Chapter S3: Chemical Terrorism

The use of chemical warfare agents (CWAs) in modern warfare dates back to World War I (WWI). Sulfur mustard and nerve agents were used by Iraq against the Iranian military and Kurdish civilians. Most recently the nerve agent sarin, GB, was used by the Syrian military against their civilian population. Since the Japanese sarin attacks in 1994–1995 and the terrorist strikes of September 11, 2001, the all-too-real possibility of chemical or biological terrorism against civilian populations anywhere in the world has attracted increased attention.

Military planners consider the WWI blistering agent sulfur mustard and the organophosphorus nerve agents as the most likely agents to be used on the battlefield. In a civilian or terrorist scenario, the choice widens considerably. For example, many of the CWAs of WWI, including chlorine, phosgene, and cyanide, are used today in large amounts in industry. They are produced in chemical plants, are stockpiled in large tanks, and travel up and down highways and railways in large tanker cars. The rupture of any of these stores by accident or on purpose could cause many injuries and deaths. In three attacks in February 2007, for example, insurgents in Iraq used chlorine gas released from tankers after explosions as a crude form of chemical weaponry; these attacks killed 12 people and intoxicated more than 140 others. Countless hazardous materials (HAZMATs) that are not used on the battlefield can be used as terrorist weapons. Some of them, including insecticides and ammonia, could wreak as much damage and injury as the weaponized chemical agents.

Many mistakenly believe that chemical attacks will always be so severe that little can be done except to bury the dead. History proves the opposite. Even in WWI, when IV fluids, endotracheal tubes, and antibiotics were unavailable, the mortality rate among U.S. forces on the battlefield from CWAs—chiefly sulfur mustard and the pulmonary toxicants—was only 1.9%. That figure was far lower than the 7% mortality rate from conventional wounds. In the 1995 Tokyo subway sarin incident, among the 5500 patients who sought medical attention at hospitals, 80% were not actually symptomatic and only 12 died. Recent events should prompt not a fatalistic attitude but a realistic wish to understand the pathophysiology of the syndromes these agents cause, with a view to treating expeditiously all patients who present for care and an expectation of saving the vast majority. As we prepare to defend our civilian population from the effects of chemical terrorism, we also must consider the fact that terrorism itself can produce sequelae such as physiologic or neurologic effects that may resemble the effects of nonlethal exposures to CWAs. These effects are due to a general fear of chemicals, fear of decontamination, fear of protective ensembles, or other phobic reactions. The increased difficulty in differentiating between stress reactions and nerve agent–induced organic brain syndromes has been pointed out. As with natural catastrophes, large-scale chemical spills, etc. knowledge of the psychological effects of terrorism and of CWAs and medical countermeasures are crucial for mass casualty planning. For the reader’s benefit, the CWAs, their two-letter North Atlantic Treaty Organization (NATO) codes (which were established by a NATO international convention and convey no clinical implications), their unique physical features, and their initial effects are listed in Table S3-1. Table S3-2 provides guidelines for immediate treatment. The focus of this chapter is on the blister and nerve CWAs, which have been employed in battle and against civilians and have had a significant public health impact.

The use of chemical warfare agents (CWAs) in modern warfare dates to World War I (WWI). After many years of disarmament efforts many countries still retain stockpiles of these agents. Sulfur mustard and nerve agents were used by Iraq in the 1980s against Iran and Kurdish civilians. Chlorine was used as a weapon of war in the Iraq theater in the 1990s. The nerve agent sarin was used on several occasions in 2013–2017 by the Syrian military against civilians. Since the sarin attacks in Japan in 1994–1995, the possibility of chemical or biological terrorism against civilian populations has been acknowledged. These developments have led to the formation of international agencies and agreements, notably, the Chemical Warfare Convention banning the production, stockpiling, and use of these agents, which has been ratified by 192 countries.

Sulfur mustard has been a military threat since it first appeared on the battlefield in Belgium during WWI. In modern times, it remains a threat on the battlefield as well as a potential chemical terrorism weapon because of the simplicity of its manufacture and its extreme effectiveness. Sulfur mustard accounted for 70% of the 1.3 million chemical casualties in WWI. Occasional cases of sulfur mustard intoxication continue to occur in the United States among people exposed to WWI- and WWII-era munitions.

