A biochemical hypothesis explaining the generation of pathology in human skin by mustard gas (HD) is presented which links the initiation of DNA damages to local alterations of metabolism and subsequent development of blisters. The proposed sequence involves HD alkylation of purines in DNA which are processed to form apurinic sites. Apurinic endonucleases act at these sites to produce backbone breaks in DNA which cause activation of the chromosomal enzyme poly(ADP-ribose)polymerase. This enzyme utilizes NAD+ as a substrate and, at vesicating doses of HD, would deplete the cells of their NAD+ content. The depletion in NAD+ would cause inhibition of glycolysis, and the resulting accumulation of common intermediates would stimulate the NADP+-dependent hexosemonophosphate shunt (HMS). Such stimulation of the HMS has been associated with DNA damage and enhancement of protease synthesis and release. These proteases could be responsible for development of subepidermal blisters which result from fluid accumulation in the cavity created by separation of the moribund basal cell layer from the basement membrane--a characteristic feature of HD-exposed human skin. Partial validation of this biochemical hypothesis has been achieved. DNA alkylated with either monofunctional or bifunctional sulfur mustards, followed by spontaneous or enzymatic depurination, was shown to be sensitized to degradation by apurinic endonuclease. Studies on the effect of HD on human skin grafted to athymic nude mice demonstrated dose- and time-related decreases in NAD+ levels. These decreases in NAD+ levels preceded and correlated to the predicted severity of pathology. The participation of poly(ADP-ribose)polymerase activity in the HD-induced NAD+ loss was substantiated by prevention of this loss in the presence of inhibitors of the enzyme. Additional supporting evidence for the proposed mechanism was obtained at the cellular level by studies which utilized human leukocytes. The subsequent involvement of the HMS and proteases in HD-induced vesication is discussed.