Development of tolerance to a pneumotoxic impurity of malathion.

O,O,S-Trimethyl phosphorothioate (OOS-Me) is a pneumotoxic impurity present in various organophosphorus insecticides. OOS-Me produces morphological alteration of bronchiolar epithelial Clara cells accompanied by an increase in pulmonary lavage lactate dehydrogenase activity and severe weight loss in rats. Tolerance to the pneumotoxicity of OOS-Me was induced rapidly by oral pretreatments with small doses of OOS-Me itself. O,O-Dimethyl-S-ethyl phosphorothioate (OOS-Et), a pneumotoxic trialkyl phosphorothioate that is closely related in structure to OOS-Me, also produced a tolerance by oral pretreatment with small doses of OOS-Et itself. Pretreatment of rats with OOS-Me produced tolerance to OOS-Et, pretreatment did not produce tolerance to OOS-Me. Pretreatment of rats with tolerance-inducing doses of OOS-Me or OOS-Et had no effect on pulmonary or hepatic monooxygenase activities. Malathion and phenthoate carboxylesterases in pulmonary and hepatic microsomes were inhibited by these pretreatments. Activity of superoxide dismutase in lung or glutathione content in lung or liver was not affected by these pretreatments. Although the mechanism(s) remains unknown, the present study demonstrated the tolerance development to the chemical-induced pneumotoxicity.