STUDIES OF DISULFOTON TOLERANCE IN RATS

Disulfoton (O,O, diethyl S-2-(ethylthio)ethyl phosphorodithioate) and other organophosphorus ester compounds are insecticides which inhibit acetylcholinesterase. Chemicals of this class cause signs of toxicity in mammals which are referable to acculmulation of acetylcholine at neuroeffector sites. A tolerance to this toxic action can be induced in experimental animals by giving multiple, sublethal doses of the compounds. There is strong evidence that disulfoton tolerance occurs because of a reduction in the sensitivity of tissues in the affected animals to acetylcholine.^ Experiments were designed to test the possibility that a decrease in the number of muscarinic cholinergic receptors could be downmodulating the sensitivity of tissues to acetylcholine. It was found that, concomitant with the onset of disulfoton tolerance, there was a decrease relative to control values in the specific binding of {('3)H} quinuclidinyl benzilate ({('3)H}QNB, a compound which selectively labels muscarinic cholinergic receptors) to homogenates of rat brain and ileal muscle. The decrease in {('3)H}QNB binding was due to a reduction in the density of muscarinic receptors. There was, however, no alteration in the binding of {('3)H} QNB, or the muscarinic agonists {('3)H} oxotremorine-M and oxotremorine to atria from disulfoton-tolerant rats. The possibility that cardiac tissue was not subsensitive to cholinergic agonists was ruled out in experiments testing the effect of the muscarinic agonist carbachol on heart rate in vivo, and the negative chronotropic effect of oxotremorine on atria from disulfoton-tolerant rats: a clear reduction in the sensitivity to cholinergic agonists was seen in each case. It was, therefore concluded that the specificity and temporal correlation of {('3)H}QNB binding decreases suggested that the loss of muscarinic receptors might play a role in modulating the sensitivity of several tissues to acetylcholine, but that other mechanisms also contribute to the tolerance phenomenon.^ Other experiments revealed that disulfoton tolerance, as measured by resistance to the lethal effects of carbachol, could be induced by feeding rats low levels of the organophosphorus ester in the diet. The concentration of disulfoton used inhibited acetylcholinesterase, but not to the extent that overt signs of toxicity were observed. These results suggested that tolerance to organophosphorus ester insecticides could be induced in rodents with a dosing scheme which more closely modeled the sort of low level exposures which would be expected in humans environmentally or occupationally in contact with these compounds. ^