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. Author manuscript; available in PMC: 2022 May 1.
Published in final edited form as: Toxicol Mech Methods. 2020 Dec 22;31(4):288–292. doi: 10.1080/15376516.2020.1861670

Phosgene Oxime: A Highly Toxic Urticant and Emerging Chemical Threat

Satyendra K Singh 1, Joshua A Klein 1, Holly N Wright 1, Neera Tewari-Singh 1,*
PMCID: PMC8087642  NIHMSID: NIHMS1687366  PMID: 33297803

Abstract

Highly toxic industrial chemicals that are widely accessible, and hazardous chemicals like phosgene oxime (CX) that can be easily synthesized, pose a serious threat as potential chemical weapons. In addition, their accidental release can lead to chemical emergencies and mass casualties. CX, an urticant, or nettle agent, grouped with vesicating agents, causes instant pain, injury and systemic effects, which can lead to mortality. With faster cutaneous penetration, corrosive properties, and more potent toxicity compared to other vesicating agents, CX causes instantaneous and severe tissue damage. CX, a potential chemical terrorism threat agent, could therefore be weaponized with other chemical warfare agents to enhance their harmful effects. CX is the least studied vesicant and its acute and long-term toxic effects as well as its mechanism of action are largely unknown. This has hampered the identification of therapeutic targets and the development of effective medical countermeasures. There are only protective measures, decontamination, and supportive treatments available for reducing the toxic effects from CX exposure. This review summarizes CX toxicity, its known mechanism of action, and our current studies exploring the role of mast cell activation and associated signaling pathways in CX cutaneous exposure under the National Institutes of Health Countermeasures Against Chemical Threats program. Potential treatment options and the development of effective targeted countermeasures against CX-induced morbidity and mortality is also discussed.

Keywords: Phosgene oxime, urticant, vesicating agent, toxicity, molecular mechanisms, inflammation, mast cells, medical countermeasures

1. Introduction

Among the weapons of mass destruction (WMD), chemical substances whose toxic properties can be utilized to kill, incapacitate, or cause devastating injuries to human beings, are known as chemical weapons. Chemical weapons have been synthesized, stockpiled, and used in warfare as chemical warfare agents (CWAs) or in acts of terrorism on the civilian population (Dacre and Goldman 1996; Ganesan et al. 2010). The main categories of CWAs include: i) nerve agents (G-agents are sarin, cyclosarin, tabun, and soman; V-agents include VE, VG, VM, VR and VX), ii) vesicating agents (blistering agents nitrogen mustard and sulfur mustard, arsenical agents like lewisite, and urticant phosgene oxime), iii) choking agents or asphyxiants (phosgene, chlorine, chloropicrin etc), iv) riot control agents (tear gases; chloroacetophenone, chlorobenzylidenemalononitrile, dibenzoxazepine, diphenylaminoarsine), v) blood agents (cyanide), and vi) toxic industrial chemicals/toxic industrial materials (TICs/TIMs; chlorine, bromine, hydrogen sulfide, methyl isocyanate, etc.) (Watson and Griffin 1992; Saladi et al. 2006; Geraci 2008; Edward T. Dickinson 2017; Goswami et al. 2018). The first well-documented report on the use of CWAs was in April 1915, when the German Army used thousands of cylinders of chlorine gas in the Battle of Ypres during World War I (WWI) (Ganesan et al. 2010). Toxic chemicals including chlorine, sulfur mustard (mustard gas; SM), phosgene, and nerve agents like sarin have been used in various conflicts since WWI, including the Iran-Iraq war in the 1980s (Ganesan et al. 2010).

