Are DNA adducts relevant markers of carcinogenic risk?

The formation of DNA adducts by the covalent binding of genotoxic chemicals to DNA and subsequent activation of proto-oncogenes is regarded as one of the initiating events in the process of carcinogenesis. An animal study was instigated using mice (SWR (high), Balb/c (intermediate) and C57BL/6J (low)) varying in their susceptibility to lung carcinogenesis, dosed with a single intraperitoneal injection of saline or /V-nitrosodiethylamine (NDEA) at 15 or 90 mg/kg body weight. Target (lung) and non-target tissues were removed 5h, 10h, 24h, 4d, 7d, 28d and 56d after dosing. Further groups of mice dosed with the same regime were left up to 18 months to allow for the development of tumours. Immunoslot-blot analysis was used for the determination of N-7 ethylguanine (N-7 EtG) and O6 ethylguanine (O6 EtG) adduct levels in the DNA from the tissues. Results from the high dose indicated a high tumour incidence, however there was no major significant difference in the levels or persistence of DNA adducts in target and non-target tissue of the three strains of mice. The relevance of these results is unclear since at this dose toxicity may have occurred resulting in cell death and induction of tumours by compensatory cell proliferation. No results were obtained for DNA adduct levels in the target tissue from the low dose group due to insufficient sensitivity of the immunoslot-blot method. The incidence of tumours in C57BL/6J mice was lower compared to the other two strains. These results do not allow decisive conclusions to be drawn concerning relationship between total levels of DNA adducts and differences in tumour susceptibility for the strains of mice. However the increased presence of DNA adducts in the target tissues (as exemplified by the C57BL/6J mice) significantly increased the likelihood of tumour development implying that DNA adducts are relevant markers for carcinogenic risk.