Framework Analysis for the Carcinogenic Mode of Action of Nitrobenzene

Abstract

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.

^†These authors contributed equally to this work.

Key words:

• Carcinogenesis
• Epigenetic
• Free radicals
• Genotoxicity
• Inflammation
• Methylation
• Mode of action
• Nitrobenzene

DISCLAIMER: The views and opinions expressed in this article are exclusively those of the authors and are not to be construed as the views or opinions of the U.S. Environmental Protection Agency. This work was supported in part by fellowships from the Japan Society for the Promotion of Science (Invitational Research Fellowship to CHH and a Bilateral Exchange Fellowship to MB).

Notes

^†These authors contributed equally to this work.

^a All tumor incidences in this table displayed statistically significant, dose-related trends in the Cochran-Armitage test (p < 0.05).

^b Only combined numbers reported by study authors (CIIT, 1993).

^c ND = no data.