Organophosphates inhibition potency

The UK Pesticide Safety Directorate (PSD) has decided to use the TEF approach for assessment of combined risk from exposure to mixtures of acetyl cholinesterase inhibitors (organophosphate (OP) compounds and carbamates) (PSD 1999). Despite clear differences in the action of carbamates and OP compounds, the index compounds selected for all acetyl cholinesterase inhibitors were either aldicarb (carbamate) or chlorpyrifos (OP). The POD for determining relative potency was predetermined as the dose level that produced 20% inhibition of red blood cell cholinesterase in a 90-day dietary study in rats. 

The potency of the anticholinesterase activity of nerve agents and other organophosphates is expressed by the bimolecnlar rate constant (k ) for the reaction of the phosphate compound with the enzyme and by the molar concentration causing 50% inhibition of the enzyme when tested in vitro (I50). I50 data for several organophosphate nerve agents have been tabnlated by Dacre (1984). The relationship between I50 and kj as a function of time (t) is expressed by the following equation (Eto, 1974) ... 

The insecticides could have various effects on the nervous system but are unlikely to cause harm unless drunk in significant quantities. Chlorpyrifos is an organophosphate insecticide, and so could inhibit the enzyme acetylchoHnesterase in the blood and nervous tissue. It can have a cumulative effect, and so after repeated use, say on a daily basis, the level of inhibition may be sufficient to cause unpleasant or even life-threatening effects (as described on pp. 98-103). These include difficulty in breathing, muscular weakness, and convulsions. Organophosphates vary greatly in their potency, however, and the more toxic are now less readily available. Those for home use are the least poisonous to humans and other mammals. 

The effectiveness of a given inhibitor of the enzyme, as with substrate specificity, varies with the source of cholinesterase. values, defined as the molar concentration of inhibitor giving 50% enzymic activity, are often used to compare the potency of inhibitors. By no means, however, do all investigators specify the experimental conditions under which their measurements were made. It is therefore advisable to use 50 values only as crude indices of inhibitor potency. Differences between the reactivities of horse serum isoenzymes with organophosphates have been reported (C6, R3). Inhibition of horse serum cholinesterase is stereospecific (B28), and thus the enzyme reacts with optically pure (—)-sarin at least 4000 times faster than with ( + )-sarin. 

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