The use of nerve agents and vesicating agent SM in civilian attacks in Syria and Iraq has been recently reported, which emphasizes that terrorist attacks using extremely toxic chemicals are a high possibility (SAMSFoundation 2015; Kohnavard 2016; Chulov 2017; Nebehay 2017; Tewari-Singh N. 2020). In addition, toxic chemicals (TICs and TIMs) are widely used in the manufacturing process of various pesticides and in pharmaceutical industries. An accidental or deliberate release of these TICs/TIMs from industrial plants, stockpiles, or their transport, can lead to chemical emergencies (Ganesan et al. 2010). The readily available TICs/TIMs, and other chemicals that can be easily synthesized, pose a serious future threat to the human population as chemical terrorism weapons in the present world scenario. Manufactured chemical phosgene oxime [CX; dichloroformoxime; N-(dichloromethylidene)hydroxylamine; Cl2CNOH] is easy to synthesize, and due to its highly toxic nature, unknown mechanism of action, and no available antidote, is considered to be a hazardous chemical with both military and terrorist potentials (Goswami et al. 2018; Tewari-Singh N. 2020).

2. History of CX use and Its Toxic Effects

CX is classified as a vesicating agent, a group of chemicals which consists of alkylating mustard and arsenical agents like SM [bis(2-chloroethyl)sulfide], nitrogen mustards [HN1; (bis(2-chloroethyl) ethylamine, HN2; (2,2’-dichloro-N-methyldiethylamine, and HN3; (tris(2-chloroethyl)amine hydrochloride), and lewisite [L; dichloro(2-chlorovinyl) arsine] (Young 2009). However, CX, a halogenated oxime, is an urticant or nettle agent, with chemical properties and toxicity that significantly differ from other vesicants (Patočka and Kuča 2011; Goswami et al. 2018; Tewari-Singh N. 2020). CX was first synthesized in 1929 by the German researchers Prandtl and Sennewald (Zajtchuk 1997). It was stockpiled during World War II by Germany and Russia; however, its use in the battlefield is not reported. Due to its instantaneous toxic effects, CX was developed as a potential chemical warfare agent which could be employed alone or with other chemical warfare agents (Patočka and Kuča 2011; Goswami et al. 2018; Tewari-Singh N. 2020). The extreme pain from CX exposure can lead to the removal of protective clothing, causing rapid skin damage, which can make skin more susceptible to injury from other CWAs. CX can penetrate garments and rubber much faster than other chemical warfare agents, causing rapid incapacitation and death (Zajtchuk 1997; Rosenbloom et al. 2002; Patočka and Kuča 2011; Tewari-Singh N. 2020). Although not confirmed, Iraqi use of an agent against Iran, whose effects resembled CX, is reported (OSAGWI, 1990). In March 2019, an FBI investigation found large quantities of synthesized CX inside a Lawton, Oklahoma home (https://www.news9.com/story/40170458/fbi-investigation-finds-chemical-warfare-agent-inside-lawton-home). If released accidentally or intentionally, inhalation and skin absorption of toxic chemical CX could have caused a massive chemical emergency with mass casualties.

Vesicants or blister agents, are tissue-injuring agents that cause acute damage to the eyes, respiratory system, and internal organs (Balali-Mood et al. 2005; Kehe K. et al. 2008; Ghabili et al. 2010). The toxic effects of mustard vesicants are delayed and do not appear till hours after their exposure; however, the toxic effects of CX are instant and appear within minutes of its exposure (Shakarjian et al. 2010; Patočka and Kuča 2011; Tewari-Singh N. et al. 2017). Injury symptoms caused by the vesicants and CX depends on their dose, duration, route and form of exposure (Patočka and Kuča 2011; Goswami et al. 2018; Tewari-Singh N. 2020). Both liquid and vapor forms of CX can cause severe pain and local tissue injury/corrosion via cutaneous, ocular, or pulmonary routes of exposure (McAdams 1965; Patočka and Kuča 2011). CX mainly affects the skin, eyes, respiratory system, and gastrointestinal tract. Immediate CX exposure symptoms include itching, cough, throat pain, enhanced lachrymation, and damaged vision (Augerson 2000). Cutaneous CX exposure does not lead to blistering, but leads to severe itching and rashes similar to a breakout of hives (Augerson 2000). It is the most dangerous chemical categorized with the vesicating agents, with corrosive properties causing instant toxic effects and injuries resembling those caused by urticants and acids (Armstrong and Bishop 2002; Dang et al. 2002; Rosenbloom et al. 2002; Patočka and Kuča 2011; Schraga 2016; Goswami et al. 2018).