Mechanism

Sulfur mustard constitutes both a vapor and a liquid threat to all exposed epithelial surfaces. The effects are delayed, appearing hours after exposure. The organs most commonly affected are the skin (with erythema and vesicles), the eyes (with manifestations ranging from mild conjunctivitis to severe eye damage), and the airways (with effects ranging from mild upper airway irritation to severe bronchiolar damage). After exposure to large quantities of mustard, precursor cells of the bone marrow are damaged, with consequent pancytopenia and secondary infection. The gastrointestinal mucosa may be damaged, and there are sometimes central nervous system (CNS) signs of unknown mechanism. No specific antidotes exist; management is entirely supportive. Immediate decontamination of the liquid is the only way to reduce damage. Complete decontamination in 2 min stops clinical injury; decontamination at 5 min reduces skin injury by ~50%. The section on decontamination and Table S3-2 provide more detail about decontamination after exposure to mustard and other CWAs.

Mustard dissolves slowly in aqueous media such as sweat, but, once dissolved, it rapidly forms cyclic ethylene sulfonium ions that are extremely reactive with cell proteins, cell membranes, and especially DNA in rapidly dividing cells. The ability of mustard to react with and alkylate DNA gives rise to the effects by which it has been characterized as “radiomimetic”—i.e., similar to radiation injury. Mustard has many biologic actions, but its actual mechanism of action is largely unknown. Much of the biologic damage from mustard results from DNA alkylation and cross-linking in rapidly dividing cells: corneal epithelium, basal keratinocytes, bronchial mucosal epithelium, gastrointestinal mucosal epithelium, and bone marrow precursor cells. This damage may lead to cellular death and inflammatory reactions. In the skin, proteolytic digestion of anchoring filaments at the epidermal-dermal junction may be the major mechanism of action resulting in blister formation. Mustard also has mild cholinergic activity, which may be responsible for effects such as early gastrointestinal and CNS symptoms. Mustard reacts with tissue within minutes of entering the body. Its circulating half-life in unaltered form is extremely brief.

Clinical Features

Topical effects of mustard occur in the skin, airways, and eyes; the eyes are most sensitive and the airways next most sensitive. Absorbed mustard may produce effects in the bone marrow, gastrointestinal tract, and CNS. Direct injury to the gastrointestinal tract also may occur after ingestion of the compound through contamination of water or food.

Erythema is the mildest and earliest form of mustard skin injury. It resembles sunburn and is associated with pruritus, burning, or stinging pain. Erythema begins to appear within 2 h to 2 days after vapor exposure. Time of onset depends on severity of exposure, ambient temperature and humidity, and type of skin. The most sensitive sites are warm moist locations and areas of thin delicate skin, such as the perineum, external genitalia, axillae, antecubital fossae, and neck.

Within the erythematous areas, small vesicles can develop, which may later coalesce to form bullae (Fig. S3-1). The typical bulla is large, dome-shaped, flaccid, thin-walled, translucent, and surrounded by erythema. The blister fluid, a transudate, is clear to straw-colored and becomes yellow, tending to coagulate. The blister fluid does not contain mustard, is not itself vesicant, and does not produce secondary lesions. Lesions from high-dose liquid exposure may develop a central zone of coagulation necrosis with blister formation at the periphery. These lesions take longer to heal and are more prone to secondary infection than are the uncomplicated lesions seen at lower exposure levels. Severe lesions may require skin grafting.

The primary airway lesion is necrosis of the mucosa with possible damage to underlying smooth muscle. The damage begins in the upper airways and descends to the lower airways in a dose-dependent manner. Usually the terminal airways and alveoli are affected only as a terminal event. Pulmonary edema is not usually present unless the damage is very severe, and then it becomes hemorrhagic.

