Non-Neoplastic and Neoplastic Pleural Endpoints Following Fiber Exposure

University of California, San Francisco, San Francisco, California, USA.
Journal of Toxicology and Environmental Health Part B (Impact Factor: 4.97). 05/2011; 14(1-4):153-78. DOI: 10.1080/10937404.2011.556049
Source: PubMed


Exposure to asbestos fibers is associated with non-neoplastic pleural diseases including plaques, fibrosis, and benign effusions, as well as with diffuse malignant pleural mesothelioma. Translocation and retention of fibers are fundamental processes in understanding the interactions between the dose and dimensions of fibers retained at this anatomic site and the subsequent pathological reactions. The initial interaction of fibers with target cells in the pleura has been studied in cellular models in vitro and in experimental studies in vivo. The proposed biological mechanisms responsible for non-neoplastic and neoplastic pleural diseases and the physical and chemical properties of asbestos fibers relevant to these mechanisms are critically reviewed. Understanding mechanisms of asbestos fiber toxicity may help us anticipate the problems from future exposures both to asbestos and to novel fibrous materials such as nanotubes. Gaps in our understanding have been outlined as guides for future research.

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    • "Although macrophages play critical roles in clearance as well as inflammation and cell signaling in response to pathogenic fibers in the airways and interstitium of the lung, little is known about whether or not they are required for translocation of asbestos fibers to the pleura or are essential for pleural inflammation and genesis of pleural diseases (reviewed in [8]). For example, accumulation of fibers in localized acellular areas (pleural plaques) is observed on the pleural surface as opposed to fiber-laden alveolar macrophages and asbestos bodies (iron-coated fibers linked to accumulation and death of macrophages) in the lung [1,5,6,8]. "
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    ABSTRACT: Pleural fibrosis and malignant mesotheliomas (MM) occur after exposures to pathogenic fibers, yet the mechanisms initiating these diseases are unclear. We document priming and activation of the NLRP3 inflammasome in human mesothelial cells by asbestos and erionite that is causally related to release of IL-1beta, IL-6, IL-8, and Vascular Endothelial Growth Factor (VEGF). Transcription and release of these proteins are inhibited in vitro using Anakinra, an IL-1 receptor antagonist that reduces these cytokines in a human peritoneal MM mouse xenograft model. These novel data show that asbestos-induced priming and activation of the NLRP3 inflammasome triggers an autocrine feedback loop modulated via the IL-1 receptor in mesothelial cell type targeted in pleural infection, fibrosis, and carcinogenesis.
    Particle and Fibre Toxicology 08/2013; 10(1):39. DOI:10.1186/1743-8977-10-39 · 7.11 Impact Factor
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    • "In vitro, chrysotile was shown to be toxic, caused chromosomal aberrations and preneoplastic transformations [39]; it was reported to be the most potent inflammatory stimulus among all asbestos types [47]. At the same time, there is evidence from epidemiological studies that chrysotile is less efficient in MM induction than the amphiboles [48] [49]. Some epidemiological data favoring chrysotile have been revised at a later date [50]. "
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    ABSTRACT: Asbestos-related health risks have been evaluated on the basis of past experience, when occupational exposures were much higher; while the linear no-threshold (LNT) approach has usually been applied. However, applicability of the LNT dose-response pattern to low levels of asbestos exposure has never been proven. Asbestos-related research has been influenced by vested interests and biases. Furthermore, current evidence does not provide sufficient support for a separate approach to serpentine (chrysotile) and amphibole asbestos by official regulations, the more so as the international trade provides for mixing of different asbestos types. Carcinogenicity and other harmful properties of different asbestos fibers, and of man-made asbestos substitutes, should be tested in large-scale animal experiments. Importantly, researchers must be independent from vested interests. In the meantime, the All Fibers Equal basis for the asbestos-related regulations would be an optimal solution. Current asbestos-related policies are irrational: asbestos production and use are banned by some countries, while others are increasing the manufacturing and exports. The rules and regulations should be internationally coordinated and revised on the basis of scientific knowledge.
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    • "One experimental issue concerns the dissimilarities between the pleural cavities of different species. Despite these differences, much has been learned about the mechanisms of pleural disease, particularly the interactions between fibers and target cells, both in the pleural cavities of laboratory animals and in in vitro studies using both animal and human cells (Broaddus et al. 2011). Non pulmonary effects after asbestos exposure are not well understood. "
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    ABSTRACT: Although asbestos in general is well known to cause a range of neoplastic and non-neoplastic human health effects, not all asbestos fiber types have the same disease-causing potential, and the mode of action (MOA) of specific types of asbestos and related fibers for various health outcomes are not well understood. A workshop was held to discuss the state of the science of the MOA for asbestos-related disease. The objective was to review the range of asbestos-induced health effects (including those at sites remote to the respiratory tract). We sought to identify existing knowledge gaps and define what research is needed to address these gaps and advance asbestos research. Discussions centered on areas of uncertainty in the field, including the ways asbestos is defined and characterized, the role of different fiber characteristics (e.g., length and mineralogy) in disease, and the impact of low-dose exposures on human health. Studying the dosimetry and mode of action of multiple fiber types would enhance our understanding of asbestos-related disease. To better elucidate the MOA of specific asbestos fibers, the risk assessor requires data as to specific characteristics of asbestos in determining fiber toxicity (e.g., surface area, mineral type), which may inform efforts to assess and control exposures and prevent adverse human health outcomes for the diverse range of fiber types. Specific research aims were defined for these topics and for overarching issues to be addressed, including the use of standardized terminology, test materials, and better experimental models to aid in data extrapolation to humans. To resolve these and other issues, participants agreed that diverse scientific disciplines must coordinate to better understand the MOA leading to the various asbestos-related disease end points.
    Environmental Health Perspectives 08/2011; 119(12):1806-10. DOI:10.1289/ehp.1003240 · 7.98 Impact Factor
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