists for the biological damage caused by mustard agents. The toxic effects of mustards depend on their rapid covalent binding to a large number of biological molecules and in the formation of a reactive cyclic ethylene sulfonium ion. Mustard agent molecules contain 2 reactive binding groups. Mustards can bind to nucleophiles such as nitrogen in the base components of nucleic acids and sulfur in SH-groups in proteins and peptides. Mustards can destroy a large number of cellular substances by alkylation of DNA, which leads to DNA strand breaks and apoptosis.

Mustards also bind to cellular glutathione, a small peptide that is a major free radical scavenger.   Glutathione depletion leads to inactivation of enzymes, loss of calcium homeostasis, lipid peroxidation, cellular membrane breakdown, and cell death. Pretreatment of cells with N -acetylcysteine has shown benefit in some studies.

Mortality/Morbidity

The concentration-time product capable of killing 50% of exposures (LCt50) of mustard vapor is 1500 mg·min/m³, and the lethal dose to 50% of exposures (LD50) of liquid mustard on the skin is 100 mg/kg.

Mustards are mutagenic resulting in a slight increased incidence of lung cancer, bladder cancer, and leukemia.

Clinical

Physical

• The clinical presentation of exposure to a vesicant depends on the route of administration and the agent used.
• The eyes are most sensitive and vulnerable to mustard. Ocular effects precede cutaneous manifestations and occur at lower concentrations (as low as 1/10^th) than that required to affect the airways. HN causes more severe and earlier ocular lesions than HD.
  • Conjunctivitis follows an exposure time of approximately 1 hour to a concentration barely perceptible by odor that does not affect the skin or respiratory mucosa significantly.
  • In World War I, 75% of eye exposures were classified as mild conjunctivitis.
  • After mild exposure, a latent period of 4-12 hours is followed by lacrimation, a sensation of grit in the eyes, conjunctival injection, and edema (palpebral and bulbar). Recovery requires 1-2 weeks.
  • After heavy exposure, eye signs and symptoms appear after 1-3 hours, and severe lesions may appear. Blepharospasm is common.
  • A steamy haziness of the cornea or an orange-peel roughening of the cornea may occur. Spotty hemorrhagic discolorations of the iris may be observed. Temporary blindness is common, but permanent blindness is rare.
  • Mild corneal involvement demonstrates corneal erosions with fluorescein staining. Superficial corneal scarring and vascularization or iritis may occur.
  • With severe corneal involvement, dense corneal opacification with deep ulceration and vascularization occurs. Local necrosis of the cornea may rupture the globe. Panophthalmitis may occur and result in eye loss if appropriate therapy is not instituted.
  • Recovery from the ocular effects, especially with corneal involvement, may take months.
• Severity of cutaneous effects of mustard and the rapidity with which they develop are influenced by the degree of exposure and the weather. Hot, humid weather results in more severe lesions. Warm, moist areas, such as the perineum, external genitalia, axillae, antecubital fossae, and neck, are most susceptible.
  • The latent period from contact with liquid or vapor exposures is usually 6-12 hours but may be as short as 1 hour when the weather is hot and humid. The effects appear more rapidly from liquid agent than from vapor.
  • The initial cutaneous effect is erythema, resembling sunburn. Slight skin edema may occur with mild exposures, but in severe burns, edema is greater. Vapor exposures may not cause skin lesions. Systemic symptoms such as malaise, vomiting, and fever may develop approximately at onset of erythema.
  • Intense cutaneous pruritus is common, may last for several days, and may persist after healing.
  • Erythema is followed by vesication as a result of liquefaction necrosis in the epidermal basal cell keratinocytes. A liquid droplet with 10 mcg of mustard produces vesication. Vesicles are more concentrated in warm, moist areas such as the groin and axilla. Vesicles and bullae may be painful and are filled with yellow transudate that tends to coagulate. This fluid does not contain mustard and is not a risk to contacts. Reabsorption of the fluids takes place in approximately 1 week if the vesicles or bullae do not rupture. If rupture occurs, the burn is considered an open wound and is susceptible to secondary infection. Spontaneous healing occurs slowly with little scar formation.
