Abstract

Intravenous pretreatment of animals with sodium thiosulfate was observed to prevent the toxic effects of N, N'-ethylene-bis[5-(2-bromoethylthio) valeramide] (I; half-life, approximately four seconds), but not N,N'-ethylene-bis[(2-chloroethylthio) acetamide] (II; halflife, 15 minutes). Only the latter exists sufficiently long after i.v. injection to pass from the thiosulfate-rich extracellular water into the thiosulfate-free intracelluar compartment where it can produce toxic akylations. (Thiosulfate does not alter the half-life). Compound I, however, is toxic in the absence of thiosulfate indicating that its toxic alkylations are produced in the extracellular compartment. N,N'-bis-(2-chloroethyl)-N-methylamine (HN2) was observed to pass from the extracellular water more rapidly than its charged form N-2-chloroethyl-N-methylaziridinium chloride (III). The latter is more toxic and most susceptible to thiosulfate pretreatment. These observations also suggest an extracellular location as the site of the toxic reaction.