Introduction
Background
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.
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. These products are found in common household solvents, paint removers, and dry cleaning fluids. Occupational exposure can occur when welders heat metals treated with these chemicals and in organic chemistry laboratories that use chloroform. 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.
Pathophysiology
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.
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. 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.
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.
- 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.
Clinical
History
Diagnosis of phosgene toxicity depends largely on history of exposure. Consider phosgene toxicity in patients involved in the manufacture of dyes, resins, coal tar, and pesticides. Query patients regarding occupation and any exposure to chemicals, especially around sources of heat. In the work setting and at home, phosgene can be produced by the combustion of methylene chloride (paint remover) or trichloroethylene (a degreasing solvent). Patients typically have an asymptomatic period of 30 minutes to 72 hours, but most significant exposures have a latent period less than 24 hours. The duration and concentration of exposure determine the time to symptom onset.
- Pulmonary
- Cough (initially nonproductive, later frothy white-to-yellow sputum) or hemoptysis
- Dyspnea (exertional early on, subsequently becomes resting dyspnea)
- Chest tightness or discomfort (may be pleuritic but frequently is described as retrosternal burning)
- Head, ears, eyes, nose, and throat
- Mucosal irritation - More common with intense exposure
- Eye irritation and tearing
- Nasal irritation (irritation and burning of the nasal passages) - Occurs with phosgene concentrations higher than 3 ppm, but, with lower respiratory tract disease, may occur at even lower concentrations
- Throat irritation extending to the retrosternal area - Common with exposures more than 5 ppm and may be described as a burning sensation
- Sudden death secondary to laryngospasm with large exposures
- Cardiovascular (caused by volume depletion or hypoxemia)
- Lightheadedness, palpitations
- Angina
- Headache (thought to be secondary to the hypoxemia and the inflammatory response initiated in the pulmonary parenchyma)
- Anorexia, nausea, and vomiting
- Flat metallic taste when smoking cigarettes or overall altered taste sensation
- Weakness
- Anxiety and sense of impending doom (likely from the hypoxemia and tachycardia)
- Skin burning if the patient has been sweating or if clothing is wet (caused by the breakdown to hydrochloric acid)
Physical
Physical examination is useful with patients with active symptoms. Patients who relate a recent exposure may be in the latent phase and have no specific findings related to the exposure.
- Pulmonary
- Tachypnea and bronchorrhea
- Wheezes, crackles, or rales on auscultation
- Cyanosis
- Apnea (late finding)
- Head, ears, eyes, nose, and throat (Upper airway findings are not good prognostic indicators because significant injury may occur to the lower airways without upper airway involvement.)
- Conjunctival injection and lacrimation
- Oropharyngeal hyperemia and salivation
- Nasal mucosa hyperemia associated with rhinorrhea
- Cardiovascular
- Tachycardia
- Hypotension
- Skin
- Cyanosis from pulmonary injury and resultant hypoxemia
- Chemical burns from liquefied phosgene (Although it also is considered a frostbite hazard in the compressed liquid form)
Causes
The major risks are occupational exposure and close proximity to an industrial incident.
- Present day exposures described in literature are caused by the combustion products from chlorinated chemicals (eg, methylene chloride, trichloroethylene).
- Welding metals recently treated with degreasers, such as trichloroethylene, may produce phosgene. Solvents used for degreasing purposes should be stored more than 200 feet from a welding arc, as the exposure to UV light can create phosgene by photodegradation.
- Use of methylene chloride, a commonly used chemical paint remover, near a heat source allows the release of phosgene.
- Carbon monoxide is released in vivo as a metabolic product of methylene chloride.
- Phosgene is a breakdown product of chloroform that is stored for more than 6 months, even if the chloroform is stabilized with amylene.
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References
Balmes J. Phosgene. In: Olson KR, ed. Poisoning and Drug Overdose. 2nd ed. Appleton & Lange; 1994:256.
Bardana EJ. 8. Occupational asthma and allergies. J Allergy Clin Immunol. Feb 2003;111(2 Suppl):S530-9. [Medline].
Borak J, Diller WF. Phosgene exposure: mechanisms of injury and treatment strategies. J Occup Environ Med. Feb 2001;43(2):110-9. [Medline].
British War Office. Medical Manual of Chemical Warfare. London: 1941:31-38.
Dombi A, Fekete ZA, Kiricsi I. In Situ Photocatalytic Reactor with FT-IR Analysis for Heterogeneous Catalytic Studies. Applied Catalysis. 2000;193:L5-L8.
Ellenhorn MJ. Chemical warfare. In: Ellenhorn's Medical Toxicology. 2nd ed. Lippincott Williams & Wilkins; 1997:1301-2.
