Since current evidence suggests that the tumor promotion stage is a primary determinant in susceptibility to multistage carcinogenesis, we have characterized the genetics of susceptibility to phorbol ester skin tumor promotion in inbred mice. Susceptibility of hybrids (B6D2F1), between DBA/2 (sensitive) and C57BL/6 (resistant) parents, initiated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA) was similar to DBA/2 mice at doses of 13.6 nmol per mouse but clearly less when doses of 1.7-6.8 nmol per mouse were used. In addition, no significant differences were observed between male and female B6D2F1 mice in terms of tumor incidence although some differences were observed in tumor multiplicities between male and female F1 mice at the highest TPA dose. Reciprocal F1 mice initiated with DMBA (i.e. D2B6F1) were also responsive to TPA. Female D2B6F1 mice were of lower sensitivity at lower doses of TPA, compared to female DBA/2, a finding similar to that observed with B6D2F1 mice initiated with MNNG. Further analyses of the susceptibility of B6D2F2 and B6D2F1 X C57BL/6 backcross mice to TPA promotion indicated that more than one dominant genetic locus must account for the differences in promotion sensitivity between DBA/2 and C57BL/6 mice. To understand further the genes responsible for promotion sensitivity, histological evaluations were performed on DBA/2, C57BL/6 and B6D2F1 mice. Histological examination revealed that the epidermis of DBA/2 mice showed a marked hyperplasia and the presence of a much greater number of dark basal keratinocytes (DCs) compared with C57BL/6 mice 48 h after the last of four applications of TPA (doses greater than or equal to 3.4 nmol). A marked dermal infiltration of polymorphonuclear leukocytes (PMNs) was observed in DBA/2 mice, whereas little infiltration was observed in the skin of C57BL/6 mice. The hyperplasia in the skin of B6D2F1 mice was intermediate between DBA/2 and C57BL/6 mice at all TPA doses examined except the lowest dose (1.7 nmol), whereas the DC response, although significantly lower at doses of 6.8 nmol or below, was similar to DBA/2 mice at higher TPA doses (13.6 and 17.0 nmol). The infiltration of PMNs in the dermis of B6D2F1 mice was similar to or greater than DBA/2 mice at all doses of TPA tested.(ABSTRACT TRUNCATED AT 400 WORDS)