Chloropicrin (CCl 3 NO 2 ) is a widely used soil fumigant with an unknown mechanism of acute toxicity. We investigated the possible involvement of dechlorination in CCl 3 NO 2 toxicity by considering its metabolism, inhibition of pyruvate and succinate dehydrogenases, cytotoxicity in cultured cells, and interaction with hemoproteins. In a newly discovered pathway, CCl 3 NO 2 is metabolized to thiophosgene, which is characterized as the cyclic cysteine adduct (raphanusamic acid) in the urine of mice. CCl 3 NO 2 inhibits porcine heart pyruvate dehydrogenase complex (IC-50 4 lM) and mouse liver succinate dehydrogenase complex (IC-50 13 lM), whereas its dehalogenated metabolites (CHCl 2 NO 2 and CH 2 ClNO 2 ) are more than 10 times less effective. The inhibitory potency of CCl 3 NO 2 for these dehydrogenase complexes is similar to that of captan, folpet, and dichlone fungicides (IC-50 2-6 lM). CCl 3 NO 2 cytotoxity with Hepa 1c1c7 mouse hepatoma cells (IC-50 9 lM) is not correlated with glutathione depletion. Mice treated intraperitoneally with CCl 3 NO 2 at 50 mg/kg but not with an equivalent dose of CHCl 2 NO 2 show increased concentrations of oxyhemoglobin in liver. The acute toxicity of CCl 3 NO 2 in mice is due to the parent compound or metabolites other than CHCl 2 NO 2 or CH 2 ClNO 2 and may be associated with inhibition of the pyruvate dehydrogenase complex and elevated oxyhemoglobin.