Kennedy TP, Michael JR, Hoidal JR, et al. Dibutyryl cAMP, aminophylline, and beta-adrenergic agonists protect against pulmonary edema caused by phosgene. J Appl Physiol. Dec 1989;67(6):2542-52. [Medline].
Nelson LS. Simple asphyxiants and pulmonary irritants. In: Goldfrank L, ed. Goldfrank's Toxicologic Emergencies. 6th ed. New York: McGraw-Hill; 1998:1530.
Ng TP, Tsin TW, O'Kelly FJ. An outbreak of illness after occupational exposure to ozone and acid chlorides. Br J Ind Med. Oct 1985;42(10):686-90. [Medline].
Noort D, Hulst AG, Fidder A, et al. In vitro adduct formation of phosgene with albumin and hemoglobin in human blood. Chem Res Toxicol. Aug 2000;13(8):719-26. [Medline].
Parkhouse DA, Brown RF, Jugg BJ, Harban FM, Platt J, Kenward CE. Protective ventilation strategies in the management of phosgene-induced acute lung injury. Mil Med. Mar 2007;172(3):295-300. [Medline].
Parrish JS, Bradshaw DA. Toxic inhalational injury: gas, vapor and vesicant exposure. Respir Care Clin N Am. Mar 2004;10(1):43-58. [Medline].
Phosgene Medical Experts Group. Phosgene: Information on Options for First Aid and Medical Treatment. American Chemistry Council: Phosgene Panel. Available at http://www.americanchemistry.com/s_acc/bin.asp?CID=1175&DID=4396&DOC=FILE.PDF. Accessed 3/3/2008.
Schelble DT. Phosgene and phosphine. In: Haddad LM, Shannon MW, Winchester J, eds. Clinical Management of Poisoning and Drug Overdose. 3rd ed. Philadelphia: WB Saunders; 1998:960-3.
Sciuto AM. Assessment of early acute lung injury in rodents exposed to phosgene. Arch Toxicol. Apr 1998;72(5):283-8. [Medline].
Sciuto AM, Stotts RR. Posttreatment with eicosatetraynoic acid decreases lung edema in guinea pigs exposed to phosgene: the role of leukotrienes. Exp Lung Res. May-Jun 1998;24(3):273-92. [Medline].
Sciuto AM, Stotts RR, Hurt HH. Efficacy of ibuprofen and pentoxifylline in the treatment of phosgene- induced acute lung injury. J Appl Toxicol. Sep-Oct 1996;16(5):381-4. [Medline].
Sciuto AM, Strickland PT, Kennedy TP, et al. Intratracheal administration of DBcAMP attenuates edema formation in phosgene-induced acute lung injury. J Appl Physiol. Jan 1996;80(1):149-57. [Medline].
Sciuto AM, Strickland PT, Kennedy TP, Gurtner GH. Postexposure treatment with aminophylline protects against phosgene- induced acute lung injury. Exp Lung Res. Jul-Aug 1997;23(4):317-32. [Medline].
Sciuto AM, Strickland PT, Kennedy TP, Gurtner GH. Protective effects of N-acetylcysteine treatment after phosgene exposure in rabbits. Am J Respir Crit Care Med. Mar 1995;151(3 Pt 1):768-72. [Medline].
Selden A, Sundell L. Chlorinated solvents, welding and pulmonary edema. Chest. Jan 1991;99(1):263. [Medline].
Sidell FR, Takafuji ET, Franz DR. Toxic inhalation injury. In: Textbook of Military Medicine: Medical Aspects of Chemical and Biological Warfare. Walter Reed Army Medical Center; 1997:257-60.
Sjogren B, Plato N, Alexandersson R, et al. Pulmonary reactions caused by welding-induced decomposed trichloroethylene. Chest. Jan 1991;99(1):237-8. [Medline].
Snyder RW, Mishel HS, Christensen GC 3d. Pulmonary toxicity following exposure to methylene chloride and its combustion product, phosgene. Chest. Mar 1992;101(3):860-1. [Medline].
Warden CR. Respiratory agents: irritant gases, riot control agents, incapacitants, and caustics. Crit Care Clin. Oct 2005;21(4):719-37, vi. [Medline].
Weiss SJ, Lesser SH. Hazards associated with metalworking by artists. South Med J. Jul 1997;90(7):665-71. [Medline].
Further Reading
Keywords
phosgene toxicity, phosgene exposure, phosgene poisoning, COCl2, carbonic dichloride, carbon oxychloride, carbonyl dichloride, chloroformyl chloride, d-stoff, green cross, CG, pulmonary irritant
