Mechanisms of genotoxicity of particles and fibers

Our plain-English summary of Mechanisms of genotoxicity of particles and fibers, by R.P. Schins (Inhalation Toxicology, 2002).

The study

• Author: R.P. Schins
• Journal: Inhalation Toxicology
• Published: 2002;14(1):57-78
• Type of article: Review
• Cited by: 155 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

With regard to genotoxicity testing and cancer risk assessment, particles and fibers form a rather specific group among all toxicants. First, the physicochemical behavior of fibrous and nonfibrous particles is usually very different from that of nonparticulate, chemical carcinogens. Reactive oxygen species (ROS) are believed to play a major role in primary genotoxicity of particles, which may derive from their surface properties, the presence of transition metals, intracellular iron mobilization, and lipid peroxidation. Other aspects relevant to primary genotoxicity are particle size, shape, crystallinity (e.g., silica), and solubility, and may also include particle uptake, interaction with cell division machinery (e.g., asbestos), and the presence of mutagens carried with the particle (e.g., diesel exhaust particles, DEP). Excessive and persistent formation of ROS from inflammatory cells is considered as the hallmark of the secondary genotoxicity of nonfibrous and fibrous particles. Since lung inflammation is known to occur and persist only at sufficient particle dose, this secondary pathway is considered to contain a threshold (Greim et al., 2001). Identification of (mechanisms of) particle genotoxicity has been/can be achieved via (1) acellular assays, (2) in vitro tests, (3) in vivo studies, usually in mice or rats, and finally (4) biomarker studies in humans with (occupational) exposure. The significance of acellular assays and biomarker studies for risk assessment is limited, but has provided some mechanistic insights (e.g., in oxidant generating properties of quartz and asbestos) and may also contribute to hazard identification. In vitro studies have lead to identification of primary genotoxic properties of particles, whereas recent in vivo studies provide further support for the correlation between particle-induced lung inflammation and secondary genotoxicity. Proper risk assessment of particles necessitates identification of the relative impact of primary versus secondary genotoxicity in realistic exposure conditions. However, since it is impossible to discern between primary and secondary genotoxicity with current in vivo tests, concomitant in vitro assays are required to determine primary genotoxicity. In vivo tests should ideally be designed using different doses to allow dose-effect analysis for both inflammation and genotoxicity.

In plain English

This 2002 review gave an overview of how particles and fibers may damage genetic material (genotoxicity). It highlighted selected studies, mainly on quartz and amorphous silica, coal dust, diesel exhaust particles, airborne particulate matter and occasionally asbestos. The author separated "primary" genotoxicity, caused directly by the particle, from "secondary" genotoxicity, caused by reactive oxygen species from inflammatory cells, which the author said has a threshold. For asbestos, the review noted that laboratory cell tests had shown primary genotoxicity and that direct interaction with the cell-division spindle had been proposed. It also cited a study finding increased mutation frequencies in transgenic rats after asbestos was injected into the abdominal cavity, rising with dose and time. The author wrote that blood-cell studies in exposed workers may be of rather limited relevance for determining particle and fiber genotoxicity, but that these studies may be highly relevant for identifying hazards and susceptible individuals. The author concluded that animal tests cannot completely separate primary from secondary genotoxicity, so laboratory cell tests are needed, and that animal tests should use several doses to analyze inflammation and genotoxicity.

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 highlighting selected studies on mechanisms of particle and fiber genotoxicity, not a review of all available data
• Who was studied: Published acellular, cell-culture, animal and human biomarker studies, mainly on crystalline (quartz) and amorphous silica, coal dust, diesel exhaust particles and ambient particulate matter, and occasionally asbestos fibers
• Exposure: Nonfibrous and fibrous particles, including quartz, amorphous silica, coal dust, carbon black, titanium dioxide, diesel exhaust particles, ambient particulate matter and asbestos fibers
• Main results:
  • The author summarized that primary genotoxicity of particles and fibers can be caused by direct actions involving reactive oxygen species
  • Primary genotoxicity of particles had been shown in laboratory (in vitro) genotoxicity testing, with asbestos as an example
  • For asbestos fibers, a direct interaction with the mitotic spindle apparatus had been proposed as an important mechanism of primary genotoxicity
  • Because lung inflammation occurs and persists only at sufficient dose, the author stated that secondary genotoxicity contains a threshold
  • A cited observation (Jaurand, 1997) was that asbestos tested negative more often in chromosomal aberration tests that used lymphocytes than in tests using other cell types. That author hypothesized this was because lymphocytes cannot take up particles (phagocytosis)
  • In a cited transgenic-rat study (Unfried et al., 2000), mutation frequencies increased after intraperitoneal injection of asbestos (2 mg and 5 mg, 4 to 24 wk) in a dose- and time-dependent manner. The author noted it remains to be determined whether such effects are direct or due to inflammation
  • The author wrote that, although human data are not the most appropriate to determine particle genotoxicity, human biomarker studies may be highly relevant for hazard identification and for identifying susceptible individuals
  • In the author's own laboratory work with quartz in A549 cells, coating the quartz with PVNO or aluminum lactate prevented hydroxyl radical generation as well as oxidative DNA damage
  • In a cited rat inhalation study (Johnston et al., 2000), crystalline silica markedly increased mutation frequency at 13 weeks. Amorphous silica produced no increase despite a much higher lung burden and similar inflammation
• The authors' conclusion: The author concluded that current animal tests cannot completely separate primary from secondary genotoxicity. Laboratory cell tests are therefore required to determine primary genotoxicity, and animal tests should preferably use different doses to allow dose-effect analysis of both inflammation and genotoxicity.
• Limitations the authors state:
  • The article highlights selected studies rather than reviewing all available data
  • Human biomarker studies usually test blood cells, which are a surrogate rather than a target tissue, so their relevance to particle and fiber genotoxicity research may be rather limited
  • No animal test system can completely distinguish primary from secondary genotoxicity
  • Discrepancies have been found for similar materials tested with the same genotoxicity assay

Topics

Medical terms in this study, explained in our Lexicon: Genotoxicity, Reactive Oxygen Species (ROS), Inflammation, Biomarker.

Related studies

• Appropriate in vitro test conditions for genotoxicity testing of fibers — G. Speit (2002)
• A study of the effect of chrysotile fiber surface composition on genotoxicity in vitro — M.J. Keane, J.W. Stephens, et al. (1999)
• Chrysotile and rock wool fibers induce chromosome aberrations and DNA damage in V79 lung fibroblast cells — Y. Cui, J. Ma, et al. (2018)
• 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)
• Carboxylated short single-walled carbon nanotubes but not plain and multi-walled short carbon nanotubes show in vitro genotoxicity — M. Mrakovcic, C. Meindl, et al. (2015)
• Mechanisms of fiber-induced genotoxicity — M.C. Jaurand (1997)

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