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Comparative Carcinogenicities of 1-, 2-, and 4-Nitropyrene and Structurally Related Compounds in the Female CD Rat¹

Department of Chemical Carcinogenesis, Michigan Cancer Foundation, Detroit, Michigan 48201

The comparative carcinogenicities of N-hydroxy-N-acetyl-1-aminopyrene, N-acetyl-1-aminopyrene, and 1-, 2-, and 4-nitropyrene were determined following i.p. injection into weanling female CD rats (67 µmol/kg body weight in dimethyl sulfoxide; 3 times/week for 4 weeks). At sacrifice 61 weeks after the first injection the incidences of malignant mammary tumors were increased significantly to 45 and 24% in the 4-nitropyrene-and N-hydroxy-N-acetyl-2-aminofluorene-treated groups, respectively. Cellular altered foci in the liver were increased significantly in the N-acetyl-1-aminopyrene-, N-hydroxy-N-acetyl-1-aminopyrene-, and N-hydroxy-N-acetyl-2-aminofluorene-treated groups; the latter two compounds also led to significantly increased formation of hyperplastic nodules in this organ. Significant increases in leukemia induction were observed in animals treated with 2-nitropyrene or N-hydroxy-N-acetyl-2-aminofluorene.

In an experiment designed to compare the influence of the route of administration on the carcinogenic potential of this agent, 1-nitropyrene was injected i.p. or s.c. into weanling female CD rats (100 µmol/kg body weight; once a week for 4 weeks). The animals were sacrificed at 87 to 90 weeks after the first treatment. The incidences of mammary gland tumors in animals receiving injections of 1-nitropyrene by either route (59%) were significantly higher than in solvent-injected controls (37%). The incidences of adenocarcinoma in the i.p. 1-nitropyrene group (28%) and fibroadenoma in the s.c. 1-nitropyrene group (52%) were significantly higher than in the control animals (7 and 27%, respectively). These data suggest that the demonstration of the weak carcinogenicity of 1-nitropyrene is probably more a function of the length of the observation period than of the routes of administration used here.

A further exploration of the effect of the route of administration involved treatment of weanling female CD rats by direct injection of 1-, 2-, or 4-nitropyrene into the mammary fat pads. A total of 2.04 µmol of the nitrocompound in dimethyl sulfoxide was injected into the mammary glands under each of the 6 left nipples. The right mammary glands were treated with the solvent only. Injections of the thoracic nipple areas were carried out on day 1; inguinal areas were treated on day 2. The animals were sacrificed after 77 weeks. The number of mammary tumor-bearing animals (23 of 28), the number with fibroadenoma (15 of 28), and the number with adenocarcinoma (19 of 28) were significantly increased in the 4-nitropyrene-treated group as compared with animals treated with only dimethyl sulfoxide. Animals that had received 1- or 2-nitropyrene or the solvent dimethyl sulfoxide had mammary tumor incidences of only 21 to 22%. A majority of the animals that had been given 4-nitropyrene (i.e., 22 of 28) had tumors of the treated mammary glands as compared with only a few that developed tumors of the solvent-treated mammary glands (i.e., 5 of 28). These data confirm the carcinogenicity of 1-nitropyrene for rat mammary gland and demonstrate that 4-nitropyrene is the most potent of the three isomeric mononitropyrenes for this organ. The direct carcinogenicity of 4-nitropyrene for the mammary gland establishes that this target organ possesses the enzymes necessary for the metabolic activation of this carcinogen.

¹ This report from the A. Taubman Facility of the Michigan Cancer Foundation was supported by U.S. Public Health Service Grants CA 23386 and CA 23800 and Contract 83-14 from the Health Effects Institute.

² Present address: Division of Pathology, National Institute of Hygienic Sciences, Tokyo 158, Japan.

³ Present address: First Department of Pathology, Nagoya City University Medical School, Nagoya 467, Japan.

⁴ Present address: Metabolism and Pharmacokinetics, Bristol-Myers Co., Syracuse, NY 13221.

Received 10/31/90. Accepted 3/25/91.

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