Mode of action of the delayed toxicity of O,O,S-trimethyl phosphorothioate in the rat

As preliminary probes to determine the mode of delayed toxic action of O,O,S-trimethyl phosphorothioate (I) in the rat, the effect of I on rat tissue and organs, and on blood, urine, and pharmacokinetic parameters was investigated. Following oral administration, 30 to 200 mg/kg I caused liver necrosis as a major pathological effect. Morphological changes were also observed in the heart, adrenal, tissues of the small intestine, and kidney. Most animals treated with I developed bronchopneumonia after 3 days. Blood samples taken from rats poisoned with 60 mg/kg I showed severe hemoconcentration; however, serum Na⁺, Cl^?, albumin, and total carbonate/bicarbonate varied only slightly. Na⁺ and Cl^? concentrations in the urine showed a steady decline with time following poisoning but K⁺ levels remained relatively constant. Pharmacokinetic studies showed that ¹⁴C levels in the blood following intraperitoneal or intravenous administration of 60 mg/kg [CH₃O¹⁴C]I were not affected when the animals were cotreated with 5% of the antagonist O,O,O-trimethyl phosphorothioate. However, lower levels of ¹⁴C were found in antagonized animals following oral administration.