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PubMed2004

Effects of asbestos and smoking on the levels and rates of change of lung function in a crocidolite exposed cohort in Western Australia.

BACKGROUND: Increased rates of death from asbestos related diseases have been reported in former workers and residents exposed to crocidolite (blue asbestos) at Wittenoom, Western Australia. Exposure to asbestos is associated with reduced static lung volumes, gas transfer and lung compliance, and a restrictive ventilatory abnormality. METHODS: The effects of crocidolite exposure and smoking history on levels and rates of change of lung function were evaluated using a linear mixed model. Lung function was measured as forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC. RESULTS: Cumulative doses of asbestos and the presence of radiographic asbestosis were associated with lower levels of FEV1 and FVC and a steeper decline during the period of observation. Subjects exposed to asbestos at a younger age had lower levels of FEV1 and FVC. Current smokers had lower levels and a steeper decline in lung function than never smokers. No significant interactions between crocidolite exposure and smoking on the levels or rates of change of lung function were found. CONCLUSIONS: The deleterious effects of crocidolite exposure on lung function persist in this population, despite asbestos exposure having ceased more than 30 years ago. No significant interactions were found in this population between asbestos and smoking at the first visit or longitudinally.

Asbestos, Crocidolite↗

PubMed2003

Asbestos induces mitochondrial DNA damage and dysfunction linked to the development of apoptosis.

To test the hypothesis that asbestos-mediated cell injury is mediated through an oxidant-dependent mitochondrial pathway, isolated mesothelial cells were examined for mitochondrial DNA damage as determined by quantitative PCR. Mitochondrial DNA damage occurred at fourfold lower concentrations of crocidolite asbestos compared with concentrations required for nuclear DNA damage. DNA damage by asbestos was preceded by oxidant stress as shown by confocal scanning laser microscopy using MitoTracker Green FM and the oxidant probe Redox Sensor Red CC-1. These events were associated with dose-related decreases in steady-state mRNA levels of cytochrome c oxidase, subunit 3 (COIII), and NADH dehydrogenase 5. Subsequently, dose-dependent decreases in formazan production, an indication of mitochondrial dysfunction, increased mRNA expression of pro- and antiapoptotic genes, and increased numbers of apoptotic cells were observed in asbestos-exposed mesothelial cells. The possible contribution of mitochondrial-derived pathways to asbestos-induced apoptosis was confirmed by its significant reduction after pretreatment of cells with a caspase-9 inhibitor. Apoptosis was decreased in the presence of catalase. Last, use of HeLa cells transfected with a mitochondrial transport sequence targeting the human DNA repair enzyme 8-oxoguanine DNA glycosylase to mitochondria demonstrated that asbestos-induced apoptosis was ameliorated with increased cell survival. Studies collectively indicate that mitochondria are initial targets of asbestos-induced DNA damage and apoptosis via an oxidant-related mechanism.

Animals↗

PubMed1993

Asbestos exposure increases human bronchial epithelial cell fibrinolytic activity.

Chronic exposure to asbestos fibers results in fibrotic lung disease. The distal pulmonary epithelium is an early target of asbestos-mediated injury. Local plasmin activity may be important in modulating endoluminal inflammatory responses in the lung. We studied the effects of asbestos exposure on cell-mediated plasma clot lysis as a marker of pericellular plasminogen activation. Exposing human bronchial epithelial (HBE) cells to 100 micrograms/ml of asbestos fibers for 24 h resulted in increased plasma clot lysis. Fibrinolytic activity was augmented in a dose-dependent fashion, was not due to secreted protease, and occurred only when there was direct contact between the plasma clot and the epithelial monolayer. Further analysis showed that asbestos exposure increased HBE cell-associated urokinase-type plasminogen activator (uPA) activity in a time-dependent manner. The increased cell-associated PA activity could be removed by acid washing. The increase in PA activity following asbestos exposure required new protein synthesis because it was abrogated by treatment with either cycloheximide or actinomycin D. Therefore, asbestos exposure increases epithelial-mediated fibrinolysis by augmenting expression of uPA activity at the cell surface by mechanisms that require new RNA and protein synthesis. These observations suggest a novel mechanism whereby exposure of the distal epithelium to inhaled particulates may result in a chronic inflammatory response that culminates in the development of fibrotic lung disease.

