Toxicodynamic modeling of highly toxic organophosphorus compounds.
Although the in vitro effect of organophosphorus (OP) compounds on acetylcholine-esterase (AChE) has been studied extensively, the hypothesis that OP inhibition of AChE is the primary mechanism of acute in vivo OP toxicity has been controversial. For example, a recent review (Pope and Liu, 2004) suggested that OP compounds have direct toxic effects on other enzymes, ACh receptors, and receptor/ channel complexes that are independent of AChE inhibition. The purpose of this report is to examine the hypothesis that AChE inhibition is the mechanism of acute toxicity of OP compounds by mathematically modeling the in vivo lethal effects of highly toxic OP compounds and determining the amount of variation in OP toxicity that is explained by AChE inhibition.
Maxwell
D M
DM
United States Army Medical Research Institute of Chemical Defense, Research Division, Aberdeen Proving Ground, MD 21010-5400, USA. donald.maxwell@us.army.mil
Brecht
K M
KM
Chang
F-C T
FC
Koplovitz
I
I
Shih
T-M
TM
Sweeney
R E
RE
D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D007928:Lethal Dose 50; D010755:Organophosphates / Q000633:toxicity*; D010091:Oximes / Q000633:toxicity
D002800:Cholinesterase Inhibitors; D010755:Organophosphates; D010091:Oximes; D002265:Carboxylic Ester Hydrolases