A symptomatological assessment of organophosphate-induced lethality in mice: comparison of atropine and clonidine protection.
A comprehensive symptomatological observational battery in conjunction with acute toxicity testing, evaluated with the method of a hyperbolic curve relating survival time (T) to dose (D), was used to characterize quantitatively the lethal toxicities of the organophosphorus (OP) compound, sarin, in mice. The experimental data observed with sarin (0.4-4.0 mg/kg s.c.), alone or in combination with atropine (ATR) (20 mg/kg i.p.), were plotted as a graph of D/T against D, a linearizing transformation of the hyperbolic function. This linearized plot gave two straight lines, deflecting at 1.2 mg/kg, in terms of latency to whole body tremor (BT) and loss of the righting reflex (LR). At lower lethal doses of sarin (0.4-1.2 mg/kg) with ATR pretreatment, the D/T vs. D curves of BT and LR were shifted in parallel to the left, while at high lethal doses (1.6-4.0 mg/kg) these curves interpolatedly converged. The sequelae and/or severity of symptoms were also comparatively different between the range of lower and high lethal doses as noted above. It has been claimed that the protective actions of ATR and clonidine (CLD) against the lethal effects of cholinesterase inhibitors are associated with different underlying mechanisms, i.e. presynaptic versus post-synaptic cholinergic inhibition. The protective effects of a single dose of ATR (20 mg/kg) and CLD (1.0 mg/kg), after 38 and 15 min of intraperitoneal pretreatment, respectively, alone or in combination, challenged with 2 x, 4x and 8x LD50's of sarin were also comparatively evaluated. ATR resulted in a nonsignificant increase in latency to onset of BT and LR. CLD significantly delayed the onset of these symptoms against all 3 dose levels of sarin intoxication, whereas ATR plus CLD additively increased the latency to the onset of these symptoms. The present results indicate that at lower dosages of sarin (less than or equal to 4 x LD50's) its mode of action appears to be mediated mainly by a/muscarinic mechanism, whereas at high doses it is mediated by some other non-specific actions superimposed on the cholinergic actions of sarin. The present study also lends support to the hypothesis of the existence of different forms of OP intoxication on the strength of lethal exposure. The possible mechanisms of both sarin lethality and ATR- and CLD-mediated protection are briefly discussed.
Liu
W F
WF
Laboratory of Behavioral Pharmacology and Toxicology, Fourth Research Division, CSIST, Taiwan, Republic of China.
D000818:Animals; D001285:Atropine / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D062025:Organophosphate Poisoning; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000633:toxicity*; D011041:Poisoning / Q000188:drug therapy / Q000517:prevention & control; D012524:Sarin / Q000008:administration & dosage / Q000506:poisoning / Q000633:toxicity*
D009943:Organophosphorus Compounds; D001285:Atropine; D012524:Sarin; D003000:Clonidine