Mechanisms of Genotoxicity of Particles and Fibers

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.

Inhibitory effect of silver nanoparticles mediated by atmospheric pressure air cold plasma jet against dermatophyte fungi

“…This may result in reduction in viability of the fungal cells and consequently diminish keratinase production. The literature proves the importance of reactive particle surface in ROS generation (Vallyathan & Shi, 1997;Schins, 2002). ROS are produced from the surface of nanoparticles when both the oxidants and free radicals attach to the particle surface.…”

Expression of the T Cell Receptor Vβ Repertoire in a Human T Cell Resistant to Asbestos-Induced Apoptosis and Peripheral Blood T Cells from Patients with Silica and Asbestos-Related Diseases

“…There have been many studies concerning asbestosinduced apoptosis in these cells. Experimentally, these cells have undergone apoptosis on a relatively high-level, short-term exposure to asbestos via the production of ROS and RNS with activation of the mitochondrial apoptotic pathway (2)(3)(4). Thus, it has been considered that during low-level and long-term exposure to asbestos in the human body, alveolar epithelial and mesothelial cells escape from these apoptotic pathways due to genetic changes and undergo malignant transformation (2)(3)(4).…”

Titanium dioxide (respirable fraction) [MAK Value Documentation, 2009]

“…In summary it can be said that although the contribution of the pulmonary epithelial cells to their (oxidant-transmitted) mutagenesis and autocrine stimulation of proliferation cannot be excluded, its quantitative influence is, however, far below that of the phagocytes (Dalton et al 1999;Schins 2002;Schins and Donaldson 2000;Schins and Knaapen 2007).…”