The physiology and toxicology of acute inhalation phosphine poisoning in conscious male rats

Abstract

Phosphine (PH₃) is a toxidrome-spanning chemical that is widely used as an insecticide and rodenticide. Exposure to PH₃ causes a host of target organ and systemic effects, including oxidative stress, cardiopulmonary toxicity, seizure-like activity and overall metabolic disturbance. A custom dynamic inhalation gas exposure system was designed for the whole-body exposure of conscious male Sprague-Dawley rats (250–350 g) to PH₃. An integrated plethysmography system was used to collect respiratory parameters in real-time before, during and after PH₃ exposure. At several time points post-exposure, rats were euthanized, and various organs were removed and analyzed to assess organ and systemic effects. The 24 h post-exposure LCt₅₀, determined by probit analysis, was 23,270 ppm × min (32,345 mg × min/m³). PH₃ exposure affects both pulmonary and cardiac function. Unlike typical pulmonary toxicants, PH₃ induced net increases in respiration during exposure. Gross observations of the heart and lungs of exposed rats suggested pulmonary and cardiac tissue damage, but histopathological examination showed little to no observable pathologic changes in those organs. Gene expression studies indicated alterations in inflammatory processes, metabolic function and cell signaling, with particular focus in cardiac tissue. Transmission electron microscopy examination of cardiac tissue revealed ultrastructural damage to both tissue and mitochondria. Altogether, these data reveal that in untreated, un-anesthetized rats, PH₃ inhalation induces acute cardiorespiratory toxicity and injury, leading to death and that it is characterized by a steep dose-response curve. Continued use of our interdisciplinary approach will permit more effective identification of therapeutic windows and development of rational medical countermeasures and countermeasure strategies.

Keywords:

• Inhalation exposure
• phosphine
• respiratory dynamics
• genomics
• metabolic poison

Acknowledgments

The views, opinions and findings contained herein are those of the authors and should not be construed as an official Department of Army position, policy or decision unless so designated by other documentation. Special thanks to the Comparative Pathology Branch for providing outstanding pathology support. The authors would like to thank Dr. Bryan McCranor for his scientific insight, Ms. Robyn Lee for her statistical analyses and guidance, and CPT Sabrina McGraw, Ms. Robin Deckert, Dr. Dorian Olivera and Ms. Jannitt Simons for their scientific, technical and administrative assistance throughout the project. RL, JT, KS and JA were supported in part by appointments to the Research Participation Program for the US Army Medical Research and Materiel Command administered by the Oak Ridge Institute for Science and Education through an agreement between the US Department of Energy and US Army Medical Research and Materiel Command.

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

This work was supported by an interagency agreement between the National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) and USAMRICD [“Chemicals Affecting the Respiratory Tract – Pulmonary Toxicant Gases” IAA# AOD16027-001-00000].