HEPATIC BREAKTHROUGH THRESHOLDS FOR PARATHION AND PARAOXON AND THEIR IMPLICATIONS TO TOXICITY IN NORMAL AND DDE-PRETREATED RATS

Systemic exposure to parathion and paraoxon in normal and DDE-pretreated amle Sprague-Dawley rats was investigated by means of blood analyses following oral parathion doses and continuous parathion infusion into the perfused liver. Not only parathion, but paraoxon was also shown to undergo chromatographic translobular migration. As predicted from this, perfusion experiments, blood analyses, and autoradiography substantiated the existence of two discrete hepatic breakthrough thresholds for influent parathion, one for parathion and the other for paraoxon generated from parathion in the liver. In control rats, the former was slightly higher than the latter, resulting in systemic exposure to paraoxon without parathion exposure at sublethal toxic doses. Toxic symptoms correlated with the appearance of paraoxon in the jugular vein blood. In DDE-pretreated rats, both thresholds were substantially elevated, but enzyme induction had a greater impact on paraoxon breakthrough than on parathion release. Thus, significant amounts of parathion survived metabolism during migration through the lobules to appear in systemic blood, even at subtoxic doses. In contrast, paraoxon did not emerge from the liver under acute intoxication, although paraoxon was detected in the jugular vein. These results indicated that in DDE-pretreated rats paraoxon affecting the neural target was extrahepatically generated whereas the target is attacked by paraoxon originating in the liver in the control rats. © 1990.