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The Physiology and Toxicology of Acute Inhalation Phosphine Poisoning in Conscious Male Rats

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Journal Article - Open Access

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US Army Medical Research Institute of Chemical Defense Aberdeen Proving Ground United States

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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 250350 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 hr post-exposure LCt50, determined by probit analysis, was 23,270 ppmmin 32,345 mgminm3.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.

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