title: Neurobehavioral and Cardiovascular Effects of Potassium Cyanide Administered Orally to Mice.
abstract: The Food and Drug Administration Animal Rule requires evaluation of cardiovascular and central nervous system (CNS) effects of new therapeutics. To characterize an adult and juvenile mouse model, neurobehavioral and cardiovascular effects and pathology of a single sublethal but toxic, 8 mg/kg, oral dose of potassium cyanide (KCN) for up to 41 days postdosing were investigated. This study describes the short- and long-term sensory, motor, cognitive, and behavioral changes associated with oral dosing of a sublethal but toxic dose of KCN utilizing functional observation battery and Tier II CNS testing in adult and juvenile mice of both sexes. Selected tissues (histopathology) were evaluated for changes associated with KCN exposure with special attention to brain regions. Telemetry (adult mice only) was used to evaluate cardiovascular and temperature changes. Neurobehavioral capacity, sensorimotor responsivity or spontaneous locomotor activity, and rectal temperature were significantly reduced in adult and juvenile mice at 30 minutes post-8 mg/kg KCN dose. Immediate effects of cyanide included bradycardia, adverse electrocardiogram arrhythmic events, hypotension, and hypothermia with recovery by approximately 1 hour for blood pressure and heart rate effects and by 2 hours for body temperature. Lesions consistent with hypoxia, such as mild acute tubular necrosis in the kidneys corticomedullary junction, were the only histopathological findings and occurred at a very low incidence. The mouse KCN intoxication model indicates rapid and completely reversible effects in adult and juvenile mice following a single oral 8 mg/kg dose. Neurobehavioral and cardiovascular measurements can be used in this animal model as a trigger for treatment.
authors.affiliation: Battelle, Columbus, OH, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hawk
authors.affiliation: Battelle, Columbus, OH, USA.
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Ritchie
authors.affiliation: Battelle, Columbus, OH, USA.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Henderson
authors.affiliation: Battelle, Columbus, OH, USA.
authors.forename: Katherine A B
authors.initials: KA
authors.lastname: Knostman
authors.affiliation: Battelle, Columbus, OH, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Roche
authors.affiliation: Battelle, Columbus, OH, USA.
authors.forename: Zhenxu J
authors.initials: ZJ
authors.lastname: Ma
authors.affiliation: Battelle, Columbus, OH, USA.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Matthews
authors.affiliation: Department of Health and Human Services (HHS), Office of the Assistant Secretary for Preparedness and Response (ASPR), The Biomedical Advanced Research and Development Authority (BARDA), Washington, DC, USA sabourinc@battelle.org.
authors.forename: Carol L
authors.initials: CL
authors.lastname: Sabourin
authors.affiliation: Department of Health and Human Services (HHS), Office of the Assistant Secretary for Preparedness and Response (ASPR), The Biomedical Advanced Research and Development Authority (BARDA), Washington, DC, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Wakayama
authors.affiliation: Battelle, Columbus, OH, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Sabourin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D004195:Disease Models, Animal; D004562:Electrocardiography; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009420:Nervous System / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects; D011190:Potassium Cyanide / Q000008:administration & dosage* / Q000633:toxicity*
chemical_list: D011190:Potassium Cyanide
keywords: adult; animal model; cardiovascular; cyanide; intoxication; juvenile; mice; neurobehavioral; oral