The earliest effects of mustard—and perhaps the only effects of a low concentration—involve the nose, sinuses, and pharynx. There may be irritation or burning of the nares, epistaxis, sinus pain, and pharyngeal pain. As the concentration increases, laryngitis, voice changes, and nonproductive cough develop. Damage to the trachea and upper bronchi leads to a productive cough. Lower airway involvement causes dyspnea, severe cough, and increasing quantities of sputum. Terminally, there may be necrosis of the smaller airways with hemorrhagic edema into surrounding alveoli. Hemorrhagic pulmonary edema is rare.

Necrosis of airway mucosa causes “pseudomembrane” formation. These membranes may obstruct the bronchi. During WWI, high-dose mustard exposure caused acute death via this mechanism in a small minority of cases (Fig. S3-2).

The eyes are the organs most sensitive to mustard vapor injury. The latent period is shorter for eye injury than for skin injury and is also dependent on exposure concentration. After low-dose vapor exposure, irritation evidenced by reddening of the eyes may be the only effect. As the dose increases, the injury includes progressively severe conjunctivitis, photophobia, blepharospasm, pain, and corneal damage (Fig. S3-3). About 90% of eye injuries related to mustard heal in 2 weeks to 2 months without sequelae. Scarring between the iris and the lens may follow severe effects; this scarring may restrict pupillary movements and predispose victims to glaucoma. The most severe damage is caused by liquid mustard. Extensive eye exposure can be followed by severe corneal damage with possible perforation of the cornea and loss of the eye. In some individuals, latent chronic keratitis, sometimes associated with corneal ulcerations, has been described as early as 8 months and as late as 20 years after initial exposure, and may result in blindness.

The mucosa of the gastrointestinal tract is susceptible to mustard damage from either systemic absorption or ingestion of the agent. Mustard exposure in small amounts will cause nausea and vomiting lasting up to 24 h. The mechanism of the nausea and vomiting is not understood, but mustard does have a cholinergic-like effect. The CNS effects of mustard also remain poorly defined. Exposure to large amounts can cause seizures in animals. Reports from WWI and from the Iran–Iraq war described people exposed to small amounts of mustard acting sluggish, apathetic, and lethargic. These reports suggest that minor psychological problems could linger for ≥1 year.

The cause of death in the majority of mustard poisoning cases is sepsis and respiratory failure. Mechanical obstruction via pseudomembrane formation and agent-induced laryngospasm is important in the first 24 h, but only in cases of severe exposure. From the third through the fifth day after exposure, secondary pneumonia due to bacterial invasion of denuded necrotic mucosa can be expected. The third wave of death is caused by agent-induced bone marrow suppression, which peaks 7–21 days after exposure and causes death via sepsis.

Treatment

The organophosphorus nerve agents are the deadliest of the CWAs. They work by inhibition of tissue synaptic acetylcholinesterase, creating an acute cholinergic crisis. Death ensues because of respiratory depression and can occur within seconds to minutes.

The nerve agents tabun and sarin were first used on the battlefield by Iraq against Iran during the first Persian Gulf War (1984–1987). Estimates of casualties from these agents range from 20,000 to 100,000. In 1994 and 1995, the Japanese cult Aum Shinrikyo used sarin in two terrorist attacks in Matsumoto and Tokyo. Two U.S. soldiers were exposed to sarin while rendering safe an improvised explosive device in Iraq in 2004. Estimates by the U.S. government and various relief agencies suggest there were from several hundred to 1450 sarin casualties in Ghouta, Syria, in 2013.

The “classic” nerve agents include tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and VX; VR, similar to VX, was manufactured in the former Soviet Union (Table S3-1). All the nerve agents are organophosphorus compounds, which are liquid at standard temperature and pressure. The “G” agents evaporate at about the rate of water and thus probably will have evaporated within 24 h after deposition on the ground. Their high volatility thus makes a spill of any amount a serious vapor hazard. In the Tokyo subway attack in which sarin was used, 100% of the symptomatic patients inhaled sarin vapor that spilled out on the floor of the subway cars. The low vapor pressure of VX, an oily liquid, makes it much less of a vapor hazard but potentially a greater environmental hazard because it persists in the environment far longer.

