The influence of age on the toxicity and metabolism of methyl parathion and parathion in male and female rats

Abstract

To determine the mechanisms responsible for the variations in toxicity of methyl parathion and parathion, the in vitro metabolism of these insecticides and cholinesterase sensitivity to their respective oxygen analogs methyl paraoxon and paraoxon were studied in male and female rats of several ages. For rats of five ages studied (1, 12–13, 23–24, 35–40, and 56–63 days), there was a gradual decrease in susceptibility to poisoning by both insecticides with increasing age up to 35–40 days for both sexes. Age differences in susceptibility were not related to differences in sensitivity of cholinesterase to inhibition by paraoxon or methyl paraoxon in vitro. Oxidative formation of the oxygen analogs, oxidative aryl cleavage, and glutathione-dependent dealkylation and dearylation of methyl parathion and parathion were assayed in liver homogenates of male and female rats of the five ages. Rates of enzymatic detoxification of their corresponding oxygen analogs by A-esterase, glutathione- S-aryl-, and - S-alkyl-transferase and inactivation by binding were also investigated. Correlation coefficients for rates of metabolism versus LD50 values for the different ages were calculated. In general, changes in LD50 values with age for methyl parathion and parathion correlated better with changes in rates of reactions which represented detoxification pathways for methyl paraoxon and paraoxon than for reactions which represented direct metabolism of the parent insecticides. Both male and female rats became much less sensitive to the acute lethal effects of methyl paraoxon and paraoxon with increasing age. This is consistent with a hypothesis that changes in LD50 values of methyl parathion and parathion with age are due to changes in rates of metabolism of the oxygen analogs.