ABSTRACT
Metabolic activation of benzene may occur by a pathway analogous to that accepted for polynuclear aromatic hydrocarbons (PAHs) involving ring epoxidation, enzymatic hydrolysis to the dihydrodiol, and further epoxidation to the diolepoxide. This hypothesis was explored by testing benzene oxide (BzO) and enantiomers and racemates of benzene dihydrodiols and diolepoxides for their capacity to induce lung tumors in a newborn mouse assay. Although benzene and benzene diolepoxide-1 [(+/-)-BzDE-1] were inactive, BzO and racemates of benzene dihydrodiol [(+/-)-BzDh] and benzene diolepoxide-2 [(+/-)-BzDE-2] induced dose-dependent increases in lung tumor incidence and multiplicity. (+/-)-BzDE-2 may be an ultimate tumorigenic metabolite of benzene since it was the most active compound tested on a molar basis with an estimated ED50 (dose inducing lung tumors in 50% of mice) of 12.0 mumol and an estimated TM1.0 (total dose inducing 1.0 lung tumor/mouse) of 16.2 mumol. No stereoselectivity was apparent in the tumorigenic activity of dihydrodiol and diolepoxide enantiomers since at equimolar doses the resolved (+)-BzDh was equally tumorigenic as the (+/-)-BzDh racemate and the resolved (+)- and (-)-BzDE-2 were both equally active as (+/-)-BzDE-2.
Subject(s)
Adenocarcinoma/chemically induced , Adenoma/chemically induced , Benzene Derivatives/toxicity , Carcinogens/toxicity , Lung Neoplasms/chemically induced , Adenocarcinoma/pathology , Adenoma/pathology , Animals , Animals, Newborn , Biotransformation , Carcinogenicity Tests/methods , Cyclohexanes/toxicity , Lung Neoplasms/pathology , Mice , Mice, Inbred Strains , Structure-Activity RelationshipABSTRACT
A BLU:Ha newborn mouse lung adenoma bioassay was employed to compare the tumorigenicity of selected mononitroarenes and unsubstituted parent compounds 6 months after initial treatment. The presence of a nitro group had a variable effect upon compound potency in which tumorigenicity was increased, abolished, or unchanged. On the basis of results with equimolar doses, the potency of benzo[a]pyrene was greater than 6-nitrobenzo[a]pyrene (inactive), 6-nitrochrysene was much greater than chrysene (inactive), 3-nitrofluoranthene (active) was equal to fluoranthene (active), and 1-nitropyrene (inactive) was equivalent to pyrene (inactive). The potency series among the mononitroarenes was 6-nitrochyrsene much greater than 3-nitrofluoranthene greater than 6-nitrobenzo[a]pyrene (inactive) = 1-nitropyrene (inactive). Lung tumor incidence and multiplicity were similar for both males and females. No consistent pattern was observed for the occasional appearance of lymphoma or hepatic nodular hyperplasia in the various treatment groups.
Subject(s)
Adenoma/chemically induced , Carcinogens, Environmental/toxicity , Lung Neoplasms/chemically induced , Polycyclic Compounds/toxicity , Animals , Animals, Newborn , Benzopyrenes/toxicity , Chrysenes/toxicity , Dose-Response Relationship, Drug , Female , Fluorenes/toxicity , Male , Mice , Polycyclic Compounds/metabolism , Pyrenes/toxicity , Structure-Activity RelationshipABSTRACT
Cyclopenta[cd]pyrene (CPP) was a potent tumorigen when tested over a 5-fold dose range in the newborn mouse assay. A 20-fold increase in lung tumor multiplicity and a nearly 8-fold increase in tumor incidence was observed at the lowest total dose tested (1.55 mumol) with the dose-response relationship indicating a saturation of tumor multiplicity at approximately 7 tumors/animal. No liver nodules or lymphatic system tumors were noted. Analysis of dose-response data for benzo[a]-pyrene (BaP) and 6-nitrochrysene (6-NC) showed that tumor multiplicity for BaP also saturated at approximately 7 tumors/animal, whereas no similar saturation was found for 6-NC at up to 40 tumors/animal. Progression of lung adenomas to adenocarcinomas, as measured by the incidence of mice bearing malignant tumors, was essentially a linear function of dose. To facilitate comparison and maximize quantitative data obtainable from the newborn mouse assay-parameters were defined for tumor incidence (ED50), tumor multiplicity (TM1.0) and tumor malignancy (malignancy index). Values for the ED50 and TM1.0 were similar for the same compound and a tumorigenic potency series of 6-NC greater than BaP greater than CPP was obtained corresponding to a ratio of approximately 1:10-25:76.5-135, respectively. The malignancy index, however, indicated increased adenocarcinoma induction in the order CPP greater than 6-NC greater than BaP as expressed by the ratio 1:1.4:8.3, respectively.
Subject(s)
Adenoma/chemically induced , Benzo(a)pyrene , Biological Assay/methods , Carcinogens , Chrysenes/toxicity , Lung Neoplasms/chemically induced , Phenanthrenes/toxicity , Pyrenes/toxicity , Animals , Animals, Newborn , Dose-Response Relationship, Drug , Female , Male , Mice , Mice, Inbred ICR , Skin Neoplasms/chemically inducedABSTRACT
A newborn mouse (BLU:Ha) lung adenoma bioassay demonstrated that 6-nitrochrysene was a highly potent tumorigen. It induced 100% incidence of lung tumors and a 150-fold increase in their number (20.84 tumors/mouse) at the lowest dose level tested (total dose: 38.5 micrograms/mouse). 70% of the 6-nitrochrysene treated mice had malignant lung tumors (adenocarcinomas). Lymphomas and nodular hyperplasia of the liver were also observed in treated, but not control, animals. The tumorigenicity of 6-nitrochrysene relative to other polynuclear aromatic hydrocarbons and their mononitro-derivatives has been discussed.
