The mechanisms by which DNA-incorporated radionuclides impart lethal damage to mammalian cells were investigated by examining the capacity of dimethyl sulfoxide (DMSO) to protect against lethal damage to Chinese hamster V79 cells caused by unbound tritium ((3)H(2)O), DNA-incorporated (125)I- and (131)I-iododeoxyuridine ((125)IdU, (131)IdU), and cytoplasmically localized (210)Po citrate. The radionuclides (3)H and (131)I emit low- and medium-energy beta particles, respectively, (125)I is a prolific Auger electron emitter, and (210)Po emits 5.3 MeV alpha particles. Cells were radiolabeled and maintained at 10.5 degrees C for 72 h in the presence of different concentrations of DMSO (5-12.5% v/v), and the surviving fraction compared to that of unlabeled controls was determined. DMSO afforded no protection against the lethal effects of the high-LET alpha particles emitted by (210)Po. Protection against lethal damage caused by unbound (3)H, (131)IdU and (125)IdU depended on the concentration of DMSO in the culture medium. Ten percent DMSO provided maximum protection in all cases. The dose modification factors obtained at 10% DMSO for (3)H(2)O, (131)IdU, (125)IdU and (210)Po citrate were 2.9 +/- 0.01, 2.3 +/- 0.5, 2.6 +/- 0.2 and 0.95 +/- 0.07, respectively. These results indicate that the toxicity of Auger electron and beta-particle emitters incorporated into the DNA of mammalian cells is largely radical-mediated and is therefore indirect in nature. This is also the case for the low-energy beta particles emitted by (3)H(2)O. In contrast, alpha particles impart lethal damage largely by direct effects. Finally, calculations of cellular absorbed doses indicate that beta-particle emitters are substantially more toxic when incorporated into the DNA of mammalian cells than when they are localized extracellularly.