Role of Mutagenicity in Asbestos Fiber-Induced Carcinogenicity and Other Diseases

Abstract

The cellular and molecular mechanisms of how asbestos fibers induce cancers and other diseases are not well understood. Both serpentine and amphibole asbestos fibers have been shown to induce oxidative stress, inflammatory responses, cellular toxicity and tissue injuries, genetic changes, and epigenetic alterations in target cells in vitro and tissues in vivo. Most of these mechanisms are believe to be shared by both fiber-induced cancers and noncancerous diseases. This article summarizes the findings from existing literature with a focus on genetic changes, specifically, mutagenicity of asbestos fibers. Thus far, experimental evidence suggesting the involvement of mutagenesis in asbestos carcinogenicity is more convincing than asbestos-induced fibrotic diseases. The potential contributions of mutagenicity to asbestos-induced diseases, with an emphasis on carcinogenicity, are reviewed from five aspects: (1) whether there is a mutagenic mode of action (MOA) in fiber-induced carcinogenesis; (2) mutagenicity/carcinogenicity at low dose; (3) biological activities that contribute to mutagenicity and impact of target tissue/cell type; (4) health endpoints with or without mutagenicity as a key event; and finally, (5) determinant factors of toxicity in mutagenicity. At the end of this review, a consensus statement of what is known, what is believed to be factual but requires confirmation, and existing data gaps, as well as future research needs and directions, is provided.

Acknowledgments

This review article is part of the “Asbestos Workshop: A Science-Based Examination of the Mode of Action of Asbestos and Related Mineral Fibers” funded by NIEHS. This work was supported in part by grants from the National Institutes of Health R01-ES05786-12, Superfund P42 ES10349, NIEHS Center Grant ES09089 (TKH), and a Merit Review grant from the Department of Veterans Affairs (DWK). We thank David Bernstein, Thomas Hesterberg, Morton Lippmann, Roger McCellan, Günter Oberdörster, and Haining Yang for their critical reading of the draft article.