Fluoroacetate (FA) is a tasteless, odorless, water-soluble metabolic poison with severe toxicological effects. Characterized in the mid-1900s, it has been used as a rodenticide but is comparably lethal to all mammals. Many countries have restricted its use, and modern-day accidental human exposures are rare, but recently, concerns have been raised about its application as a chemical weapon with no known antidote. A combined treatment of methylene blue (MB), an antioxidant, and monosodium glutamate (MSG), a precursor of the citric acid cycle substrate alphaketoglutarate, has been recommended as an effective countermeasure; however, no peer-reviewed articles documenting the efficacy of this therapy have been published. Using a rodent model, we assessed the effects of MB and MSG on the neurologic, cardiac, and pulmonary systems. Transcriptomic analysis was used to elucidate inflammatory pathway activation and guide bioassays, which revealed the advantages and disadvantages of these candidate countermeasures. Results show that MB and MSG can reduce neurologic signs observed in rats exposed to sodium FA and improve some effects of intoxication. However, while this strategy resolved some signs of intoxication, ultimately it was unable to significantly reduce lethality.
Exposure to phosphine (PH 3), a common grain fumigant, is characterized by diverse nonspecific symptoms and a high mortality rate. Although PH 3 poisoning is thought to target oxidative respiration, the exact mechanism of action remains largely unknown, resulting in limited treatment options. In our study, the effects of PH 3 on female rats were assessed to elucidate potential sex-specific differences and obtain a more comprehensive understanding of PH 3 toxicity. Lethality, physiology, and behavior were evaluated in female rats exposed to gaseous PH 3 (13,200-26,400 ppm × min), and results were compared with corresponding findings in male rats. Median lethal concentration-time (LCt 50) and time of death (t TOD) did not differ significantly between the sexes. Cardiopulmonary changes induced by PH 3 were also of comparable magnitude, although temporally, respiratory responses occurred earlier and cardiovascular variations manifested later in female rats. Behavioral observations corroborated physiological findings and indicated a response to hypoxic conditions and low cardiac output. Together, these results provided insights on the toxic mechanisms of PH 3 , in particular, its potential interference with oxygen transport and circulation.
Carfentanil (CRF) is a potent synthetic opioid primarily used in anaesthetizing large animals. Exposure to CRF can cause both respiratory and central nervous system depression. Respiratory depression can lead to hypoxia, which may lead to cardiac damage and ultimately death. Myocardial damage has been observed in ferrets exposed to aerosolized CRF. Troponin is a protein complex that plays an integral part in muscle contractions within the myocardium and is used as an indicator of myocardial damage. An increase in blood levels of troponin in exposed ferrets would suggest underlying cardiac damage. Select animals were treated with naloxone (NX), an opioid antagonist, to investigate whether reversing opioid effects altered cardiac function or troponin levels. Male telemetrized ferrets were exposed to aerosolized CRF in a whole‐body plethysmography chamber. Cardiac parameters and respiratory dynamics were collected before, during, and after CRF exposure. Ferrets received no treatment, an oral or intramuscular (i.m.) dose of NX (0.375, 0.75, 1.5, or 3 mg/mL), or water 30 minutes post‐exposure. Euthanasia occurred 24 hours post‐exposure, and blood was collected via descending aorta or heart stick. Serum was separated from blood and analyzed using a high sensitivity rat cardiac troponin‐I enzyme‐linked immunosorbent assay (ELISA). Average troponin levels for all animals ranged from 0.00 – 6.30 ng/mL. Troponin levels were not statistically different across treatment groups, though we observed an increase in mean arterial pressure (MAP) and increased incidents of premature junction complexes for animals exposed to CRF, indicating potential cardiac distress. The increase in MAP could be a compensatory mechanism to overcome hypoxia due to decreased respiration induced by CRF. Both control and exposed animals showed an increase in MAP following treatment; however, sham‐exposed animals had no rise in MAP post‐treatment. This rise in MAP could be due to a combination of NX treatment and a response to being handled for the injection. Overall, our results suggest that CRF does not directly cause myocardial damage, nor do surgically implanted cardiac telemetry devices cause an explicit, permanent increase in troponin levels. Further investigation is needed to determine if cardiac abnormalities observed in ferrets are caused via hypoxia or other unknown mechanisms. Support or Funding Information Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the US Army. This research complied with the Animal Welfare Act and implementing Animal Welfare Regulations and adhered to the principles noted in The Guide for the Care and Use of Laboratory Animals. This research was supported by DTRA RD‐CB. E.P., W.Y.T., M.R. S.P., A.D., and V.D.C. were supported in part by an appointment to the Postgraduate Research Participation Program at the US Army Medical Research Institute of Chemical Defense administered by the Oak Ridge Institute for Science and Education through an interagenc...
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