  • Exposed areas of skin may develop a persistent brown pigmentation except at the site of actual vesication, where a temporary depigmentation is seen. The rate of healing typically is 1-2 weeks for facial lesions and up to 2-4 weeks or longer for other areas of the skin. Secondary infection may increase the severity of the lesions and delay healing.
  • Arsenical vesicants such as phenyldichloroarsine (PD) or chlorovinyldichloroarsine (L) often are mixed with mustard agents for chemical warfare weapons. When mixed as such, the resulting skin lesions are not more severe than either agent alone but tend to confuse and make the specific diagnosis difficult.
• A longer latent period (18-24 h) may occur before the onset of respiratory symptoms. In patients with eye symptoms, expect the development of respiratory effects. Inhalation of mustard vapors may damage the laryngeal and tracheobronchial mucosa. Single exposure to a low concentration of vapor does not cause significant injury. Repeated or chronic exposures may lead to the development of pulmonary fibrosis, chronic bronchitis, and bronchiectasis.
  • Respiratory effects develop slowly and reach maximal severity in several days. Symptoms begin in the upper airways and progress to the lower airways.  Early symptoms begin with hoarseness and loss of voice. This is followed by a cough, which subsequently becomes productive. Fever, dyspnea, rhonchi, and wet crackles may develop. Mild symptoms last 1-2 weeks. Recovery is slow, and coughing may persist for 1 or more months.
  • Moderate acute exposure leads to mucous membrane hyperemia, edema, and necrosis. Profuse, thin, mucopurulent rhinorrhea occurs; sinusitis may develop later. Mucosal findings range from small discrete ulcerations to extensive sloughing.
  • Pharyngitis usually appears 1-3 days after inhaling mustard vapors and may occur with nasal involvement in mouth breathers. The palate, uvula, tonsils, and pharynx are hyperemic and edematous. Multiple whitish ulcerations appear, varying in size according to severity of exposure. Laryngeal involvement resembles that of the pharynx. Edema and necrosis may lead to airway obstruction. Hoarseness, which almost always is present, may last 3-6 weeks or longer.
  • Severe inhalation exposures lead to a diphtherialike pseudomembrane, which may form a cast of the tracheobronchial tree. Mechanical obstruction from pseudomembrane formation and laryngospasm may cause death in the first 24 hours. Mild patchy pulmonary edema and focal atelectasis occur. Chemical pneumonitis may appear after the first 24 hours. Hemorrhagic pulmonary edema is not common and occurs only with severe damage. Suppurative bacterial bronchitis and bronchopneumonia are frequent complications; the latter is responsible for almost all deaths from vapor exposure.
  • In World War I, early mortality occurred in slightly more than 2% of US troops exposed to mustard and was caused almost entirely by pulmonary complications. Approximately 10% of the Iranian casualties treated in western European hospitals during the Iran-Iraq War developed progressive stenosis of the tracheobronchial tree.
• Liquid mustard ingestion leads to mucosal necrosis and hemorrhage. Initial symptoms include nausea, vomiting, painful diarrhea, and prostration. Severe gastrointestinal (GI) effects from mustard poisoning are relatively infrequent. Vomiting and bloody diarrhea beginning days after a high-dose exposure imply a poor prognosis.
• Moderate-to-severe liquid cutaneous, inhalational, or GI exposures cause systemic symptoms of nausea, vomiting, fever, malaise, and prostration.
  • Immediate bronchospasm and respiratory distress may occur.
  • The most severe patients also may present with CNS symptoms (eg, CNS depression) and parasympathetic effects such as bradycardia and other dysrhythmias.
  • Hemoconcentration and hypovolemic shock may occur due to fluid shifts and losses or GI hemorrhaging.
  • With systemic absorption of near lethal doses, hematopoietic and lymphatic tissue injuries occur, resulting in myelosuppression (leukopenia, thrombocytopenia, and anemia). The thymus, spleen, and lymph nodes may involute rapidly. The development of shock, thrombocytopenia, leukopenia, and hemorrhagic diathesis are grave prognostic signs. Bone marrow failure resulting in fulminant sepsis and bleeding is the most frequent cause of late deaths from mustard exposure.

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