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.