Holder J W
National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC 20460, USA.
Toxicol Ind Health. 1999 Aug;15(5):445-57.
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.
尚未有关于硝基苯（NB）对人类癌症影响的研究报道，但有动物研究报告。三种啮齿动物品系吸入NB后，在八个部位诱发癌症。B6C3F1小鼠出现乳腺恶性肿瘤以及雄性肺部和甲状腺良性肿瘤；F344/N雄性大鼠出现肝脏恶性肿瘤以及甲状腺和肾脏良性肿瘤，而雌性大鼠出现子宫内膜息肉。雄性斯普拉格-道利大鼠（CD品系）出现肝脏良性肿瘤。NB被氧化成各种酚类代谢产物，同时在盲肠中以及在微粒体中被全身还原为亚硝基苯（NOB）、苯羟胺（PH）、相关自由基和苯胺（AN）。基于结构和作用机制的相似性，NB可与其他动物和人类致癌性硝基芳烃及芳香胺相比较。还原型NB首先形成硝基阴离子自由基，它可与O2反应生成超氧阴离子O2*。重复给予NB会在红细胞（RBC）中产生持续的氧化还原对NOB<==>PH，生成高铁血红蛋白并消耗NAD(P)H。NOB形成活性谷胱甘肽（GSH）共轭物。这些生化效应可能导致关键的氧化还原失衡和大分子结合。已知的NB效应包括含铁血黄素沉着症、高铁血红蛋白血症和贫血，以及现在在啮齿动物中出现的分散性癌症。基于动物、代谢和构效关系研究，确定NB通过任何暴露途径都可能是人类致癌物。
