The role of keratinocyte derived inflammatory or growth factors in arsenic (7440382) induced skin cancer was examined. Primary human epidermal keratinocytes were incubated with up to 8 micromolar (microM) sodium-arsenite (7784465) for 2 to 18 hours (hr). The proliferative effects of sodium-arsenite treatment were determined by measuring changes in cell numbers and incorporation of tritiated thymidine by the cells. The cells were analyzed for granulocyte macrophage colony stimulating factor (GM/CSF), transforming growth factor alpha (TGFa), and tumor necrosis factor alpha (TNFa). The level of expression of mRNA coding for GM/CSF, TGFa, and TNFa was determined. Only the 8microM dose was cytotoxic, reducing cell viability by less than 12%. Sodium-arsenite at concentrations below 8microM caused concentration dependent increases in keratinocyte proliferation, cellular GM/CSF, TNFa, and TGFa levels, and expression of mRNA coding for GM/CSF, TNFa, and TGFa. TG.AC-mice, carrying the v-Ha-ras oncogene, and wild type FVB/N-mice were administered 0 or 0.02% arsenic as sodium-arsenite in their drinking water for 6 weeks (wk). They were then administered 0 or 2.5 micrograms 12-O-tetradecanoylphorbol-13-acetate (TPA) topically twice weekly during the last 2wk of arsenic treatment. Skin specimens were collected at 2wk intervals for up to 8wk after the end of TPA treatment for histological evaluation. The RNA was extracted from some samples to determine the level of expression of RNA coding for TGFa and GM/CSF. TPA induced a small number of papillomas at the skin application sites in TG.AC-mice, but not in control or FVB/N-mice after 4wk. Sodium-arsenite alone induced no papillomas; however, sodium-arsenite treated TG.AC-mice developed epidermal thickening and hyperkeratosis after 4wk. Significant increases in the incidence of papillomas were seen in sodium- arsenite and TPA treated TG.AC-mice after 6wk. This was taken as evidence that sodium-arsenite could enhance papilloma formation. The level of GM/CSF mRNA and TGFa mRNA expression was significantly increased in skin samples from sodium-arsenite treated mice. The authors suggest that arsenic enhances papilloma development by means of chronic stimulation of keratinocyte derived growth factors.