Varying doses of ellipticine (EL), flavone (FL), or 7,8-benzoflavone (78BF) were applied to mouse skin 5 min before an initiating dose of 10 nmol 7,12-dimethylbenz[a]anthracene (DMBA), 47.5 nmol 7,14-dimethylbenzo[a,h]anthracene (DDBA), or 200 nmol dibenzo[a,h]anthracene (DBA) and the development of skin tumors in the mice then promoted by topical applications of 2 micrograms 12-O-tetradecanoylphorbol-13-acetate (TPA). As expected, treatment with 78BF (37 nmol or 370 nmol) markedly inhibited the skin tumor initiation by DMBA (greater than 70%). High doses of FL (4500 nmol) or EL (410 nmol) also inhibited DMBA tumorigenesis (52% and 82%, respectively) but lower doses of FL (450 nmol) or EL (4.1 nmol) stimulated DMBA tumorigenesis (greater than 40%). As was the case with DMBA initiation, the higher doses of FL or EL inhibited DDBA skin tumorigenesis and the lower doses of these two modifiers stimulated the DDBA tumorigenesis. In contrast with the results with DMBA initiation, treatment with 78BF (370 nmol or 3700 nmol) slightly enhanced DDBA tumorigenesis (22% and 6%, respectively). Treatment with EL and FL at all doses tested stimulated DBA tumorigenesis (range 4-51%), while treatment with 370 nmol 78BF slightly stimulated DBA tumorigenesis (19%) and treatment with 3700 nmol slightly inhibited DBA tumorigensis (9%). The effects of a range of 78BF doses upon skin tumor initiation by 40 nmol DMBA were also investigated. While all doses of 78BF tested (0.37-370 nmol) inhibited the DMBA tumorigenesis, the dose response was not linear; treatment with 3.7 nmol 78BF resulted in more papillomas per mouse (12.20) than did treatment with either 0.37 nmol 78BF (8.70) or 37 nmol 78BF (5.97). It is concluded that modifiers such as 78BF, FL and EL may have a variable, dose-dependent effect upon skin tumor initiation by carcinogenic polycyclic arylhydrocarbons. Some implications of this proposal are discussed.