A single hyperthermia treatment given near the time of initiation with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or 7,12-dimethylbenz[a]anthracene (DMBA) increased the number of initiated cells in the skin of SENCAR mice subjected to a two-stage tumorigenesis protocol. In animals subsequently promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA), a 44 degrees C, 30-min hyperthermia treatment given just before, just after or 24 h before MNNG initiation increased the average papilloma frequency by 40-50%. In the groups of animals that received a hyperthermia treatment just before MNNG initiation, tumor latency was reduced by 40-60%. Treatment with MNNG in the absence of hyperthermia produced two classes of initiated cells. One type, formed in low yield, was independent of TPA promotion and formed tumors with a high probability of progression to malignancy. The other type was promotion dependent, and formed in relatively high yield but produced tumors with a probability of progression to carcinomas approximately 10-fold less than promotion-independent initiated cells. A single hyperthermia treatment given just before or just after MNNG initiation increased the yield of both promotion-dependent and promotion-independent initiated cells, and consequently increased the yield of carcinomas. In animals given a single hyperthermia treatment 24 h prior to initiation (to induce thermotolerant skin cells), MNNG exposure resulted in an increased yield of promotion-dependent initiated cells but no change in the yield of promotion-independent initiated cells. Hyperthermia treatment of DMBA-initiated skin increased the yield of initiated cells (promotion-dependent) only when given just after exposure to the initiator. The extra initiated cells produced by hyperthermia treatment of MNNG or DMBA exposed skin had the same probability of progression to carcinomas as initiated cells produced by the same initiation in the absence of hyperthermia. As noted previously for DMBA-initiated mice, hyperthermia given at the time of each application of TPA promoter also suppressed the formation of papillomas initiated by MNNG. Only the promotion and progression of promotion-dependent initiated cells, and not of promotion-independent cells, was suppressed. The results show that a single hyperthermia treatment near the time of exposure to an alkylating agent increased the number of both promotion-dependent and promotion-independent initiated cells and, as a consequence, increased the risk of carcinogenesis associated with that exposure.(ABSTRACT TRUNCATED AT 400 WORDS)