COMPARISON IN HUMAN AND RAT HEPATOCYTES OF THE DNA-DAMAGING ACTIVITY OF 5 CHEMICALS PROBABLY CARCINOGENIC TO HUMANS

Five chemicals-acrylonitrile, adriamycin, bischloroethyl nitrosourea, phenacetin and procarbazine-classified by the International Agency for Research on Cancer as probably carcinogenic to humans were assayed fo r DNA-damaging activity in primary cultures of human and rat hepatocyt es in order to assess possible interspecies differences that might cas t doubt on the extrapolation to humans of results obtained in rodents. DNA damage was measured by the alkaline elution technique. In the ran ge of subtoxic concentrations indicated, dose-related increases in the frequencies of DNA single-strand breaks were induced in cells of both species by acrylonitrile (1.0-5.6 mM) and procarbazine (5.6-18 mM), w hereas phenacetin was inactive up to the maximal soluble dose (3.2 mM) . Adriamycin (1.8-5.6 mu M) and bischloroethyl nitrosourea (18-56 mu M ) produced in cells of both species dose-dependent increases in the fr equencies of both DNA breaks and cross-links. The responses of human h epatocytes were qualitatively similar to those of rat hepatocytes, but modest statistically significant differences between the two species in the average frequencies of DNA lesions were observed with the four active agents: the amount of DNA damage was greater in rat than in hum an hepatocytes with acrylonitrile (1.7-fold), adriamycin (1.4-fold), a nd BCNU (1.3-fold), whereas procarbazine was more genotoxic (1.4-fold) for human hepatocytes. However, as the interindividual variability of the response was greater than that occurring between the two species, the results should be interpreted as indicating that rat hepatocytes are good predictors of metabolic activation/detoxification and DNA-dam aging activity in humans for the five chemicals studied.