Potentiation of carbaryl toxicity to the hybrid red-legged partridge following exposure to malathion

Pretreatment of hybrid red-legged partridges (Alectoris rufa cross) with a single oral dose of 167 mg/kg malathion resulted in a marked potentiation of the toxicity of the carbamate insecticide, carbaryl, given I hr after malathion. Oral administration of 200 mg/kg carbaryl was lethal to 4 out of 12 malathion-pretreated birds, and a further 6 showed symptoms of cholinesterase poisoning. Birds given either malathion or carbaryl alone showed no visible signs of toxicity. The inhibition of serum butyrylcholinesterase activity was found to be high (75-91%) in both corn oil- and malathion-pretreated birds at 1 and 3 hr after dosing with carbaryl, with no significant difference between them. However, malathion and carbaryl given in combination produced an 88% depression of brain acetylcholinesterase activity compared to a 56% depression in corn oil-pretreated birds given carbaryl; this difference was highly significant. Malathion alone produced a small nonsignificant 5% elevation of activity. Concentrations of carbaryl in the serum and brain were found to be 2- and 7.5-fold greater, respectively, in birds pretreated with malathion compared to those given corn oil. In vitro metabolism of [14C]carbaryl in the presence of NADPH from control birds resulted in the formation of two metabolites (46% of the carbaryl was metabolized), whereas metabolism of carbaryl by microsomes from birds pretreated with malathion was substantially less: only 3% of the carbaryl was metabolized. The inactivation of cytochrome P450 by reactive sulfur liberated during the oxidative desulfuration of malathion is thought to be responsible for these differences in carbaryl metabolism. The potentiation of carbaryl toxicity by malathion was attributed to an inhibition of metabolic detoxication, due largely or entirely to the inhibition of certain forms of cytochrome P450. Other types of pesticides metabolized by cytochrome P450s, such as pyrethroids and organophosphorus insecticides not requiring activation for toxicity, may, like carbaryl, be potentiated following inhibition.