Behavioral toxicity of sodium cyanide following oral ingestion in rats: Dose-dependent onset, severity, survival, and recovery

Abstract

Sodium cyanide (NaCN) is a commonly and widely used industrial and laboratory chemical reagent that is highly toxic. Its availability and rapid harmful/lethal effects combine to make cyanide a potential foodborne/waterborne intentional-poisoning hazard. Thus, laboratory studies are needed to understand the dose-dependent progression of toxicity/lethality following ingestion of cyanide-poisoned foods/liquids. We developed an oral-dosing method in which a standard pipette was used to dispense a sodium cyanide solution into the cheek, and the rat then swallowed the solution. Following poisoning (4-128 mg/kg), overt toxic signs were recorded and survival was evaluated periodically up to 30 hours thereafter. Toxic signs for NaCN doses higher than 16 mg/kg progressed quickly from head burial and mastication, to lethargy, convulsions, gasping/respiratory distress, and death. In a follow-on study, trained operant-behavioral performance was assessed immediately following cyanide exposure (4-64 mg/kg) continuously for 5 h and again the following day. Onset of behavioral intoxication (i.e., behavioral suppression) occurred more rapidly and lasted longer as the NaCN dose increased. This oral-consumption method with concomitant operantbehavioral assessment allowed for accurate dosing and quantification of intoxication onset, severity, and recovery, and will also be valuable in characterizing similar outcomes following varying medical countermeasure drugs and doses.

Behavioural and physiological assessments of dimethyl trisulfide treatment for acute oral sodium cyanide poisoning

“…DMTS did not appear to have a significant impact on the rate or degree of behavioural recovery, but instead only promoted survival. Our past research has shown that untreated survivors typically recover within a 5‐hour behavioural assessment and perform equivalently to baseline levels the following day . The recovery observed here in survivors that received lower DMTS doses is equivalent to our past work and suggests that any persistent behavioural deficits in the current study were most likely resulting from the high‐dose DMTS injection.…”

“…Therefore, a test that begins immediately after cyanide poisoning and that continues for several hours would be ideal for capturing the time course of cyanide‐induced deficits, including onset and recovery. In this regard, a recent study by some of the present authors characterized NaCN ingested acutely (4‐64 mg/kg) and revealed a rapid and dose‐dependent decrease across multiple response measures in a 5‐hour operant task (variable‐interval 90‐second schedule of food pellet reinforcement after lever pressing). In that study, deaths occurred within the first hour and no fatalities were ever observed thereafter.…”

“…The primary technician gently inserted the pipette tip approximately 1.4 cm into the rat's cheek pouch and dispensed the liquid solution by depressing the pipette's plunger (Gilson, Inc, Middleton, WI, USA; MicroMan M100 pipette with Gilson CP100 pipette tips). Visualization of the swallowing response was then confirmed by the primary technician (an illustration of the technique is shown in our previous work). Volumes used during training and poisoning ranged from 70 to 80 µL.…”

“…Rats ingested 98.2 mg/kg NaCN (twice the median lethal dose) and then received DMTS via IM injection 1 minute later. The doses originally selected for this experiment were 50, 100 and 200 mg/kg based upon previous research in mice .…”

“…The exposure model and behavioural assessment used here are identical to the procedures used by our laboratory for a previously published assessment of sodium cyanide oral toxicity (repeated here for clarity), with the addition of IM injections for treatment administration and additional physiological analyses of treatment safety as described below. The study was conducted in accordance with the Basic & Clinical Pharmacology & Toxicology policy for experimental and clinical studies …”