THE EFFECTS OF A BINARY MIXTURE OF BENZO(a)PYRENE AND 7H-DIBENZO(c,g)CARBAZOLE ON LUNG TUMORS AND K-RAS ONCOGENE MUTATIONS IN STRAIN A/J MICE

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Polycyclic aromatic hydrocarbons (PAH) and N -heterocyclic aromatic hydrocarbons (NHA) are environmental pollutants formed during the incomplete combustion of organic materials. Benzo(a)pyrene (BaP) and 7H-dibenzo(c,g)carbazole (DBC) are well-characterized representatives of the PAH and NHA classes of compounds, respectively. Both are demonstrated carcinogens that frequently co-occur in environmental mixtures. This preliminary study was conducted to investigate the effects of a binary mixture of BaP and DBC on lung carcinogenicity in the strain A/Jmouse as manifested by tumor development and mutations in the K-ras gene. Male A/Jmice were administered the following single intraperitoneal dose (mg/kg) combinations of BaP and DBC dissolved in a 0.2-mL volume of tricaprylin - 10 DBC:10 BaP; 2 DBC:10 BaP; 2 DBC:100 BaP; and 10 DBC: 100 BaP, and each of the compounds alone at the same doses. Mice were sacrificed 8 months after carcinogen treatment and lung tumor multiplicity and K-ras mutations determined (high-dose combination). The combination of DBC and BaP produced fewer tumors than the sum of all tumors produced by each compound acting alone. The frequency of tumors with K-ras mutations was also less in a sample of the 10 DBC:100 BaP treatment group than in the same-dose, single compound-treated animals. The dominant mutations produced by BaP and DBC were expressed in tumors from animals treated with the mixture.