Comparison in human and rat hepatocytes of the DNA-damaging activity of five chemicals probably carcinogenic to humans

Abstract 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 for DNA-damaging activity in primary cultures of human and rat hepatocytes in order to assess possible interspecies differences that might cast doubt on the extrapolation to humans of results obtained in rodents. DNA damage was measured by the alkaline elution technique. In the range 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 m m ) and procarbazine (5.6–18 m m ), whereas phenacetin was inactive up to the maximal soluble dose (3.2 m m ). Adriamycin (1.8–5.6 μ m ) and bischloroethyl nitrosourea (18–56 μ m ) produced in cells of both species dose-dependent increases in the frequencies of both DNA breaks and cross-links. The responses of human hepatocytes 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 human hepatocytes with acrylonitrile (1.7-fold), adriamycin (1.4-fold), and 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-damaging activity in humans for the five chemicals studied.