title: Nitrobenzene potential human cancer risk based on animal studies.
abstract: Inhaled nitrobenzene (NB) in animals produces cancer at eight sites in three rodent strains. B6C3F1 mice respond with mammary gland malignant tumors and male lung and thyroid benign tumors, and F344/N male rats respond with liver malignant tumors and thyroid and kidney benign tumors, while females respond with endometrial polyps. Male Sprague-Dawley male rats (CD strain) respond with liver benign tumors. NB is oxidized to various phenolic metabolites, while also being reduced to nitrosobenzene (NOB), phenylhydroxylamine (PH), related free radicals, and aniline (AN) in the cecum by bacteria and in the body by the microsomes. In reduction, NB first forms the nitroanion free radical, which can react with O2 to form O2*-. Repeated NB dosing produces a persistent redox couple NOB<==>PH in red blood cells that generates met-Hb and expends NAD(P)H. NOB forms activated glutathione conjugates. These biochemical effects may lead to critical redox imbalances and macromolecular binding. Known effects are hemosiderosis, methemoglobinemia, and anemia--and now dispersed cancer in rodents. Based on structural and mechanistic similarities, NB compares with other animal and human carcinogenic nitroarenes and aromatic amines. The cancer hazard evaluation of NB is that it is a probable human carcinogen by any route of exposure. The maximum response is in F344/N male rats which is used for dose-response modelling. The model to estimate the upper 95% confidence limit (UCL95%) of NB human carcinogenicity is a no-threshold, linear low-dose, and multistaged animal model (LMS). The UCL95% of cancer slope is estimated to be 0.11(6) mg/kg/day (mkd). At de minimus risk (1:10(6)), the virtually safe dose (VSD) is estimated to be 9.1 ng/kg/day (nkd).
authors.affiliation: National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC 20460, USA. holder.james@epa.gov
authors.forename: J W
authors.initials: JW
authors.lastname: Holder
mesh_terms: D000818:Animals; D015197:Carcinogenicity Tests; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008954:Models, Biological; D009374:Neoplasms, Experimental / Q000139:chemically induced*; D009578:Nitrobenzenes / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D018570:Risk Assessment; D014481:United States; D014484:United States Environmental Protection Agency
chemical_list: D009578:Nitrobenzenes; C036077:nitrobenzene