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

CBRNE - Lung-Damaging Agents, Phosgene

Author: Joy C Wethern, DO, Resident Physician PGY3, Department of Emergency Medicine, Carl R Darnall Army Medical Center, Ft Hood, Texas
Coauthor(s): Kermit D Huebner, MD, FACEP, Research Director, Carl R Darnall Army Medical Center
Contributor Information and Disclosures

Updated: May 27, 2009

Introduction

Background

Phosgene is produced and utilized across numerous industries for legitimate chemical synthetic processes, but it has been used in the past as a chemical weapon by warring nations and extremist groups. It has the potential to function as a weapon of mass destruction by any group with simple chemical synthetic capabilities or with the means to sabotage an existing industrial phosgene source. Its primary mode of action is as an irritant pulmonary toxin that produces delayed-onset noncardiogenic pulmonary edema.

Phosgene is also known as carbonyl chloride and has the chemical structure COCl₂. The British chemist John Davy first synthesized phosgene in 1812 by combining chlorine gas and carbon monoxide with activated charcoal as a catalyst (CO + Cl₂ ® COCl₂). Although it is typically colorless as a gas, phosgene may appear as a white cloud under conditions of concentrated release due to slow hydrolysis with airborne water vapor. Phosgene has a boiling point of 8°C (47°F) and exists as a gas at room temperature. Below the boiling point, it exists as a colorless fuming liquid. Vaporization is still significant at lower temperatures, making inhalational exposure possible even in cold conditions. Phosgene is usually transported as a compressed liquefied gas, and direct contact with this form of the substance may produce frostbite injuries.

Although phosgene is nonflammable, it is a strongly reactive substance and demonstrates electrophilic properties. It reacts with alkalis, ammonia, amines, copper, and aluminum. It can also attack plastics and rubber materials. Because phosgene is poorly soluble in water, it reacts minimally with oropharyngeal and conducting airway tissues and as a result can penetrate deeply into the lung, where it exerts its effects at the alveolar-capillary membrane.

The odor of newly mown hay characterizes phosgene gas exposures, but this olfactory warning signal may not be appreciated by all individuals. Since the odor detection threshold concentration is approximately 0.5-1.5 ppm, which is at least 5 times the permissive exposure limit of 0.1 ppm¹ set by the National Institute for Occupational Safety and Health (NIOSH) and the American Conference of Government Industrial Hygienists (ACGIH), significant exposure may occur before any unusual scent is perceived. This odor detection threshold approaches the NIOSH-defined immediately dangerous to life and health (IDLH) level of 2 ppm¹ . As a result, the odor of new mown hay is an insufficient warning signal for dangerously high phosgene levels. Other pulmonary irritant gases such as chlorine are so noxious that exposed persons flee the immediate area of release, but persons exposed to phosgene may inadvertently remain in a highly contaminated area, unaware that they are in any danger.

Because phosgene is 4 times denser than air, it tends to remain close to the ground and to collect in low-lying areas. This distribution of contamination should be considered when planning evacuation routes in the event of a phosgene release. Children may be at risk for higher exposure levels as a result of increased gas distribution closer to the ground. Children may also be at higher risk for severe exposure to this irritant gas due to their larger minute volume-to-weight ratios and their larger lung surface area–to–body weight ratios.

Phosgene is used in the synthesis of plastics, pharmaceutical agents, isocyanates, polyurethanes, dyes, and pesticides. Industries in the United States produce over 1 billion pounds of phosgene per year. Unfortunately, industrial accidents involving phosgene are not uncommon. On March 6, 2000, a phosgene gas leak from a Thai plastics factory killed 1 person and injured 814 others. A laboratory accident involving inadvertent phosgene release in Fuzhou, China, on June 16, 2004, killed 1 person and injured more than 260 others. A phosgene-containing pipe rupture on September 8, 1994, in Yeochon, Korea, resulted in multiple injuries and 3 deaths.

Small-scale exposures to phosgene have also occurred, as phosgene is a product of thermal decomposition of chlorinated hydrocarbons. Such agents include refrigeration coolants, dry cleaning fluids (carbon tetrachloride), metal degreasing agents (trichloroethylene), and paint strippers (methylene chloride). When these chlorinated hydrocarbons are exposed to a heat source such as welding, a fire, or heat gun application, phosgene may be liberated. Several case reports document phosgene-induced pulmonary injury via these routes of exposure.

The Germans used phosgene first as a weapon in World War I, although this gas was also used in an offensive capability by French, American, and British forces. The initial World War I deployment of phosgene occurred when the Germans released approximately 4000 cylinders of gas against the British near Ypres on December 19, 1915. In this conflict, phosgene was often combined with chlorine in liquid-filled shells, so it is difficult to state the number of casualties and deaths attributable solely to phosgene. Because trench warfare typified much of World War I, heavier-than-air gases such as phosgene readily inflicted casualties in these low-lying areas. Between the world wars, phosgene was assigned the military designation CG and was classified as a nonpersistent agent because of its rapid evaporation. In military publications, it has been referred to as a choking agent, pulmonary agent, or irritant gas.

Since World War I, phosgene has rarely been used by traditional militaries, but the extremist cult Aum Shinrikyo used this agent to attack the Japanese journalist Shouko Egawa in 1994. Egawa had been reporting on the cult's activities, and the cult retaliated against her by introducing phosgene into her Yokohama apartment through the mail slot while she slept.

