Neoplastic transformation of Syrian hamster fetal cells by bisulfite is associated with qualitative and quantitative polypeptide changes. Amino acid-labeled [14C]polypeptides from neoplastic and nontransformed parental fetal cells were separated by two-dimensional gel electrophoresis and analyzed by computerized microdensitometry of autoradiographic patterns. Approximately 1000 polypeptides from parental fibroblasts at population doublings ranging from 4 to 20, and those from colony-derived malignant cell lines were compared. Most were identical. Seven malignant lines exhibited 4 qualitative polypeptide changes: 2 polypeptides had shifted slightly to the acidic side, 1 new polypeptide was observed, and 1 polypeptide was absent. The transformed bisulfite lines differed quantitatively from control cells in that 10-25% and 2-4% of the polypeptides exhibited differences in expression greater than 2- and 4-fold, respectively. Furthermore, there were 21 specific polypeptides with coordinate quantitative changes in all transformed lines. Because bisulfite at neutral pH fails to induce any significant DNA changes at concentrations that cause transformation, polypeptides expressed immediately or 48 h after bisulfite treatment were compared to those of non-treated controls, and no differences were found. Even though bisulfite does not induce detectable DNA damage or early post-treatment changes in polypeptide expression, a consistent set of qualitative and quantitative changes were observed after transformation. The qualitative polypeptide changes found in the bisulfite-induced malignant lines were similar to those seen in a benzo(a)pyrene-induced malignant line. This suggests that there is a convergence of pathways responsible for carcinogenesis independent of the nature of initiation.