Asbestos↗

PubMed1994

Dibutyryl cAMP attenuates asbestos-induced pulmonary epithelial cell cytotoxicity and decline in ATP levels.

Adenosine 3',5'-cyclic monophosphate (cAMP) analogues prevent lung injury in various models by mechanisms that remain unknown. We speculated that cAMP attenuates asbestos-induced pulmonary epithelial cell injury by limiting the effects of an oxidant stress. Agents that increase intracellular cAMP [dibutyryl cAMP (DBcAMP), terbutaline, or aminophylline] but not guanosine 3',5'-cyclic monophosphate (cGMP) attenuated WI-26 cell-specific 51Cr release caused by asbestos. The protective effects of DBcAMP were associated with negligible alterations in asbestos-induced .OH formation or decline in WI-26 cell glutathione levels. Cycloheximide, an inhibitor of protein synthesis, failed to diminish the effects of DBcAMP. ATP levels were measured to determine whether the effects of DBcAMP are due to preservation of cellular ATP. Asbestos caused dose-dependent reductions in cellular ATP and DB-cAMP attenuated these effects. To determine whether the protective effects of DBcAMP related to alterations in WI-26 cell growth, we assessed the effects of DBcAMP on WI-26 cell number over time. DBcAMP diminished WI-26 cell replication and increased the doubling time. These results demonstrate that DBcAMP diminishes asbestos-induced cytotoxicity to cultured WI-26 cells in part by maintaining intracellular ATP levels and inhibiting cellular replication. The reduction in asbestos-induced WI-26 cell injury occurs despite a persistent oxidant stress. The data suggest a novel strategy to limit pulmonary toxicity from asbestos that warrants further investigation.

Adenosine Triphosphate↗

PubMed2004

The gamma-glutamylcysteine synthetase and glutathione regulate asbestos-induced expression of activator protein-1 family members and activity.

Asbestos fibers cause persistent increases in activator protein-1 (AP-1) family member proto-oncogenes in lung epithelial and mesothelial cells that are linked to proliferation and cell transformation. Using lung epithelial cells, the progenitor cells of lung cancers, we report that crocidolite asbestos initially depletes intracellular glutathione followed by up-regulation of both catalytic and modifier subunits of gamma-glutamylcysteine synthetase. In vivo asbestos inhalation experiments confirm increased protein levels of gamma-glutamylcysteine synthetase in mouse lungs. We also show that asbestos-induced mRNA levels of fos/jun proto-oncogenes, fra-1 transactivation, and AP-1 to DNA binding activity are glutathione-dependent. Epidermal growth factor receptor activity by asbestos is blocked by N-acetyl-l-cysteine, suggesting that it is an initial redox-activated event leading to downstream AP-1 proto-oncogene up-regulation. The overexpression of subunits of gamma-glutamylcysteine synthetase in combination completely blocked asbestos-induced up-regulation of AP-1 proto-oncogene expression. However, when overexpressed individually, the modifier subunit had more dramatic effects than the catalytic subunit. Our work shows that the glutathione-controlled redox status of the epithelial cell plays a pivotal role in asbestos-induced epidermal growth factor receptor and proto-oncogene activation as well as AP-1 activity.

Acetylcysteine↗

PubMed2006

A novel SV40 TAg transgenic model of asbestos-induced mesothelioma: malignant transformation is dose dependent.

Although it has been clear for >40 years that mesothelioma can be caused by asbestos, not all patients with this disease have a history of asbestos exposure. Other factors, including non-asbestos fibers and ionizing radiation, are known to cause malignant transformation of mesothelial cells. In addition, it is likely that genetics will play some role in susceptibility. Recently, it has been suggested that SV40 viral oncogenes could contribute to the carcinogenicity of asbestos. To better understand the role of SV40, we used the mesothelin promoter to construct MexTAg mice that express SV40 large T antigen (TAg) in the mesothelial compartment. We generated four MexTAg lines that carry high, intermediate, and low copy numbers of the transgene. All of these mice show a relatively low level of spontaneous tumor development. High-copy, 299h mice rapidly developed mesotheliomas when exposed to asbestos, and these tumors were faster growing and more invasive than those developing in wild-type and single-copy (266s) mice. In addition, we found a direct relationship between transgene copy number and survival after exposure to asbestos. A single copy of TAg was sufficient to immortalize mesothelial cells in vitro, but these cells did not show evidence of malignant transformation. In contrast, cell lines developed from mesothelial cells of animals carrying multiple copies of TAg were growth factor independent and could be cloned at limiting dilution in soft agar. These data provide the first in vivo demonstration of co-carcinogenicity between SV40 and asbestos.

