Nitrobenzene carcinogenicity in animals and human hazard evaluation

Nitrobenzene (NB) human cancer studies have not been reported, but animals studies have. Three rodent strains inhaling NB produce cancer at eight sites. B6C3F1 mice respond with mammary gland malignant tumors and male lung and thyroid benign tumors, F344/N male rats respond with liver malignant tumors and thyroid and kidney benign tumors, while females respond with endometrial polyps. Male Sprague-Dawley rats (CD strain) respond with liver benign tumors. NB is oxidized to various phenolic metabolites, while also being reduced in the cecum and systemically in the microsomes to nitrosobenzene (NOB), phenylhydroxylamine (PH), related free radicals, and aniline (AN). Based on structural and mechanistic similarities, NB compares with other animal and human carcinogenic nitroarenes and aromatic amines. Reduced NB first forms the nitroanion free radical, which can react with O2 to form superoxide O2*. Repeated NB dosing produces a persistent redox couple NOB<==>PH in red blood cells (RBCs) that generates met-Hb and expends NAD(P)H. NOB forms activated glutathione (GSH) conjugates. These biochemical effects may lead to critical redox imbalances and macromolecular binding. Known NB effects are hemosiderosis, methemoglobinemia, and anemia--and now dispersed cancer in rodents. On the basis of animal, metabolic and structure-activity studies, NB is determined to be a probable human carcinogen by any route of exposure.