Phosgene Toxicity 

Phosgene (COCl₂) is a highly toxic gas or liquid that is classified as a pulmonary irritant. Synonyms for phosgene include carbonic dichloride, carbon oxychloride, carbonyl dichloride, chloroformyl chloride, d-stoff, and green cross. The military symbol for phosgene is CG, and its United Nations/Department of Transportation number is UN#1076. The American Chemical Society's Chemical Abstracts Service (CAS) registry number for phosgene is #75-44-5. Phosgene's structure is depicted in the image below.

Sir Humphrey Davy first synthesized phosgene in 1812 by passing carbon monoxide and chloride through charcoal. During World War I, it was used in combination with chlorine gas for combat purposes by the German army. This combination allowed phosgene emission to be hastened in cold weather. The German army switched to mustard gas in 1917 because of the development of effective gas masks. More effective agents and improved personal protective equipment make phosgene an unlikely agent to be used in future battles.

Present day exposure occurs during the manufacture of aniline dyes, polycarbonate resins, coal tar, pesticides, isocyanates, polyurethane, and pharmaceuticals. Phosgene exposure also occurs in the uranium enrichment process and during the bleaching of sand for glass production. Exposures related to the heating or combustion of chlorinated organic compounds, such as carbon tetrachloride, chloroform, and methylene chloride, also occur.^[1] These products are found in common household solvents, paint removers, and dry cleaning fluids.^[2] Occupational exposure can occur when welders heat metals treated with these chemicals and in organic chemistry laboratories that use chloroform.^{[3, 4]} Similarly, vehicle crashes involving trains or trucks transporting phosgene (or chlorinated hydrocarbons, such as methylene chloride, that could combust to form phosgene) could expose numerous individuals to this toxin.^[1]

Phosgene is a colorless gas with the odor of newly mown hay or green corn. Olfactory fatigue may occur with a large exposure. Exposure to concentrations of 3 ppm may not cause noticeable symptoms for 12-24 hours. Exposures to 50 ppm may be rapidly fatal. While an odor threshold of 1.5 ppm has been reported in some humans, this does not protect against toxic inhalation effects.^{[5, 6, 7]}

Phosgene is considered to have poor warning properties and, hence, may reach the lower airways before it is noticed. It is 4 times heavier than air and is a gas above 47°F (8°C). Because of hydrolysis from atmospheric water, it appears as a white cloud in an outside environment.

There are 2 mechanisms of injury, hydrolysis and acylation.^[8] In hydrolysis, damage caused by phosgene is due to the presence of a highly reactive carbonyl group attached to 2 chloride atoms. The gas dissolves slowly in water, but when this occurs, it hydrolyses to form carbon dioxide and hydrochloric acid. This slow dissolution allows phosgene to enter the pulmonary system without significant damage to the upper airways. However, in the lower airways and alveoli, the tissue undergoes necrosis and inflammation. After the first few hours of exposure, the carbonyl group attacks the surface of the alveolar capillaries, causing leakage of serum into the alveolar septa. The tissue fills with fluid, causing hypoxia and apnea. Massive amounts of fluid (up to 1 L/h) leak out of the circulation, leading to a noncardiogenic pulmonary edema, with associated hypoxemia and volume depletion.

Acylation involves the reaction of phosgene with nucleophilic moieties causing denaturation of proteins, changes in cell membranes, and disruption of enzymes. The permeability of the blood-air barrier is altered, leading to interstitial edema, and the inflammatory cascade is activated. This primarily occurs in the bronchioli and alveoli since they are not protected by a mucous layer.

Researchers in the past decade have discovered 2 important facts that may lead to improved therapy. First, phosgene stimulates the synthesis of lipoxygenase-derived leukotrienes. Second, phosgene combines with glutathione to form diglutathionyl dithiocarbonate. When the glutathione stores become depleted, phosgene binds to the cellular macromolecules, causing cell necrosis in the renal and hepatic tissues.

Frequency

United States

Clinically significant phosgene exposure occurs infrequently. Sporadic exposures in recent years are related to industrial accidents or isolated.^[9]

International

In view of currently available war gases, which are much more lethal than phosgene, and improved respiratory protection, phosgene is no longer considered a significant threat.

Mortality/Morbidity

The Occupational Safety and Health Administration permissible exposure limit (OSHA PEL) for the workplace is 0.1 ppm (0.4 mg/m) as an 8-hour time weighted average. The level immediately dangerous to life or health (IDLH) is 2 ppm. Even a short exposure to 50 ppm may result in rapid fatality.

Another means to assess exposure and potential complications is using the inhaled dose instead of concentration alone. An inhaled dose of greater than 25 ppm-min leads to subclinical biochemical lung alterations, greater than 150 ppm-min causes overt alveolar edema, greater than 300 ppm-min is possibly lethal, and the level with 50% mortality is about 500 ppm-min.^{[5, 6, 7]}

• During World War I, from December 1915 to August 1916, casualties from phosgene exposure occurred in 4.1% of gas-exposed troops. Fatality from phosgene exposure occurred in 0.7% of gas-exposed troops. Total casualties from chemical gas exposure occurred in 1.2 million troops and caused 100,000 deaths. Phosgene accounted for an estimated 80% of these cases.
• According to OSHA, millions of kilograms of phosgene are produced annually, with 10,000 workers at risk of exposure. This does not include the large number of people that may have mild-to-moderate exposures in their homes from using solvents (eg, methylene chloride) with heat guns to remove paint.
• Morbidity and mortality are related to the degree of pulmonary insult and subsequent hypoxemia. Delayed diagnosis may result from delayed signs and symptoms. Underlying medical conditions contribute to the patient's ability to withstand the hypoxic insult.

Race

No evidence has demonstrated that outcome of phosgene toxicity is dependent on race.

Sex

No sex predilection exists. Historically, most exposures have occurred in men because of their military roles. Women were exposed during World War I from developing and testing gas masks at the home front.