Development of a Pediatric Rodent Model to Characterize the Toxic Mechanisms of Inhaled Phosphine

Abstract

Phosphine (PH3) is a toxic, heavier‐than‐air gas produced from metal phosphide pesticides. Metal phosphides are commercially available and commonly used in agriculture and residential settings as fumigants. PH3 is a suspected metabolic poison and mitochondrial toxicant, although its precise mechanism of toxicity is unknown. Phosphine’s misuse in residential areas has resulted in numerous human exposures and fatalities. Documented cases of PH3 exposure indicate that children may have more severe toxicity and increased lethality following PH3 inhalation. To address this finding we have developed a pediatric rodent inhalation model of PH3 exposure. Development of this pediatric model will allow characterization of the toxic responses and toxic mechanisms induced by PH3 exposure. Male and female Sprague Dawley rats at post‐natal day (PND) 21, 28, and 42 were exposed to PH3 via nose‐only inhalation. Female rats at PND 28 were found to have the lowest median lethal concentration x time (LCt50) and were used to characterize PH3‐induced toxicity. Rats (n=4–9) were exposed to either ambient air or the LCt50 of PH3 (14,119ppm x min) for 20 minutes and removed from the inhalation system after an additional 5‐minute “off gas” period. To identify the target organ of toxicity, the heart, lung, liver, and kidney were collected at 0.5, 3, 6, and 24 hours post‐exposure and processed for histopathology. Cardiac tissue at 24 hours after phosphine exposure showed tissue degeneration and focal necrosis. Significant pathology was not observed in the other tissues evaluated, suggesting that the heart is the major target organ of toxicity following PH3 inhalation. PH3‐induced toxicity was additionally characterized using pulse oximetry, a blood gas panel, lung resistance and compliance, and complete blood counts (CBC). Pulse oximetry revealed no significant changes in tissue oxygenation; however, rats exposed to PH3 had significantly reduced heart rates at 0.5 and 3 hours post‐exposure. Assessment of blood gases found significantly reduced pH, bicarbonate, total CO2, and base excess levels in PH3‐exposed rats at 0.5 hours post‐exposure. These findings are indicative of PH3‐induced metabolic acidosis. Impairment of pulmonary function was assessed post‐exposure using resistance and compliance. There were no significant changes in resistance, compliance, elastance, inspiratory capacity, or measurements of forced expiratory volume after PH3 inhalation. This suggests that PH3‐induced symptoms of respiratory distress may be related to impaired cardiac function. CBC revealed no significant changes in red blood cell number, hemoglobin concentration, or hematocrit following PH3 exposure. These data indicate that our pediatric rat model aligns with human findings of increased lethality, cardiotoxicity, and metabolic acidosis induced by inhalation phosphine. This pediatric model will be used for the development of medical countermeasures for phosphine exposure.Support or Funding InformationThis research was supported by interagency agreement (AOD18014‐001‐00000) between the NIH Office of the Director and USAMRICD under the oversight of the Chemical Countermeasures Research Program at the National Institute of Allergy and Infectious Diseases.