Mechanism

Acetylcholinesterase inhibition accounts for the major life-threatening effects of nerve agent poisoning. The efficacy of antidotal therapy in the reversal of this inhibition proves that this is the primary toxic action of these poisons. At cholinergic synapses, acetylcholinesterase, bound to the postsynaptic membrane, functions as a turn-off switch to regulate cholinergic transmission. Inhibition of acetylcholinesterases causes the released neurotransmitter, acetylcholine, to accumulate abnormally. End-organ overstimulation, recognized by clinicians as a cholinergic crisis, ensues (Fig. S3-4).

Clinical Features

Clinical effects of nerve agent exposure are identical for vapor and liquid exposure routes if the dose is sufficiently large. The speed and order of symptom onset will differ (Table S3-2).

Exposure of a patient to nerve agent vapor will cause cholinergic symptoms in the order in which the toxin encounters cholinergic synapses. The most exposed synapses on the human integument are in the pupillary muscles. Nerve agent vapor easily crosses the cornea, interacts with these synapses, and produces miosis, described by Tokyo subway victims as “the world going black.” Rarely, this vapor also can cause eye pain and nausea. Exocrine glands in the nose, mouth, and pharynx are next exposed to the vapor, and cholinergic overload here causes increased secretions, rhinorrhea, excess salivation, and drooling. Toxin then interacts with exocrine glands in the upper airway, causing bronchorrhea, and with bronchial smooth muscle, causing bronchospasm. This combination of events can result in hypoxia.

Once the victim has inhaled, vapor can passively cross the alveolar-capillary membrane, enter the bloodstream, and incidentally and asymptomatically inhibit circulating cholinesterases, particularly free butyrylcholinesterase and erythrocyte acetylcholinesterase, both of which can be assayed. Unfortunately, the results of this assay may not be easily interpretable without a baseline, since cholinesterase levels vary enormously between individuals and over time in a healthy patient.

Usually the first organ system to become symptomatic from bloodborne nerve agent exposure is the gastrointestinal tract, where cholinergic overload causes abdominal cramping and pain, nausea, vomiting, and diarrhea. After the gastrointestinal tract becomes involved, nerve agents will affect the heart, distant exocrine glands, muscles, and brain. Because there are cholinergic synapses on both the vagal (parasympathetic) and sympathetic sides of the autonomic input to the heart, one cannot predict how heart rate and blood pressure will change once intoxication has occurred. Remote exocrine activity will include oversecretion in the salivary, nasal, respiratory, and sweat glands—the patient will be “wet all over.” Bloodborne nerve agents will overstimulate neuromuscular junctions in skeletal muscles, causing fasciculations followed by frank twitching. If the process goes on long enough, ATP in muscles will eventually be depleted and flaccid paralysis will ensue.

In the brain, since the cholinergic system is so widely distributed, bloodborne nerve agents will, in sufficient doses, cause rapid loss of consciousness, seizures, and central apnea leading to death within minutes. If respiration is supported, status epilepticus that does not respond to usual anticonvulsants may ensue (Chap. 418). If status epilepticus persists, neuronal death and permanent brain dysfunction may occur. Even in mild nerve-agent intoxication, patients may recover but may experience weeks of irritability, sleep disturbance, and nonspecific neurobehavioral manifestations.

The time from exposure to development of the full-blown cholinergic crisis after nerve agent vapor inhalation can be minutes or even seconds, yet there is no depot effect. Since nerve agents have a short circulating half-life, if the patient is supported and, ideally, treated with antidotes, improvement should be rapid, without subsequent deterioration.

Liquid exposure to nerve agents results in different speeds and orders of symptom onset. A nerve agent on intact skin will partially evaporate and partially begin to travel through the skin, causing localized sweating and then, when it encounters neuromuscular junctions, localized fasciculations. Once in muscle, the agent will cross into the circulation and cause gastrointestinal discomfort, respiratory distress, heart rate changes, generalized fasciculations and twitching, loss of consciousness, seizures, and central apnea. The time course will be much longer than with vapor inhalation; even a large, lethal droplet can take up to 30 min to exert an effect, and a small, sublethal dose could progressively take effect over 18 h. Clinical worsening that occurs hours after treatment has started is far more likely with liquid than with vapor exposure. In addition, miosis, which is practically unavoidable with vapor exposure, is not always present with low-level liquid exposure and may be the last manifestation to develop in this situation; such a delay is due to the relative insulation of the pupillary muscle from the systemic circulation.

