Effect of halogenated benzenes on the toxicity and metabolism of malathion,malaoxon, parathion,and paraoxon in mice

The halogenated benzenes, inducers of xenobiotic metabolism, were studied for their effects on the metabolism of malathion, malaoxon, and paraoxon and on the toxicity and lethality of these organophosphorus insecticides and parathion. One millimole per kilogram of 1,4-dichlorobenzene, 1,2,4-trichlorobenzene, 1,4-dibromobenzene, 1,2,4-tribromobenzene, or hexabromobenzene or 0.1 mmol/kg hexachlorobenzene was administered po to male mice daily for 7 days. In general, the trihalogenated benzenes increased the LD50 of all four insecticides two- to sixfold. These increases were larger than those observed with the di- or hexahalogenated isomers. The bromine-substituted benzenes were usually more active than the chlorinated ones with the exception being hexabromobenzene. There was a good correlation between their effects on lethality and increases in in vitro carboxylesterase activity with either malathion or malaoxon as the substrate. The trihalogenated benzenes decreased the inhibitory effect of malathion on cholinesterase activity in the brain and to a lesser degree in the red blood cells, but not in liver or plasma. There was also a good correlation between protection against parathion and paraoxon lethality, protection against inhibition of cholinesterase in the brain and liver by paraoxon, and increases in the dearylation of paraoxon by microsomal mixed-function oxidases but not by hepatic or plasma esterases. It appears that the halogenated benzenes are able to protect against organophosphorus insecticide toxicity. With malathion increases in carboxylesterase activity may be important, and with paraoxon increases in microsomal mixed-function oxidase dearylation may play a role. Other changes such as in dealkylation and tissue binding cannot be excluded from contributing to the protection seen.