IN-SITU MOLECULAR DOSIMETRY AND TUMOR RISK - UV-INDUCED DNA-DAMAGE AND TUMOR LATENCY TIME

In UV carcinogenesis there is a fundamental chain of causal events fro m UV-induced DNA damage through mutations up to tumor formation: each of the early events should be predictive of the ultimate tumor risk, I nstead of the UV surface exposure, the in situ load of DNA damage shou ld be a more direct measure of the carcinogenicity. To explore this fu rther we measured cyclobutane thymine dimer loads of epidermal cell su spensions from chronically UV-exposed hairless SKH-1 mice; shin sample s were taken after various time periods under different daily exposure s. Although the average load per cell decreased in the course of time due to dilution of damage in an increasing epidermal hyperplasia, the amount of thymine dimers in a column of epidermis (i.e. per mm(2) of s kin area) became stationary, and this amount increased with higher dai ly exposure. The median tumor latency time, t(50), is inversely relate d to this stationary load. Extrapolation of a fitted relationship woul d imply a t(50) between 450 and 1430 days for spontaneous skin carcino mas. The present data suggest that the skin strives to maintain a maxi mum level of tolerable DNA damage by lowering the average genotoxic lo ad in vital cells in It hyperplastic reaction: pseudo-repair by diluti on. This would also explain the strong hyperplastic reactions in DNA r epair-deficient mouse strains. An understanding of these short-term ad aptive reactions can refine our assessments of skin cancer risks in hu mans.