Characterization of a Mouse Model of Oral Potassium Cyanide Intoxication

Abstract

Potassium cyanide (KCN) is an inhibitor of cytochrome C oxidase causing rapid death due to hypoxia. A well-characterized model of oral KCN intoxication is needed to test new therapeutics under the Food and Drug Administration Animal Rule. Clinical signs, plasma pH and lactate concentrations, biomarkers, histopathology, and cyanide and thiocyanate toxicokinetics were used to characterize the pathology of KCN intoxication in adult and juvenile mice. The acute oral LD50s were determined to be 11.8, 11.0, 10.9, and 9.9 mg/kg in water for adult male, adult female, juvenile male, and juvenile female mice, respectively. The time to death was rapid and dose dependent; juvenile mice had a shorter mean time to death. Juvenile mice displayed a more rapid onset and higher incidence of seizures. The time to observance of respiratory signs and prostration was rapid, but mice surviving beyond 2 hours generally recovered fully within 8 hours. At doses up to the LD50, there were no gross necropsy or microscopic findings clearly attributed to administration of KCN in juvenile or adult CD-1 mice from 24 hours to 28 days post-KCN challenge. Toxicokinetic analysis indicated rapid uptake, metabolism, and clearance of plasma cyanide. Potassium cyanide caused a rapid, dose-related decrease in blood pH and increase in serum lactate concentration. An increase in fatty acid-binding protein 3 was observed at 11.5 mg/kg KCN in adult but not in juvenile mice. These studies provide a characterization of KCN intoxication in adult and juvenile mice that can be used to screen or conduct preclinical efficacy studies of potential countermeasures.

Circulatory Failure During Noninhaled Forms of Cyanide Intoxication

“…The experimental approaches we used produced effects that are extremely close to those produced by an acute CN intoxication by ingestion (10, 11). These forms of poisoning are regarded as a potential source of intoxication during a criminal act or a potential terrorist attack.…”

“…These forms of poisoning are regarded as a potential source of intoxication during a criminal act or a potential terrorist attack. Recent studies in rodents (10, 11) have established how rapidly lethal can oral intoxication be (within minutes). These effects are very well mimicked by an IP injection since during both oral or IP administration, the diffusion of CN into the blood does not depend on the level of breathing and CN will continue to diffuse at the same rate regardless of the levels of minute ventilation.…”

“…We used a systemic administration of CN, wherein CN rapidly diffuses to the blood stream, irrespective of the level of pulmonary ventilation as during CN ingestion (10, 11). These intoxications differ from those produced by the inhalation of CN during as CN diffusion into the blood does not increase during the period of hyperventilation or decrease during the period of CN-induced apnea.…”

Characterization of a Swine (Sus scrofa) Model of Oral Potassium Cyanide Intoxication

“…22 In that study, the authors determined the LD 50 of oral cyanide in these mice, noted that the natural history of oral cyanide toxicity is similar in mice and humans, and concluded that a reproducible small animal model can be used to test potential countermeasures for oral cyanide toxicity. A limitation of the cited study 22 is the use of a small animal model, where monitoring of cardiovascular parameters can prove to be challenging. In addition, given the large size difference between mice and humans, scaling the dose of any potential therapeutics might be difficult.…”

“…HCN is formed more favorably in an acidic milieu after the ingestion of cyanide salts such as KCN, and these differences in pH may explain potential differences in the toxic response to oral cyanide exposure across species. [20][21][22] In studies using animals to model human toxicity, the use of moderate-sized species such as rabbits, offers various advantages compared with smaller animals, such as mice. For example, rabbits are more amenable to cardiovascular monitoring in real-time than are mice.…”