Behavioral intoxication following voluntary oral ingestion of tetramethylenedisulfotetramine: Dose-dependent onset, severity, survival, and recovery

Abstract

Tetramethylenedisulfotetramine (tetramine, or TETS) is a highly toxic rodenticide that has been responsible for over 14,000 accidental and intentional poisonings worldwide. Although the vast majority of TETS poisonings involved tainted food or drink, the laboratory in vivo studies of TETS intoxication used intraperitoneal injection or gavage for TETS exposure. Seeking to develop and characterize a more realistic model of TETS intoxication in the present study, rats were trained to rapidly and voluntarily consume a poisoned food morsel. Initially, the overt toxic effects of TETS consumption across a large range of doses were characterized, then a focused range of doses was selected for more intensive behavioral evaluation (in operant test chambers providing a variable-interval schedule of food reinforcement). The onset of intoxication following voluntary oral consumption of TETS was rapid, and clear dose-dependent response-rate suppression was observed across multiple performance measures within the operant-chamber environment. At most doses, recovery of operant performance did not occur within 30 hours. Food consumption and body weight changes were also dose dependent and corroborated the behavioral measures of intoxication. This voluntary oral-poisoning method with concomitant operant-behavioral assessment shows promise for future studies of TETS (and other toxic chemicals of interest) and may be extremely valuable in characterizing treatment outcomes.

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

“…In an effort to better characterize NaCN intoxication as a function of dose, we analyzed lever-pressing rates within the session. We focused on lever pressing because this response measure was the most sensitive indicator of intoxication, presumably due to the greater effort it requires and its greater temporal separation from primary reinforcement [32].…”

“…The apparatus, behavioral training procedures (section 2.6), and post-exposure assessments (section 2.8) were identical to those presented in Rice et al [32] and are described here for completeness.…”

“…Prior to using the delivery method described in section 2.5, multiple attempts were made to replicate the voluntary oral ingestion method used successfully for tetramethylenedisulfotetramine (tetramine; TETS) [32]. Initially, rats were trained to eat a cereal morsel that was adulterated with water and baking soda.…”

Tetramethylenedisulfotetramine: A Health Risk Compound and a Potential Chemical Warfare Agent

“…The neurobehavioral consequences of TETS exposure, described in human survivors of acute TETS intoxication, are due to sustained seizure activity rather than a direct effect of the chemical itself [ 5 ]. Realistic models of exposure, behavioural assessments and multifaceted treatment investigations are needed to elaborate the toxicity of TETS [ 23 ]. Very recently, Lauková et al [ 24 ] implemented an investigation in developing rats of both sexes to identify any potential age- and sex-dependent vulnerability to TETS exposure.…”

Comparison of the toxicokinetics of the convulsants picrotoxinin and tetramethylenedisulfotetramine (TETS) in mice

“…In contrast, the reported LD 50 values of TETS are remarkably consistent in the literature. Irrespective of whether the administration route is oral, subcutaneously or intraperitoneally, the LD 50 in mice or rats is 0.1-0.2 mg/kg with a steep dose-response relationship typically achieving 100% lethality around 0.4 mg/kg (Laukova et al 2019a;Rice et al 2017;Shakarjian et al 2012;Zolkowska et al 2012). Juvenile rats of both sexes are slightly more sensitive to TETS than adult animals (Laukova et al 2018).…”