2.1. Skin Toxicity and Systemic Toxicity from Cutaneous Exposure

Dermal exposure to more widely-studied vesicating agent SM causes delayed toxic effects and an inflammatory response, as well as blister formation, but mortality is scarce (Tewari-Singh N. et al. 2009; Shakarjian et al. 2010; Jain AK et al. 2011; Joseph et al. 2011; Jain AK et al. 2014). Damage to several organ systems following high-dose SM exposure is reported (Dacre and Goldman 1996; Balali-Mood et al. 2005; Kehe K. et al. 2008; Ghabili et al. 2010; Sharma et al. 2010; Goswami et al. 2015). CX is absorbed more rapidly through the skin tissue compared to other vesicating agents (SM, NM, and L). Its exposure causes immediate pain and tissue destruction, leading to skin damage, severe systemic toxicity, and mortality (Patočka and Kuča 2011; Tewari-Singh N. et al. 2017; Goswami et al. 2018; Tewari-Singh N. 2020). Skin exposure or intravenous injection of CX could cause pulmonary edema, while injection into the portal vein can lead to hepatic necrosis (McAdams 1965). Recently published studies by us in SKH-1 hairless mice have shown that cutaneous CX exposure causes painful skin lesions including skin erythema (redness), urticaria, erythemous ring with blanching, itching hives, and necrosis within minutes of its exposure (Tewari-Singh N. et al. 2017). Following CX exposure, within hours, the exposed skin area turned edematous, progressing further to a dark pigmented area, severe necrosis, and desquamation followed by scab formation (Tewari-Singh N. et al. 2017). CX exposure resulted in polymorphonuclear infiltrates in the skin tissue, as well as inflammation and apoptotic cell death (Tewari-Singh N. et al. 2017). Longer-duration cutaneous exposure can lead to severe systemic toxicity, pulmonary damage, and death (Augerson 2000; Tewari-Singh N. et al. 2017; Goswami et al. 2018; Tewari-Singh N. 2020). CX exposure on to the dorsal skin of mice resulted in the dilation of the peripheral vessels and the accumulation of red blood cells (RBCs) in the vessels of the lung, liver, spleen, kidney, and heart tissues (Tewari-Singh N. et al. 2017). These observations indicate that there might be a pronounced loss of blood from the vessels into the adjacent tissues, resulting in low blood pressure and hypoxic shock, leading to death.

2.2. Ocular Toxicity

Although the eye is the most sensitive organ to vesicating agents’ exposure (Gordon 2009; Kadar et al. 2009; McNutt et al. 2012; Ghasemi et al. 2013; Kadar T. et al. 2013; Kadar Tamar et al. 2013; Goswami, Tewari-Singh, Agarwal 2016; Tewari-Singh Neera et al. 2016), there are no comprehensive studies on ocular injuries from CX exposure and no reports available on long-term ocular effects of CX. Ocular CX exposure, even at very low concentrations, can cause immediate irritation and intense pain with edema, lacrimation, conjunctivitis, blepharospasm, inflammation, and temporary blindness. High dose or long-duration CX exposure can cause severe eye damage, including keratitis, iritis, corneal perforation, permanent corneal lesions, and blindness (Medicine 1998; Patočka and Kuča 2011).

2.3. Pulmonary Toxicity

Although comprehensive studies have not been carried out, CX exposure may result in instant upper respiratory tract irritation, pain, and tissue destruction, leading to runny nose, hoarseness, and sinus pain. Complete absorption occurs following inhalational CX exposure within seconds. CX inhalation and systemic absorption at higher doses may cause necrotizing bronchiolitis, tachypnea, dyspnea, cyanosis, pulmonary vein thrombosis, and edema, which are the prominent features of severe CX inhalation exposure (Ubels et al. 1982; Augerson 2000; Patočka and Kuča 2011; Schraga 2016). CX inhalation could result in the development of pulmonary fibrosis, though it has not yet been elucidated (Augerson 2000).

