The role of genotoxicity in asbestos-induced mesothelioma: an explanation for the differences in carcinogenic potential among fiber types

Our plain-English summary of The role of genotoxicity in asbestos-induced mesothelioma: an explanation for the differences in carcinogenic potential among fiber types, by C.A. Barlow, L. Lievense, S. Gross, et al (Inhalation Toxicology, 2013).

The study

• Authors: C.A. Barlow, L. Lievense, S. Gross, C.J. Ronk, D.J. Paustenbach
• Journal: Inhalation Toxicology
• Published: 2013;25(9):553-67
• Type of article: Review
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The mechanism(s) underlying asbestos toxicity associated with the pathogenesis of mesothelioma has been a challenge to unravel for more than 60 years. A significant amount of research has focused on the characteristics of different fiber types and their potential to induce mesothelioma. These mechanistic studies of fiber toxicity have proceeded along two lines: those demonstrating biochemical mechanisms by which fibers induce disease and those investigating human susceptibility. Most recent studies focused on in vitro genotoxic effects induced by asbestos as the mechanism responsible for asbestos-induced disease. Although asbestos exerts a genotoxic effect at certain concentrations in vitro, a positive response in these tests does not indicate that the chemical is likely to produce an increased risk of carcinogenesis in exposed human populations. Thus far, findings from studies on the effects of fiber type in mesothelial cells are seriously flawed by a lack of a dose response relationship. The common limitation of these in vitro experiments is the lack of attention paid to the complexities of the human anatomy, biochemistry and physiology, which make the observed effects in these experimental systems difficult to extrapolate to persons in the workplace. Mechanistic differences between carcinogenic and genotoxic processes indicate why tests for genotoxicity do not provide much insight regarding the ability to predict carcinogenic potential in workers exposed to asbestos doses in the post-Occupational Safety and Health Administration era. This review discusses the existing literature on asbestos-induced genotoxicity and explains why these studies may or may not likely help characterize the dose-response curve at low dose.

In plain English

This was a review article on whether asbestos damages genetic material (genotoxicity) and how that relates to mesothelioma. The authors searched for published studies of asbestos effects on normal mesothelial cells, without limiting the search by fiber type, species or test. They reported that the literature showed that, at some dose, all forms of asbestos can be classed as genotoxic. In most laboratory cell tests, chrysotile produced effects similar to or greater than amphiboles. The authors also pooled earlier Italian and Finnish data on gene variants. Across all cases, four variants were significantly associated with increased odds of mesothelioma: GSTM1 null (OR 1.69, 95% CI 1.04–2.74), NAT2 fast acetylator (OR 1.74, 1.02–2.96), mEH low activity (OR 2.51, 1.11–5.68) and the XRCC3-T241M T/M variant (OR 5.13, 1.54–17.15). In the high exposure group, the GSTM1, NAT2 and mEH associations were not statistically significant. The authors noted that cell studies do not mimic human exposure. They concluded that it is unclear whether genotoxicity is a mechanism of asbestos cancer, because it is seen mostly at concentrations that kill cells.

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: Review article of published studies on asbestos-induced genotoxicity, including a literature search and a meta-analysis by the authors of earlier gene-variant (polymorphism) studies
• Who was studied: Published studies examining genotoxic effects of asbestos fibers in normal (non-cancer) mesothelial cells. The meta-analysis combined data from Italian and Finnish populations in four earlier studies (Dianzani 2006, Landi 2007, Neri 2005, 2006).
• Exposure: Asbestos fibers of any type in the reviewed studies (chrysotile, crocidolite, amosite or tremolite). In the meta-analysis, asbestos exposure was classified by relative magnitude (high versus low).
• Main results:
  • According to the reviewed literature, at some dose all mineral forms of asbestos can be classed as genotoxic
  • In most in vitro (cell culture) assays reviewed, chrysotile produced genotoxic effects similar to or greater than amphiboles; other assays gave negative results
  • Studies of blood lymphocytes from exposed people, reviewed by the authors, gave varied results in chromosomal aberration and DNA damage tests
  • Meta-analysis, all cases: GSTM1 null genotype was significantly associated with increased odds of mesothelioma, OR 1.69 (95% CI 1.04 to 2.74)
  • Meta-analysis, all cases: NAT2 fast acetylator genotype OR 1.74 (95% CI 1.02 to 2.96), mEH low activity genotype OR 2.51 (95% CI 1.11 to 5.68), and the XRCC3-T241M T/M variant OR 5.13 (95% CI 1.54 to 17.15) were significantly associated with increased odds of mesothelioma
  • GSTT1 null and various XRCC1 variants were not found to be associated with mesothelioma
  • When patients were stratified by asbestos exposure, the GSTM1, NAT2 and mEH associations were not statistically significant in the high exposure group
  • The XRCC3-T241M T/M variant association remained significantly increased regardless of asbestos exposure
  • The XRCC1-R399Q R/Q variant appeared confined to patients with high asbestos exposure, OR 2.08 (95% CI 1.00 to 4.33); the authors noted that the confidence interval includes parity
• The authors' conclusion: The authors concluded that, because genotoxicity is observed mostly at concentrations of asbestos that are toxic to cells, it is unclear whether genotoxicity is a mechanism of asbestos-induced cancer
• Limitations the authors state:
  • In vitro genotoxicity studies do not mimic human exposure
  • Many in vitro studies used concentrations much higher than those reaching target tissue in human exposure
  • Animal studies of mutation lacked dose-response data and fiber controls
  • Polymorphism studies of mesothelioma often have small sample sizes, which limits statistical power
  • Some studies (Hirvonen et al.) were not included in the meta-analysis because of a lack of reported information

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Genotoxicity, Mesothelioma, Carcinogenic, Carcinogenesis, Mesothelial Cells, Dose-response relationship.

Related studies

• In vitro genotoxicity data of nanomaterials compared to carcinogenic potency of inorganic substances after inhalational exposure — M. Roller (2011)
• Reduction of chrysotile asbestos-induced genotoxicity in human peripheral blood lymphocytes by garlic extract — K. Bhattacharya, S. Yadava, et al. (2004)
• Mechanisms of fiber-induced genotoxicity — M.C. Jaurand (1997)
• DNA fingerprint analysis reveals differences in mutational patterns in experimentally induced rat peritoneal tumors, depending on the type of environmental mutagen — N. Kociok, K. Unfried, et al. (1999)
• Cytotoxicity, oxidative stress and genotoxicity induced by glass fibers on human alveolar epithelial cell line A549 — V. Rapisarda, C. Loreto, et al. (2015)
• Can one assess genotoxic and carcinogenic risk of asbestos without mentioning ingested fibres? — C. Varga (2005)

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