A study was conducted examining the role of proinflammatory cytokines and growth factors in benzene (71432) induced skin carcinogenesis. The elaboration of interleukin-8 (IL-8) and tumor growth factor alpha (TGFa) by normal human skin keratinocytes in- vitro following exposure to benzene and its metabolic products was assessed. Secretion of TGFa and IL-8 increased following the addition of 1,4-benzosemiquinone (BQ), hydroquinone (123319) (HQ), or 1,2,4-benzenetriol (533733) (BZT) to skin cell cultures without concomitant cytotoxicity. Phenol (108952) increased the secretion of TGFa and IL-8 only at cytotoxic concentrations; IL-8 and TGFa secretion were not significantly affected by catechol (154234). Secretion of interleukin-6, tumor necrosis factor alpha, and MCP-1 was not significantly affected by BQ, HQ, or BZT. HQ induced production of IL-8 was significantly inhibited in the presence of N- acetylcysteine (NAC). BZT induced production of IL-8 was significantly inhibited by NAC as well as by dimethyl-sulfoxide and 1,1,3-tetramethylthiourea. Synergistic increases in IL-8 secretion were seen in incubations using a combination of CAT and HQ. A modest, but significant, increase in the production of IL-8 was seen following exposure to benzene. The authors conclude that exposure of human epidermal keratinocytes to relatively low concentrations of benzene or its metabolic products induces selective cytokines and growth factors. These agents may provide a mechanistic link between tumor initiation and promotion that will assist in the understanding of benzene induced skin carcinogenesis.