Mechanistic in vitro studies: What they have told us about carcinogenic properties of elongated mineral particles (EMPs)

Our plain-English summary of Mechanistic in vitro studies: What they have told us about carcinogenic properties of elongated mineral particles (EMPs), by B.T. Mossman (Toxicology and Applied Pharmacology, 2018).

The study

• Author: B.T. Mossman
• Journal: Toxicology and Applied Pharmacology
• Published: 2018;361:62-67
• Type of article: Review
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

In vitro studies using target and effecter cells of mineral-induced cancers have been critical in determining the mechanisms of pathogenesis as well as the properties of elongated mineral particles (EMPs) important in eliciting these responses. Historically, in vitro models of 'mutagenesis' and immortalized cell lines were first used to test the theory that EMPs were mutagenic to cells, and 'genotoxicity', as defined as damage to DNA often culminating in cell death, was observed in a dose-dependent fashion as responses of many cell types to a number of EMPs. As two-stage and multi-step models of cancer development emerged in the 1970s and 1980s, differentiated 3D organ cultures and monolayers of lung epithelial and mesothelial cells were used to probe the mechanisms of cancer development. These studies demonstrated a spectrum of pre-neoplastic changes, including hyperplasia and squamous metaplasia, in response to long (>5 μm in length) needlelike EMPs whereas long, curly chrysotile fibers caused acute cytotoxicity. Shorter fibers of many types were taken up by cells and encompassed in phagolysosomes. Comparative studies using chemical carcinogens showed that chemical agents interacted directly with DNA whereas long EMPs appeared to be promoters of cancers via a number of mechanisms such as inflammation, generation of oxidants, and instigation of cell division. The multitude of these signaling cascades and epigenetic mechanisms of both lung cancers and mesotheliomas have been most recently studied in normal or telomerase immortalized human cells. Importantly, many of these pathways are elicited by long, straight amphibole asbestos fibers or carbon nanotubes in rodents and not by short (<5 μm) EMPs, fragments, or nonfibrous particles. However, the chemistry and surface properties of long fibers are also critical in cell responses to minerals.

Copyright © 2018. Published by Elsevier Inc.

In plain English

This was a single-author narrative review of in vitro cell and organ culture research on how elongated mineral particles (EMPs) may cause lung cancers and mesotheliomas. It reported that asbestos of various types tested negative in many mutagenesis and transformation models and was categorized as not interacting directly with DNA, although mutations occurred at cell-killing concentrations through reactive oxygen species. It reported that long fibers (greater than 5 micrometres) of any type were more toxic than equal masses of short fibers; that in tracheal organ cultures long fibers produced hyperplasia and squamous metaplasia while mineral fragments were inactive; that long chrysotile fibers caused cell death; and that dose-response studies showed thresholds below which gene expression and cell division did not increase. The author concluded that in vitro and rodent tumor models do not mimic differences in fiber type, potency and durability seen in human mesotheliomas, because of their shorter time frame. The author also concluded that these models have confirmed the importance of long fiber length in a number of carcinogenic and fibrogenic cell responses. The author discloses paid consultation for plaintiffs and defendants in asbestos litigation.

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 (cell and organ culture) mechanistic studies
• Who was studied: Not a study of people; the review covered published in vitro work using target and effector cells of mineral-induced cancers (lung/tracheobronchial epithelial cells, mesothelial cells, macrophages, rodent and human cell lines, organ cultures)
• Exposure: Elongated mineral particles including crocidolite, chrysotile and amosite asbestos, erionite, synthetic vitreous/glass fibers, carbon nanotubes, and nonfibrous fragments (riebeckite, antigorite), compared by fiber length, type and dose
• Main results:
  • The review reported that asbestos was classed as not interacting directly with DNA, after negative results in several mutagenesis and transformation models
  • Mutations by chrysotile in a hamster-human cell model occurred only at lethal fiber concentrations, with large DNA deletions, attributed to reactive oxygen species
  • Long fibers were more toxic to cells than equal mass amounts of short fibers, for all fiber types
  • In tracheal organ cultures, long fibers caused pre-neoplastic changes while mineral fragments did not
  • Long amphibole or synthetic vitreous fibers allowed cells to proliferate over them, whereas long chrysotile fibers killed cells
  • Dose-response experiments indicated thresholds for gene expression and cell division responses to fibers
  • Reported iron-related oxidant mechanisms for crocidolite and amosite
  • Reported that global DNA hypomethylation of human mesothelial (MET5A) cells led to malignant transformation in cited work
• The authors' conclusion: The author concluded that in vitro studies and rodent tumor models do not mimic the differences in fiber type, potency and durability observed in human mesotheliomas because of their shorter time frame, but have elucidated and confirmed the importance of long (greater than 5 micrometres) fiber length in a number of carcinogenic and fibrogenic cell responses
• Limitations the authors state:
  • The author stated that in vitro and rodent tumor models do not reproduce the fiber type, potency and durability differences seen in human mesotheliomas, because of their shorter time frame
  • The author stated that many older studies did not identify the asbestos type or source and used only one concentration, making interpretation difficult
  • The author stated the link between cytotoxicity and carcinogenicity is speculative
  • The author noted that toxicity rankings between fiber types differ depending on whether fibers are compared by weight or by fiber number per cell
  • The author noted that glass fibers also caused aneuploidy and transformation of rodent cells, which questions the relevance of those findings to human carcinogenesis, and that fiber interaction with mitotic cells or chromosomes has not been seen in vivo

Topics

Medical terms in this study, explained in our Lexicon: Carcinogenic, Genotoxicity, Mesothelial Cells, Chrysotile, Phagolysosome, Inflammation, Lung Cancer, Mesothelioma.

Related studies

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• Analysis and identification of elongated mineral particles in road coated aggregates — E. Leocat, C. Rielland, et al. (2018)
• Measuring EMPs in the lung what can be measured in the lung: Asbestiform minerals and cleavage fragments — V.L. Roggli (2018)
• A comparison of asbestos fiber potency and elongate mineral particle (EMP) potency for mesothelioma in humans — D.H. Garabrant, S.T. Pastula (2018)
• Dimensions of elongated mineral particles: a study of more than 570 fibers from more than 90 cases with implications for pathogenicity and classification as asbestiform vs. cleavage fragments — V.L. Roggli, C.L. Green (2019)
• Comments on "Dimensions of elongated mineral particles with implications for pathogenicity and classification as asbestiform versus cleavage fragments" — M.M. Finkelstein (2019)

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