Evidence has been given that the standard battery of genotoxicity tests may be unable to identify tissue-specific carcinogens; certainly it does not provide information on the possible species-specificity of the test compound that should be considered in the assessment of carcinogenic risk to humans. Six chemicals, known to induce lung tumors in rats, were assayed for their ability to induce DNA fragmentation in primary cultures of rat and human lung cells and in the lung of intact rats. Significant dose-dependent increases in the frequency of DNA single-strand breaks and alkali-labile sites, as measured by the Comet assay, were obtained in primary lung cells from both rats and humans with the following subtoxic concentrations of the six test compounds: N-nitrosodimethylamine from 2.5 to 10 mM, hydrazine from 0.5 to 4 mM, cadmium sulfate and 4,4’-methylene bis(2-chloroaniline) 31.2 and 62.5 μM, isobutyl nitrite from 7.8 to 31.2 μM, and tetranitromethane from 1.9 to 15.6 μM. Interdonors differences of the minimum effective concentrations were higher in cells from humans than in cells from rats. The DNA-damaging potencies of N-nitrosodimethylamine, hydrazine and isobutyl nitrite were higher in rats than in humans, and the converse happened for the other three test compounds. Consistently with results obtained in vitro, statistically significant increases in the average frequency of DNA lesions were obtained in lungs of rats given p.o. a single dose (1/2 LD50) of the six test compounds. These findings indicate that lung genotoxic carcinogens can be identified by the DNA fragmentation/Comet assay using as target lung cells. Moreover, the DNA fragmentation produced by the six test compounds in lung cells from human donors suggests that they might increase the incidence of lung tumors in humans.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]