Unless the cholinesterase is reactivated by specific therapy (oximes), its binding to the enzyme is essentially irreversible. Erythrocyte acetylcholinesterase activity recovers at ~1% per day. Plasma butyrylcholinesterase recovers more quickly and is a better guide to recovery of tissue enzyme activity.

Treatment

Cyanide (CN^–) has become an agent of particular interest in terrorist scenarios because of its applicability to indoor targets. In recent years, for example, attacks with this agent have targeted the water supply of the U.S. Embassy in Italy. The 1993 World Trade Center bombing in New York may have been intended as a cyanide release as well.

Hydrogen cyanide and cyanogen chloride, the major forms of cyanide, are either true gases or liquids very close to their boiling points at standard room temperature. Hydrogen cyanide gas is lighter than air and does not remain concentrated outdoors for long; thus, it is a poor military weapon but an effective weapon in an indoor space such as a train station or a sports arena. Cyanide is also water-soluble and poses a threat to the food and water supply from either accidents or malign intent. It is well absorbed from the gastrointestinal tract, through the skin, or via inhalation—the preferred terrorist route. Cyanide smells like bitter almonds, but 50% of persons lack the ability to smell it.

Unique among CWAs, cyanide is a normal constituent of the environment and actually is a required cofactor in many compounds important in metabolism, including vitamin B₁₂. Cyanide is present in many plants, including tobacco; therefore, smokers, for instance, chronically carry cyanide at three times the usual level. Humans have evolved a detoxification mechanism for cyanide. Cyanide poisoning results if a large challenge of CN^– overwhelms this mechanism, while treatment of cyanide poisoning exploits it.

Mechanism

Cyanide directly poisons the last step in the mitochondrial electron transport chain, cytochrome a3, which results in a shutdown of cellular energy production. Tissues are poisoned in direct proportion to their metabolic rate, with the carotid baroreceptors and the brain—the most metabolically active tissues in the body—affected fastest and most severely. This poisoning results from cyanide’s high affinity for certain metals, notably Co and Fe⁺⁺⁺. Cytochrome a3 contains Fe⁺⁺⁺, to which CN⁻ binds. Cyanide-poisoned tissues cannot extract oxygen from the blood; even though pulmonary oxygen exchange and cardiac function are preserved, cells die of hypoxia—i.e., of histotoxic rather than cardiopulmonary cause.

Clinical Features

Hyperpnea occurs ~15 s after inhalation of a high concentration of cyanide and is followed within 15–30 s by the onset of convulsions and electrical status epilepticus. Respiratory activity stops 2–3 min later, and cardiac activity ceases several minutes after that. Exposure, especially via inhalation, to a large challenge of CN^– can cause death in as little as 8 min. Smaller challenges will cause symptom spread over a longer period; very low doses may produce no effects at all because of the body’s ability to detoxify small amounts. Cyanogen chloride additionally produces mucous membrane irritation. Many but not all patients have a cherry-red appearance because their venous blood remains oxygenated.

Differential Diagnosis

In a mass casualty incident caused by a chemical agent, the primary differential diagnosis of cyanide poisoning will be nerve agent poisoning. Cyanide-poisoned patients lack the prominent cholinergic signs seen in nerve agent poisoning, such as miosis and increased secretions. The cherry-red appearance often seen in cyanide poisoning is never seen in nerve agent poisoning. Cyanosis, confusingly, is not a prominent early sign in cyanide poisoning.

Treatment

Prognosis

Cyanide casualties tend to recover much more quickly than casualties exposed to other chemical agents. Many patients with industrial exposures have returned to work within the same shift. If a patient receives a large challenge and dies, death usually takes place within minutes of exposure. Little data exists to suggest the occurrence of long-term clinical effects in those who have recovered from acute poisoning.

ACKNOWLEDGMENT

This chapter includes material written for previous editions of Harrison’s by Charles G. Hurst, MD.