Phosgene: toxicology, animal models, and medical countermeasures

Abstract

Phosgene is a gas crucial to industrial chemical processes with widespread production (∼1 million tons/year in the USA, 8.5 million tons/year worldwide). Phosgene’s high toxicity and physical properties resulted in its use as a chemical warfare agent during the First World War with a designation of CG (‘Choky Gas’). The industrial availability of phosgene makes it a compound of concern as a weapon of mass destruction by terrorist organizations. The hydrophobicity of phosgene exacerbates its toxicity often resulting in a delayed toxidrome as the upper airways are moderately irritated; by the time symptoms appear, significant damage has occurred. As the standard of care for phosgene intoxication is supportive therapy, a pressing need for effective therapeutics and treatment regimens exists. Proposed toxicity mechanisms for phosgene based on human and animal exposures are discussed. Whereas intermediary components in the phosgene intoxication pathways are under continued discussion, generation of reactive oxygen species and oxidative stress is a common factor. As animal models are required for the study of phosgene and for FDA approval via the Animal Rule; the status of existing models and their adherence to Haber’s Rule is discussed. Finally, we review the continued search for efficacious therapeutics for phosgene intoxication; and present a rapid post-exposure response that places exogenous human heat shock protein 72, in the form of a cell-penetrating fusion protein (Fv-HSP72), into lung tissues to combat apoptosis resulting from oxidative stress. Despite significant progress, additional work is required to advance effective therapeutics for acute phosgene exposure.

Keywords:

• Phosgene
• Fv-HSP72
• heat shock protein 72
• pulmonary
• chemical warfare agent
• Haber’s rule

Acknowledgements

The authors wish to thank Dr. Robert P. Casillas and Dr. Glenn T. Reynolds for excellent and sage advice during a technical reading of the manuscript.

Disclosure statement

MHP, RAR, and STH are compensated by Rubicon Biotechnology. MHP and RAR are co-owners of Rubicon.

Additional information

Funding

The acute phosgene exposure model developed by Rubicon and our preliminary Fv-HSP72 studies in lung were supported by the National Institute of Environmental Health Sciences (NIEHS) of the National Institutes of Health (NIH) under CounterACT Award Number R21ES024028. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.