Acetylcholinesterase inhibition: does it explain the toxicity of organophosphorus compounds?
The hypothesis that acetylcholinesterase (AChE) inhibition is the mechanism of toxicity of organophosphorus (OP) compounds was examined by mathematically modeling the in vivo lethal effects of OP compounds and determining the amount of variation in OP toxicity that is explained by AChE inhibition. Mortality dose-response curves for several OP compounds (i.e., VX, soman, cyclosarin, sarin, tabun, diisopropylfluorophosphate and paraoxon) exhibited steep probit slopes (> 9.6) in guinea pigs. Steep probit slopes were also observed when the mortality dose-response curves for soman were examined in mice, rats, rabbits and non-human primates. The consistently steep probit slopes of the dose-response curves for highly toxic OP compounds suggested that these compounds have a single specific mechanism of toxicity regardless of the OP compound or the species in which it was tested. Regression analysis indicated that 93% of the 3,280-fold variation in the median lethal doses (i.e., LD(50)) of OP compounds in rats was explained by the variation in their in vitro rate constants for inhibition of AChE. Conversely, 91% of the 23-fold variation in the ability of the oximes pralidoxime and obidoxime to protect against the toxicity of OP compounds in guinea pigs was explained by the variation in the in vitro ability of oximes to reactivate OP-inhibited AChE. The best explanation for this variety of observations was that the primary mechanism of in vivo toxicity for highly toxic OP compounds is the inhibition of AChE, and the residual unexplained variation in OP toxicity that might be explained by other mechanisms represents < 10% of the total variation in OP toxicity.
Maxwell
Donald M
DM
US Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, USA. donald.maxwell@amedd.army.mil
Brecht
Karen M
KM
Koplovitz
Irwin
I
Sweeney
Richard E
RE
D000818:Animals; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000494:pharmacology; D006168:Guinea Pigs; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008954:Models, Biological; D009768:Obidoxime Chloride / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000633:toxicity*; D011220:Pralidoxime Compounds / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D009943:Organophosphorus Compounds; D011220:Pralidoxime Compounds; D009768:Obidoxime Chloride; C028797:pralidoxime