NYMC Faculty Publications
DOI
https://doi.org/10.1177/23978473211055363
Journal Title
Toxicology Research and Application
First Page
1
Last Page
33
Document Type
Review Article
Publication Date
2022
Department
Pathology, Microbiology and Immunology
Second Department
Pathology, Microbiology and Immunology
Abstract
Acrylonitrile, an industrial chemical, is a multisite carcinogen in rats and mice, producing tumors in four tissues with barrier function, that is, brain, forestomach, Zymbal’s gland, and Harderian gland. To assess mechanism(s) of action (MoA) for induction of neoplasia and to evaluate whether the findings in rodents are indicative of human hazard, data on the potential key effects produced by acrylonitrile in the four rodent target tissues of carcinogenicity were evaluated. A notable finding was depletion of glutathione in various organs, including two target tissues, the brain, and forestomach, suggesting that this effect could be a critical initiating event. An additional combination of oxidative DNA damage and cytotoxic effects of acrylonitrile and its metabolites, cyanide, and 2-cyanoethylene oxide, could initiate pro-inflammatory signaling and sustained cell and tissue injury, leading to compensatory cell proliferation and neoplastic development. The in vivo DNA-binding and genotoxicity of acrylonitrile has been studied in several target tissues with no compelling positive results. Thus, while some mutagenic effects were reported in acrylonitrile-exposed rodents, data to determine whether this mutagenicity stems from direct DNA reactivity of acrylonitrile are insufficient. Accordingly, the induction of tumors in rodents is consistent primarily with a non-genotoxic MoA, although a contribution from weak mutagenicity cannot be ruled out. Mechanistic data to support conclusions regarding human hazard from acrylonitrile exposure is weak. Comparison of metabolism of acrylonitrile between rodents and humans provide little support for human hazard. Three of the tissues affected in bioassays (forestomach, Zymbal’s gland, and Harderian gland) are present only in rodents, while the brain is anatomically different between rodents and humans, diminishing relevance of tumor induction in these tissues to human hazard. Extensive epidemiological data has not revealed causation of human cancer by acrylonitrile.
Recommended Citation
Kobets, T., Iatropoulos, M. J., & Williams, G. M. (2022). Acrylonitrile Induction of Rodent Neoplasia: Potential Mechanism of Action and Relevance to Humans. Toxicology Research and Application, 6, 1-33. https://doi.org/https://doi.org/10.1177/23978473211055363
Publisher's Statement
Originally published in Toxicology Research and Application: Kobets T, Iatropoulos MJ, Williams GM. Acrylonitrile induction of rodent neoplasia: Potential mechanism of action and relevance to humans. Toxicology Research and Application. 2022;6. doi: 10.1177/23978473211055363, under CC-BY-NC.