2.4. Gastrointestinal Toxicity

Studies on gastrointestinal exposure to humans are lacking; however, there are indications that hemorrhagic inflammatory lesions may occur (CDC 2011).

3. Molecular mechanisms of CX Toxicity

There are limited reports on CX toxicity, and the mechanism of its toxicity has not been elucidated (Augerson 2000). CX toxicity could result from its different characteristics, such as nucleophilic or possible alkylating properties and the effect of chlorine, oxime, or carbonyl groups that results in enzyme inactivation, corrosive injury, and cell death with rapid tissue destruction. Further, these events could induce the recruitment and activation of different immune cells such as macrophages, neutrophils, and mast cells, along with the release of hydrogen peroxide that contributes to inflammation and long-term tissue injury (Augerson 2000; Tewari-Singh N. et al. 2017; Tewari-Singh N. 2020). CX causes toxicity symptoms that resemble the allergic and non-allergic reactions from various environmental exposure in humans. These allergic reactions, or urticaria, are reported to be mediated mainly by the activation of mast cells and release of inflammatory mediators like histamine (Hennino et al. 2006; Jain S 2014; Chang et al. 2015).

Our published and ongoing studies to uncover the mechanism of action of CX toxicity from its cutaneous exposure in mouse injury models indicate that skin injury and systemic toxicity from CX exposure involves an inflammatory response, which could be largely due to mast cell activation (Tewari-Singh, 2020). Clinical data from our published and ongoing studies have shown that CX vapor exposure on the dorsal skin of mice leads to severe skin lesions (edema, erythema, necrosis, urticaria, and blanching) (Tewari-Singh N. et al. 2017). Cutaneous CX exposure also caused decreases in heart and respiratory rates, a drop in body temperature, vasculature dilation, blood congestion in multiple organs, pulmonary hemorrhage, and mortality (at longer-duration exposure), indicating urticaria and anaphylaxis (Tewari-Singh N. et al. 2017). An increase in tryptase levels is a measure of anaphylaxis; our studies demonstrated an increase in blood plasma tryptase levels following CX exposure, indicating an anaphylactic reaction (data not shown). Our current studies also exhibit mast cell degranulation and release of inflammatory mediators, including histamine and tryptase, cytokines, cyclooxygenase 2, matrix metallopeptidase 9, myeloperoxidase, tumor necrosis factor alpha, and an inflammatory response (macrophage and neutrophil infiltration) in the skin tissue (Tewari-Singh et al., 2017; data not shown). These results indicate that the mechanism of action of CX-induced inflammation, in part, could parallel the reported mechanism of action of vesicating mustard agents (A. K. Jain et al., 2014; Shakarjian et al., 2010; Wormser et al., 2005; Tewari-Singh et al., 2017; Tewari-Singh et al., 2009). In addition to apoptotic cell death, the CX-exposed skin also exhibited DNA damage within 2 hours of its exposure in our ongoing and published studies (Tewari-Singh N. et al. 2017; Tewari-Singh N. 2020). Reported to play a significant role in vesicating agent-induced cell death and injury, DNA damage and related signaling pathways could be contributors in CX-induced toxicity (Kehe Kai and Szinicz 2005; Paromov et al. 2007; Jowsey et al. 2009; Inturi et al. 2014; Goswami, Tewari-Singh, Dhar, et al. 2016).

Based on the results obtained from our ongoing and completed studies, we are further elucidating the mechanisms of toxicity from CX exposure and exploring the role of mast cell activation, oxidative stress and DNA damage, and associated signaling pathways in CX exposure.

