Validity of the Lymphocyte Cytokinesis-Block Micronucleus Assay (L-CBMN) as biomarker for human exposure to chemicals with different modes of action: A synthesis of systematic reviews

Our plain-English summary of Validity of the Lymphocyte Cytokinesis-Block Micronucleus Assay (L-CBMN) as biomarker for human exposure to chemicals with different modes of action: A synthesis of systematic reviews, by M. Kirsch-Volders, M. Fenech, C. Bolognesi (Mutation Research. Genetic Toxicology and Environmental Mutagenesis, 2018).

The study

• Authors: M. Kirsch-Volders, M. Fenech, C. Bolognesi
• Journal: Mutation Research. Genetic Toxicology and Environmental Mutagenesis
• Published: 2018;836(Pt A):47-52
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Recently fourteen systematic reviews applying the same selection and evaluation criteria analyzed the induction of micronuclei in lymphocytes as biomarker for DNA damage induced by human exposure to a given chemical or chemical mixture. The results obtained in the individual reviews were summarized to evaluate the validity of the Cytokinesis-Block-Micronucleus assay in lymphocytes (L-CBMN) and propose recommendations for its use in occupational and environmental exposure studies. All systematic reviews found consistent increases of MN frequencies in exposed subjects versus controls in all genotoxic compounds or group of chemicals investigated, in the following decreasing order: As/Cr/Ni, vinyl chloride, formaldehyde, Hg/Pb/Cd, "miscellaneous", pesticides, cytostatics/antineoplastics, anaesthetic gasses, dust/asbestos/other fibers, polycyclic aromatic hydrocarbons, ethylene oxide, butadiene, styrene and petroleum/derivatives. Two reviews compared the results with the recommended exposure limits. For styrene, MN was found not to be induced under the recommended threshold limit. For vinyl chloride the safe exposure limit based on the L-CBMN data is lower than the current one. The L-CBMN thus appears to be a valid biomarker to assess DNA damage in populations exposed to genotoxic chemicals. Many shortcomings have been reported in assessment of confounding factors, such as lifestyle patterns, in particular diet and the major one the exposure assessment. All these factors together with methodological variables may contribute to the large variability in MN frequencies, also in controls. Information on frequency and origin of MN in more than one tissue (e.g. lymphocytes and buccal cells) in parallel, may provide better understanding of the mechanisms involved. Use of automated MN scoring systems to increase numbers of cells scored and facilitate screening more individuals would increase data reliability and provide information on the link between mutagenicity and carcinogenicity, if the studies are done prospectively. Efforts should be made to unravel the genotoxic effects induced when chronic and/or mixed exposures are involved.

Copyright © 2018 Elsevier B.V. All rights reserved.

In plain English

This article was a synthesis of fourteen earlier systematic reviews. It was not a new study of workers. Each review had looked at a blood test, the lymphocyte cytokinesis-block micronucleus assay (L-CBMN). The test counts micronuclei, small pieces of chromosome or whole chromosomes that end up outside a cell's main nucleus, as a sign of DNA damage. The reviews compared people exposed to a chemical or chemical group with unexposed controls. All fourteen reviews found consistent increases in micronucleus frequency in exposed people. One review covered dust, asbestos and other fibers. It included 15 studies with 707 exposed people and 705 controls. In that group, micronucleus frequency was on average 1.8 times that of controls (range 0.9 to 3.1). The article did not name specific fiber types. That review concluded the test should be used together with other measures. The authors concluded that the assay is a suitable and reliable biomarker of DNA damage. They noted weak exposure assessment and differences between the underlying studies.

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: Synthesis (summary) of fourteen systematic reviews, some with meta-analyses, on the L-CBMN assay in people exposed to chemicals
• Who was studied: Fourteen systematic reviews (thirteen in a 2016 special issue of Mutation Research, plus a 2017 review on vinyl chloride). They covered studies of occupational and some environmental exposures and evaluated between 7 and 47 studies each. For dust, asbestos and other fibers, one review (Bonassi et al 2016) covered 15 studies with 707 exposed people and 705 controls.
• Exposure: Fourteen chemical groups: arsenic, chromium and nickel; vinyl chloride; formaldehyde; mercury, lead and cadmium; a miscellaneous group (coal, dyes, paints, organic solvents); pesticides; cytostatic/antineoplastic drugs; anaesthetic gases; dust, asbestos and other fibers; polycyclic aromatic hydrocarbons; ethylene oxide; butadiene; styrene; and petroleum and its derivatives. No specific asbestos fiber types were named.
• Main results:
  • Every systematic review found a consistent increase in micronucleus frequency in exposed people compared with controls, for every chemical group studied.
  • Micronucleus frequency was doubled or more in exposed people compared with controls for: arsenic, chromium and nickel (3.4-fold); vinyl chloride (2.9-fold); formaldehyde (2.4-fold); mercury, lead and cadmium (2.3-fold); the miscellaneous group (2.2-fold); pesticides (2.1-fold); and cytostatic/antineoplastic drugs (2.0-fold).
  • Dust, asbestos and other fibers (Bonassi et al 2016): mean fold change in micronucleus frequency, exposed compared with controls, was 1.8 plus or minus 0.6 (range 0.9 to 3.1). This was based on 15 studies with 707 exposed people and 705 controls, and a mean quality score of 17.0 plus or minus 3.9 (range 11 to 23).
  • For dust, asbestos and other fibers, the review's conclusion on micronuclei as a biomarker was that the test should be integrated with other endpoints.
  • Except for the ethylene oxide review, the review authors considered the L-CBMN assay a good to excellent biomarker for the exposure they studied.
  • Statistically significant positive correlations with micronucleus frequency were found for duration of exposure to formaldehyde, intensity of exposure to butadiene, and both intensity and duration of exposure to vinyl chloride.
  • For styrene, micronuclei were not induced below the recommended exposure limit of 1 ppm or less. For vinyl chloride, the safe exposure limit based on the assay data was lower than the current limit.
• The authors' conclusion: The authors concluded that the L-CBMN assay is a suitable and reliable biomarker for DNA damage in people exposed to genotoxic chemicals. They said exposure assessment and the measurement of confounders such as diet and BMI urgently need improvement, and that automated scoring would add reliability.
• Limitations the authors state:
  • All the reviews identified heterogeneity among the underlying studies, especially in the number of participants and in exposure assessment. The authors called exposure assessment the major issue.
  • Few studies assessed the origin of micronuclei. As a result, it was not possible to tell how much came from whole chromosomes versus chromosome fragments.
  • Diet was often neglected as a confounder. Some studies did not follow the harmonized protocol for cytochalasin-B treatment or for the number of cells scored, which might affect statistical power.

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Systematic Review, Micronuclei, Individual Review, Environmental Exposure, Confounding.

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