Genotoxicity Versus Carcinogenicity: Implications from Fiber Toxicity Studies

Our plain-English summary of Genotoxicity Versus Carcinogenicity: Implications from Fiber Toxicity Studies, by T.K. Hei, A. Xu, D. Louie, et al (Inhalation Toxicology, 2000).

The study

• Authors: T.K. Hei, A. Xu, D. Louie, Y.L. Zhao
• Journal: Inhalation Toxicology
• Published: 2000;12 Suppl 3:141-7
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Although the association between exposure to asbestos fibers and the development of lung cancer and mesothelioma has been well established in humans, the carcinogenic potential of other natural and man-made fibers/particles is not clear. Various in vitro genotoxicity studies have been employed to assess their in vivo carcinogenic potential. Studies using mammalian cell models have suggested that fiber dimensions, surface properties, physical durability, and cell and tissue responses are important criteria for the carcinogenicity of the fibers. Studies using oncogenic transformation as an endpoint have shown that asbestos fibers can induce malignantly transformed foci in certain rodent cells and that oxygen radicals are important in the toxic, oncogenic transforming, and mutagenic effects of asbestos fibers. The mutagenicity of asbestos in mammalian cells have been demonstrated using several model systems that can detect large multilocus deletions. These findings provide a direct link between chromosomal abnormalities that have frequently been demonstrated in fiber-exposed human and rodent cell lines and carcinogenicity in vivo. Although asbestos has not been shown to malignantly transform primary human epithelial cells, it can induce neoplastic conversion of immortalized human bronchial epithelial cells in a stepwise fashion and provides a unique opportunity to assess the molecular alterations associated with each stage of the neoplastic process.

In plain English

This article is a review of laboratory (in vitro) studies on whether fibers damage genes and chromosomes, and how that relates to their ability to cause cancer. Much of it summarizes earlier work, including the authors' own group's work. That earlier work found that crocidolite and chrysotile caused mutations in human-hamster hybrid (AL) cells, mostly large deletions, and that tremolite and erionite, which contain little or no iron, were also mutagenic in these cells. In one experiment shown in the article, a drug that blocks cells from engulfing fibers (cytochalasin B) significantly reduced chrysotile-induced mutations in AL cells. The review also described an earlier study in which a 7-day chrysotile treatment changed immortalized human bronchial cells step by step into tumor-forming cells. It reported that refractory ceramic fiber (RCF-1) was less reactive than crocidolite or chrysotile in these tests. The authors noted that some test systems may not reflect how human cells become cancerous. The authors concluded that genotoxicity does not necessarily equal carcinogenicity in all cases.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of in vitro fiber genotoxicity and cell transformation studies, mainly earlier published work. It includes one presented laboratory experiment (Figure 1) on blocking phagocytosis in cultured cells.
• Who was studied: Cultured cells, not people. These included human-hamster hybrid (AL) cells, immortalized human bronchial epithelial (BEP20) cells, normal human mesothelial cells, and rodent cell systems such as C3H10T1/2 and Syrian hamster embryo cells.
• Exposure: Mineral and man-made fibers: crocidolite, chrysotile, amosite, tremolite, erionite, glass fibers and refractory ceramic fiber (RCF-1). The Figure 1 experiment used UICC chrysotile, with or without cytochalasin B.
• Main results:
  • Earlier work by the authors' group found that both crocidolite and chrysotile were mutagenic in AL cells and induced mostly deletions involving millions of base pairs.
  • In AL cells exposed to chrysotile, concurrent cytochalasin B (which inhibits cells from engulfing fibers) significantly reduced the fiber-induced CD59- mutant yield (p less than 0.05). At the 2 microgram per square centimeter dose, it brought the mutant yield down to a level similar to cytochalasin B alone.
  • Tremolites and erionites, which contain little or no iron, were reported to be mutagenic in AL cells. The authors took this to suggest that fiber-cell interaction may be an important prerequisite for fiber mutagenesis.
  • A cited earlier study found that amosite treatment extended the proliferative life span of 4 out of 16 primary human mesothelial cell cultures, but these cells eventually all senesced and entered crisis.
  • Earlier work by the authors' group found that a single 7-day chrysotile treatment transformed immortalized human bronchial epithelial (BEP20) cells into tumor-forming cells in a stepwise fashion. The tumorigenic cells showed no mutation in any ras oncogene. In cell fusion studies, fusion with nontumorigenic control cells completely suppressed their tumorigenic phenotype.
  • Asbestos was described as not oncogenic transforming in C3H10T1/2 cells but largely active in Syrian hamster embryo cells.
  • RCF-1 fibers were reported to be less biologically reactive than crocidolite or chrysotile. Results in the tabulated cell tests were negative or weak.
• The authors' conclusion: The authors concluded that in vitro genotoxicity data help identify fiber properties that affect cancer-causing ability in the body, but genotoxicity does not necessarily equate to carcinogenicity in all cases. They described fiber carcinogenicity as a complex interplay of many factors.
• Limitations the authors state:
  • Transformed Syrian hamster embryo cells are largely not immortalized, which the authors said calls into question their relevance to how human cells become cancerous.
  • No primary human cell model was available for studying asbestos transformation, because the human cell transformation frequency is too low to reproduce in a laboratory.

Topics

Medical terms in this study, explained in our Lexicon: Genotoxicity, Lung Cancer, Mesothelioma, Carcinogenic, Fiber Dimensions.

Related studies

• Mechanisms of the genotoxicity of crocidolite asbestos in mammalian cells: implication from mutation patterns induced by reactive oxygen species — A. Xu, H. Zhou, et al. (2002)
• Ferruginous bodies: implications in the mechanism of fiber and particle toxicity — A.J. Ghio, A. Churg, et al. (2004)
• Ferritin adsorption on amosite fibers: possible implications in the formation and toxicity of asbestos bodies — B. Fubini, F. Barceló, et al. (1997)
• Genotoxicity and carcinogenicity risk of carbon nanotubes — S. Toyokuni (2013)
• Cellular and molecular mechanisms of asbestos carcinogenicity: implications for biopersistence — J.C. Barrett (1994)
• Comments on "Dimensions of elongated mineral particles with implications for pathogenicity and classification as asbestiform versus cleavage fragments" — M.M. Finkelstein (2019)

Browse more research in Inhalation Toxicology, or return to medical research.