Hsu Ching-Hung, Stedeford Todd, Okochi-Takada Eriko, Ushijima Toshikazu, Noguchi Hitoshi, Muro-Cacho Carlos, Holder James W, Banasik Marek
National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency. Washington, DC, USA.
J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2007 Apr-Jun;25(2):155-84. doi: 10.1080/10590500701399234.
Nitrobenzene (CASRN: 98-95-3) has been shown to induce cancers in many tissues including kidney, liver, and thyroid, following chronic inhalation in animals. However, with a few exceptions, genotoxicity assays using nitrobenzene have given negative results. Some DNA binding/adduct studies have brought forth questionable results and, considering the available weight of evidence, it does not appear that nitrobenzene causes cancer via a genotoxic mode of action. Nitrobenzene produces a number of free radicals during its reductive metabolism, in the gut as well as at the cellular level, and generates superoxide anion as a by-product during oxidative melabolism. The reactive species generated during nitrobenzene metabolism are considered candidates for carcinogenicity. Furthermore, several lines of evidence suggest that nitrobenzene exerts its carcinogenicity through a non-DNA reactive (epigenetic) fashion, such as a strong temporal relationship between non-, pre-, and neoplastic lesions leading to carcinogenesis. In this report, we first describe the absorption, distribution, metabolism, and excretion of nitrobenzene followed by a summary of the available genotoxicity studies and the only available cancer bioassay. We subsequently refer to the mode of action framework of the U.S. Environmental Protection Agency's 2005 Guidelines for Carcinogen Risk Assessment as a basis for presenting possible modes of action for nitrobenzene-induced cancers of the liver, thyroid, and kidney, as supported by the available experimental data. The rationale(s) regarding human relevance of each mode of action is also presented. Finally, we hypothesize that the carcinogenic mode of action for nitrobenzene is multifactorial in nature and reflective of free radicals, inflammation, and/or altered methylation.
已表明，动物长期吸入硝基苯（化学物质登记号：98 - 95 - 3）会诱发包括肾脏、肝脏和甲状腺在内的许多组织发生癌症。然而，除少数例外情况外，使用硝基苯进行的遗传毒性试验均得出阴性结果。一些DNA结合/加合物研究得出了可疑结果，综合现有证据来看，硝基苯似乎并非通过遗传毒性作用模式致癌。硝基苯在其还原代谢过程中，无论是在肠道还是细胞水平，都会产生多种自由基，并且在氧化代谢过程中会产生超氧阴离子作为副产物。硝基苯代谢过程中产生的活性物质被认为是致癌的候选因素。此外，有几条证据表明，硝基苯通过非DNA反应性（表观遗传）方式发挥其致癌作用，例如非肿瘤、肿瘤前期和肿瘤性病变之间导致致癌的强烈时间关系。在本报告中，我们首先描述硝基苯的吸收、分布、代谢和排泄，接着总结现有的遗传毒性研究和唯一可用的癌症生物测定。随后，我们参考美国环境保护局《2005年致癌物风险评估指南》的作用模式框架，作为依据现有实验数据提出硝基苯诱发肝脏、甲状腺和肾脏癌症可能作用模式的基础。还阐述了每种作用模式与人类相关性的基本原理。最后，我们假设硝基苯的致癌作用模式本质上是多因素的，反映了自由基、炎症和/或甲基化改变。
