Title: Potential Antidotes to Phosphine Poisoning

Abstract:

Globally, phosphine gas (PH₃) released from metal phosphides is responsible for more poisonings (both intentional and accidental) than any other chemical agent. Metal phosphides (e.g. Ca₃P₂, AlP) produce PH₃ through hydrolysis and can react with moisture in ambient air. PH₃ is used as a fumigant pesticide and is a workplace hazard in agriculture, shipping, pest control, and the semiconductor industry where it is used as a doping agent. However, the majority of phosphine exposures are suicidal in nature. There is currently no antidote to PH₃ available. Most purposeful PH₃ poisonings occur through the ingestion of metal phosphides, which results in continuous exposure to PH₃ gas. Therefore, it is beneficial to develop an antidote with both prophylactic and therapeutic activity. PH₃ is associated with the inhibition of mitochondrial respiration at complex IV, cytochrome c oxidase, but its scope of effects is not fully understood. Methemoglobinemia and hemolysis have been reported in cases of PH₃ poisoning and are negatively associated with survival. The relationship between PH₃ and the blood remains undefined. We proposed and screened transition-metal based complexes as potential antidotes to PH₃ in an insect and mouse model. Based on inorganic principles, we hypothesized that Au(I) and Ag(I) complexes would work as effective decorporating antidotes against PH₃. We also tested some Co(II/III) complexes, shown to be effective against other complex IV inhibitors, against PH₃. Using spectroscopic methods and high-resolution respirometry, we investigated the molecular interactions of the most promising potential antidotes with PH₃ and studied the impacts of PH₃ on blood, both in vitro and in vivo.  In this work, we describe a novel method for studying PH₃ toxicity and potential antidotes using Galleria mellonella larvae, the varied activity of Au(I), Ag(I), and Co(II/III) complexes against phosphine in vivo, the ameliorative potential of catalytic PH₃ oxidation, and the contribution of methemoglobinemia and hemolysis to PH₃ toxicity with the aim of advancing the development of antidotes to PH₃ poisoning.