Pathophysiology

Phosgene interacts with biological molecules through 2 primary reactions: hydrolysis to hydrochloric acid and acylation reactions. Because phosgene is poorly soluble in water, the hydrolysis reaction (COCl₂ + H₂ O ® CO₂ + 2 HCl) contributes far less to the typical clinical presentation, but this reaction is likely responsible for the mucous membrane irritant effects observed when persons are exposed to phosgene in high concentrations. The acylation reactions occur with amino, hydroxyl, and sulfhydryl groups on biological molecules, which attack the highly electrophilic carbon molecule in phosgene. These reactions can result in membrane structural changes, protein denaturation, and depletion of lung glutathione. Acylation reactions may be particularly important with phospholipids such as phosphatidylcholine, which is a major constituent of pulmonary surfactant and lung tissue membranes.

Studies in animal models have shown that exposure to phosgene vastly increases alveolar leukotrienes, which are thought to be important mediators of phosgene toxicity to the alveolar-capillary interface. Phosgene exposure also increases lipid peroxidation and free radical formation. These processes may lead to increased arachidonic acid release and thus provide more substrate for lipoxygenase (ie, more leukotriene production). Proinflammatory cytokines, such as interleukin-6, are also found to be substantially higher 4-8 hours after phosgene exposure.² Na/K-ATPase dysfunction, resulting in increased oxidative stress and depletion of antioxidants, has also been demonstrated in mice exposed to phosgene.³

In addition, studies have shown that postexposure phosphodiesterase activity increases, leading to decreased levels of cyclic AMP. Normal cAMP levels are believed to be important for maintenance of tight junctions between pulmonary endothelial cells and thus for prevention of vascular leakage into the interstitium.

On a physiological level, the most important clinical effect of phosgene toxicity is the development of noncardiogenic pulmonary edema resulting from increased pulmonary vascular permeability due to the damaged alveolar-capillary interface. Similar to other pathologic processes resulting in noncardiogenic pulmonary edema, this state is characterized by heavy, wet lungs that have low compliance. Oxygenation and ventilation both suffer, and the work of breathing is dramatically increased. Often positive end expiratory pressure (PEEP) is required to stent open alveoli that would otherwise collapse and result in significant ventilation/perfusion (V/Q) mismatch. Arterial blood gases after severe phosgene exposure demonstrate low PaO₂, decreased oxygen saturation, and often a respiratory acidosis due to impaired gas exchange. Pulmonary function tests show a markedly decreased vital capacity and an overall restrictive pattern.

Clinical

History

Time to onset of symptoms after phosgene exposure is a critical historical detail.

• Head, ears, eyes, nose, and throat (HEENT) (immediate if high concentrations of phosgene; typically lasts 3-30 min)
  • Lacrimation
  • Conjunctival irritation/burning
  • Burning sensation in mouth/throat
  • Throat swelling/changes in phonation - May reflect laryngeal edema due to irritant effects of phosgene hydrolysis (hydrochloric acid formation) at vocal cords
• Respiratory (usually 4-24 h postexposure)
  • Cough - Initially dry, then increasing frothy white/yellow sputum
  • Chest tightness, chest pain, or substernal burning
  • Dyspnea - Present at rest but much worse on exertion
  • If patient is a smoker, metallic or unpleasant taste to cigarettes

Physical

• HEENT
  • Pharyngeal erythema
  • Conjunctivitis
  • Altered phonation
• Respiratory
  • Crackles on auscultation - Herald the onset of pulmonary edema
  • Cyanosis - Late finding
  • Thin, frothy white/yellow secretions
  • Wheezing
  • Tachypnea
  • Stridor
  • Accessory muscle use for respiratory effort
• Cardiac
  • Tachycardia
  • Hypotension - Late finding secondary to inflammation-mediated fluid diversion out of vascular system and into lung interstitium

Causes

Phosgene exposure may result from a weapon of mass destruction release by extremist groups, traditional military conflict involving chemical munitions, industrial sabotage, industrial accident, fire exposure, or small-scale accidental exposure involving the heating of chlorinated hydrocarbons. Any weapon of mass destruction release will likely produce large numbers of casualties presenting simultaneously with similar symptoms, but a large industrial accident could result in similar patient arrival patterns.

Phosgene toxicity may occur in 3 phases. The first is an immediate irritant reaction likely caused by the hydrolysis of phosgene to hydrochloric acid on mucous membranes, which results in conjunctivitis, lacrimation, and oropharyngeal burning sensations. This symptom complex occurs only in the presence of high concentration (>3-4 ppm) exposures but does not have any prognostic value for the timing and severity of later respiratory symptoms. The most important finding to identify during this stage is a laryngeal irritant reaction causing laryngospasm, which may lead to sudden death. The irritant symptoms last only a few minutes and then resolve as long as further exposure to phosgene ceases.

One of the hallmarks of phosgene toxicity is an unpredictable asymptomatic latent phase before the development of noncardiogenic pulmonary edema. Typically, the latent phase lasts 3-24 hours, but it may be as short as 30 minutes or as long as 48 hours after phosgene exposure. The duration of the latent phase is an extremely important prognostic factor for the severity of the ensuing pulmonary edema. Patients with a latent phase of less than 4 hours have a poor prognosis. Increased physical activity may shorten the duration of the latent phase and worsen the overall clinical course. Unfortunately, there are no reliable historical or physical examination findings during the latent phase to predict its duration.

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