Potentiation of Toxicity of Malathion by Triorthotolyl Phosphate.

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Abstract
The low toxicity of malathion to mammals is due to rapid detoxification catalyzed by non-specific esterases in serum and liver and agents capable of inhibiting this detoxification potentiate its toxicity. Triorthotolyl phosphate (TOTP) has been shown (Biochem. Jour. 53: 16, 1953) to inhibit non-specific esterases. The present study was undertaken to ascertain whether TOTP would potentiate the toxicity of malathion to rats. The acute intraperitoneal LD50 values were 1100 mg/kg for malathion and 2500 mg/kg for TOTP. When 3 intramuscular doses as low as 10 mg/kg of TOTP were given on alternate days, the administration of 550 mg/kg of malathion caused 100% mortality when given 24 hours after TOTP. The LD50 of malathion was reduced to 8.2 mg/kg in rats given a single dose of 110 mgAg of TOTP intraperitoneally 24 hours before malathion and to 12.3 mgAg when the same dose was applied to the skin. Experiments on the mechanism of the potentiation showed that TOTP inhibits the enzymatic detoxification of malathion by liver and serum. This was demonstrated by comparing the detoxifying ability of liver and serum from TOTP-treated rats (110 mgAg TOTP intraperitoneally 24 hours before sacrifice) with that of tissues from normal rats. As a result of preservation of malathion in the tissues the anticholinesterase action of a given dose was markedly increased. This study indicated that susceptibility to malathion can be markedly altered by chemically induced alterations in the esterase which normally catalyzes its detoxification.