4. Exposure Reduction and Development of Medical Countermeasures

CX exposure requires emergency care and immediate lifesaving efforts, including hospitalization and lifesaving surgery. In the case of a potential exposure, a self-contained breathing apparatus (SCBA) and moving upwards to get fresh air could be helpful (Patočka and Kuča 2011; Tewari-Singh N. 2020). Due to the fast penetration and rapid toxic effects of CX, immediate decontamination after CX exposure could be an effective measure to reduce toxicity and assist in wound healing. Skin decontamination of CX can be carried out by physical adsorption and/or chemical inactivation. Adsorbing powders can be employed for physical adsorption, whereas chemical inactivation can be achieved using alkaline agents. Except for the eyes, CX cannot be decontaminated with water due to the risk of spreading the chemical agent. Clothing contaminated with liquid CX poses an immediate danger. Hence, contaminated articles should be promptly removed and put into double plastic bags to prevent exposure to CX vapors (Patočka and Kuča 2011).

Although CX is the most toxic nettle agent among the vesicating agents, there is limited understanding of its mechanism of action and pathophysiology, which has hampered the identification of therapeutic targets and the development of effective medical countermeasures.

Currently available treatment options are mainly symptomatic to help reduce indications, prevent infections, and enhance healing. Systemic analgesics and dilution with water or milk could be useful in CX exposures; however, injuries could take several months to heal, and surgical intervention might be essential (Ubels et al. 1982). Analgesics and antibiotics could be beneficial in mitigating the pain, preventing infections, and promoting healing. Since CX is an urticant, mast cell activation, release of inflammatory cytokines, and the activation of related inflammatory pathways might be major contributors in CX-induced toxicity (Tewari-Singh N. et al. 2017). Hence, treatments using antihistamines with mast cell stabilizing properties, therapies that can ameliorate anaphylactic symptoms and mortality (e.g. epinephrine), and anti-inflammatory and immunosuppressant drugs could be beneficial (Tewari-Singh N. 2020). Additionally, if DNA damage is also a contributor in CX-induced toxicity, it could be due to the inflammatory response from mast cell activation-related oxidative stress or from direct event due to CX properties. Therefore, pleotropic treatments or combination treatments with anti-histamines, which can reduce inflammation and oxidative stress, as well as regulate DNA damage repair targeting multiple pathways (as reported for vesicants), can also be studied as potential treatment options (Tewari-Singh N. and Agarwal 2016).

5. Conclusions

Urticant CX is the most potent and dangerous chemical threat agent categorized with the vesicants. Compared to other vesicants, CX is absorbed very rapidly through the skin tissue and causes instantaneous and severe effects on the skin, eyes, and mucus membranes with instant pain. Due to these reasons, it can be produced and weaponized with other warfare agents to enhance the toxic effects, making it a dangerous chemical with military and terrorist potential. Even though CX can be easily manufactured and can cause rapid incapacitation and death, very little is known regarding its toxic effects and mechanism of action, and no antidote is available. We have developed cutaneous CX exposure-induced mouse injury models to investigate the toxicity and mechanism of action of CX, and for screening effective therapies. Identification of novel molecular targets from such studies could be explored for therapeutic intervention, which will assist in the development of effective countermeasures against CX-induced morbidity and mortality.

Acknowledgements

The authors would like to thank Advaita Singh for help in editing.

Funding

This work was supported by the Countermeasures Against Chemical Threats (CounterACT) Program, National Institutes of Health Office of the Director (NIH OD) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [Grant Numbers R21 AR073544 and U01 AR075470].

Abbreviations

CWAs

Chemical warfare agents

CX

Phosgene oxime

L

Lewisite

NM

Nitrogen mustard

SM

Sulphur mustard

RBCs

Red blood cells

TICs

Toxic industrial chemicals

TIMs

Toxic industrial materials

WMD

Weapons of mass destruction

WWI

World War I

Footnotes

Disclosure Statement

The Authors report no conflict of interest.

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