Development of an acute, short-term exposure model for phosgene

Abstract

Phosgene is classified as a chemical warfare agent, yet data on its short-duration high concentration toxicity in a nose-only exposure rat model is sparse and inconsistent. Hence, an exposure system for short-term/high concentration exposure was developed and characterized. Herein, we report the median lethal concentration (LC₅₀) for a 10-min nasal exposure of phosgene in a 24-h rat survival model. Male Wistar rats (Envigo) weighing 180–210 g on the day of exposure, were exposed to phosgene gas via nose-only inhalation using a system specifically designed to allow the simultaneous exposure and quantification of phosgene. After 24 h, the surviving rats were euthanized, the lung/body mass ratio determined, and lung tissues analyzed for histopathology. Increased terminal airway edema in the lungs located primarily at the alveoli (resulting in an increased lung/body mass ratio) coincided with the observed mortality. An LC₅₀ value of 129.2 mg/m³ for a 10-min exposure was determined. Furthermore, in agreement with other highly toxic compounds, this study reveals a LC₅₀ concentration value supportive of a nonlinear toxic load model, where the toxic load exponent is >1 (n_e = 1.17). Thus, in line with other chemical warfare agents, phosgene toxicity is predicted to be more severe with short-duration, high-concentration exposures than long-duration, low-concentration exposures. This model is anticipated to be refined and developed to screen novel therapeutics against relevant short-term high concentration phosgene exposures expected from a terrorist attack, battlefield deployment, or industrial accident.

KEYWORDS:

• Phosgene
• acute toxicity
• lethal dose
• lethal concentration
• defense countermeasures
• toxic load exponent
• toxic load model

Acknowledgements

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors wish to thank Dr. Claire Croutch, Ed Sistrunk, Karin Bauer and Dr. Tom Carpenter for excellent technical assistance on this project.

Disclosure statement

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

Additional information

Funding

These studies were supported by the National Institute of Environmental Health Sciences (NIEHS) of the National Institutes of Health (NIH) under Award Number R21ES024028.