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1. The metabolism of sulphur mustard, 1,1'-thiobis(2-chloroethane), in vivo was investigated following i.p. administration to rat. 2. Approx. 60% of dose was excreted in the 24 h urine. Many metabolites were present; nine have been isolated by h.p.l.c. and characterized by mass spectrometry. Structural assignments were confirmed by comparison with authentic synthetic standards. 3. Some metabolites result from initial hydrolysis of the sulphur mustard, but the majority are formed by conjugation with glutathione. These are further metabolized to N-acetylcysteine conjugates, or to methylthio/methylysulphinyl derivatives by a pathway probably involving beta-lyase, accompanied by oxidation of the mustard sulphur atom to sulphoxide or sulphone. 4. Thiodiglycol sulphoxide, 1,1'-sulphonylbis[2-S(N-acetylcysteinyl)ethane] and 1,1'-sulphonylbis[2-methylsulphinyl)ethane] or 1-methylsulphinyl-2-[2-(methylthio ethylsulphonyl]ethane were the most prevalent metabolites resulting from the three major pathways. Metabolic pathways for the formation of the excretion products are proposed.

1. Analytical methods were developed for the detection of N-terminal valine and histidine adducts in haemoglobin alkylated with sulphur mustard. 2. N-(2-hydroxyethylthioethyl)-N-terminal valine was selectively cleaved from globin with the Edman reagent pentafluorophenyl isothiocyanate. The resulting thiohydantoin derivative was analysed by high resolution gc-ms using negative ion chemical ionization. An alternative procedure, involving acid hydrolysis of globin to its constituent amino acids and conversion of the adduct to its di-TBDMS derivative, was less sensitive. 3. N-(2-hydroxyethylthioethyl)histidine was analysed, after acid hydrolysis of globin, as its fluorenylmethyloxycarbonyl derivative by lc-ms-ms using electrospray ionisation and selected reaction monitoring. 4. N-(2-hydroxyethylthioethyl)valine and (2-hydroxyethylthioethyl)histidine were detected in globin isolated from a rat treated percutaneously with sulphur mustard, and in globin from five blood samples collected from human casualties of sulphur mustard poisoning. The adducts are proposed as biological markers of sulphur mustard poisoning. in addition to urinary metabolites and DNA adducts.

1. The metabolism of thiodiglycol, 2,2'-thiobis-ethanol, was investigated following i.p. administration to rat. 2. Approximately 90% of the administered dose was excreted in the 0-24-h urine. Four metabolites were isolated by h.p.l.c. and identified by mass spectrometry. Structural assignments were confirmed by comparison with authentic synthetic standards. 3. Thiodiglycol sulphoxide was the major metabolite accounting for approximately > or = 90% of the excreted radioactivity following i.p. injection of 13C4, 35S-thiodiglycol. Thiodiglycol sulphone, S-(2-hydroxyethylthio)acetic acid and S-(2-hydroxy-ethylsulphinyl)acetic acid were identified as minor metabolites. 4. Analysis for thiodiglycol by GC-MS indicated approximately 0.5-1% of the applied dose was excreted unmetabolized.

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