LYMPHOCYTE MUTANT FREQUENCY IN RELATION TO DNA ADDUCT FORMATION IN RATS TREATED WITH TUMORIGENIC DOSES OF THE MAMMARY-GLAND CARCINOGEN 7,12-DIMETHYLBENZ[A]ANTHRACENE

The ability of the rat lymphocyte hprt assay to detect tissue-specific carcinogens was evaluated using 7,12-dimethylbenz[a]anthracene (DMBA) administered under conditions that result in mammary gland tumors. Fi fty-day-old female Sprague-Dawley rats were given single doses of 5 an d 20 mg/kg DMBA by gavage, and the frequency of 6-thioguanine-resistan t (TG(r)) T-lymphocytes was measured over a period of 21 weeks. A time - and dose-dependent increase in mutant frequency was found, with a ma ximum frequency found 9-15 weeks after treatment with 20 mg/kg of DMBA , Rats were also dosed with 1, 2.5, 5, 10, 15 and 20 mg/kg of DMSA and assayed for TG(r) mutant frequency 10 weeks after treatment. A signif icant linear dose-response was found, with all the DMBA doses resultin g in significant increases in mutant frequency. To determine whether o r not DMBA-induced mutants in rat lymphocytes reflected the DNA damage in the target tissue, rats were treated with 5 and 20 mg/kg of DMBA a nd spleen lymphocytes and mammary gland tissue were assayed for DNA ad duct formation 1, 3 and 7 days later. A similar pattern of P-32-postla beled adducts, involving both dG and dA nucleotides, was found in DNA from both the target tissue and the surrogate lymphocytes, Adduct form ation was dose responsive in both tissues, with a 2.3- to 4-fold highe r concentration in mammary gland as compared with lymphocytes, These r esults indicate that the rat lymphocyte hprt assay is sensitive to a m ammary gland carcinogen and that similar types of DNA adducts are asso ciated with both the lymphocyte mutants and the mammary gland tumors i nduced by DMBA.