Animals↗

PubMed1986

What every surgeon should know regarding asbestos-related disease.

Long-lasting occupational exposure to asbestos dust may cause pleural disease, asbestosis, bronchogenic carcinoma and mesothelioma. Many years elapse from first exposure to the appearance of symptoms. Almost all these diseases are the result of dusty working conditions 20-40 years ago. The pathological sequelae are usually irreversible and can progress after exposure ceases. There is no satisfactory treatment. Prevention is the only practical way. In spite of the fact that the general public is invariably exposed to small amounts of the material, asbestos is not a public health problem. Exemptions are the buildings not properly cared for containing sprayed asbestos. But even living in such buildings is calculated to produce a negligible risk of death. Asbestos-related diseases occur where long-lasting inhalation of high amounts of fine asbestos dust has occurred. There is no evidence to indicate that ingested asbestos fibers represent a major health problem. Industry is now replacing asbestos in many products by other fibers. Natural and synthetic organic materials used in fiber cement products are unable to reach the alveoli. They are not cancerogenic and there is no reason to believe that such fibers cause chronic pulmonary disease.

Asbestos↗

PubMed1987

Morphological aspects of interactions between asbestos fibers and human mesothelial cell cytoskeleton.

The interaction of chrysotile and amphibole asbestos fibers with the cytoskeleton of cultured human mesothelial cells from nontumoral pleural effusions was studied using scanning electron and immunofluorescence microscopy. Asbestos-exposed mesothelial cells show a massive annular condensation of cytokeratin filaments, forming a concentric ring enveloping the nucleus and the phagocytosed asbestos fibers. By detergent extraction of the cells it could be shown that the asbestos fibers are in close contact with the nuclear membrane and associated with the cytoskeletal framework of the cells. An association of cytokeratin filaments with the asbestos could be observed during phagocytosis of the fibers. The disturbance of the cell cytoskeleton and the close morphologic contact between asbestos fibers and the nuclear membrane may have some relevance in explaining the well-recognized carcinogenic effects of asbestos mineral fibers.

Antibodies, Monoclonal↗

PubMed1989

Pleural mesothelial cells stimulated by asbestos release chemotactic activity for neutrophils in vitro.

The development of the pleural inflammatory response to asbestos remains poorly defined. Importantly, the role of the pleural mesothelial cell in recruitment of neutrophils to the pleural space is not known. We hypothesized that rabbit pleural mesothelial cells stimulated by asbestos fibers release chemotactic factor(s) for neutrophils. Primary cultures of rabbit pleural mesothelial cells were established, and their purity verified by the presence of keratin and hyaluronic acid mucin. Mesothelial cells in serum-free media, in the presence of 30 micrograms/ml of crocidolite asbestos, released chemotaxins for neutrophils. This activity was not dependent on the type of asbestos fiber or fiber length. It was dose-dependent until 30 micrograms/ml of asbestos. The chemotactic fractions had the ability to increase both directed and random migration of neutrophils. The chemotactic activity was not present in sonicated fractions of unstimulated mesothelial cells, nor in supernates of asbestos fibers alone. Characterization of the chemotactic activity showed that it was heat stable (56 degrees C per 30 min) and sensitive to digestion with trypsin and papain. On Sephadex G-50 chromatography, it had a molecular weight between 6,000 and 9,000. Production of the chemotactic activity was inhibitable by cycloheximide. These results demonstrate that pleural mesothelial cells can actively synthesize a protein fraction with chemotactic activity for neutrophils. Production of this mesothelial cell-derived chemotactic activity for neutrophils may play an important role in the initiation of the inflammatory response of the pleura to asbestos.

Animals↗

PubMed1995

Vitronectin enhances internalization of crocidolite asbestos by rabbit pleural mesothelial cells via the integrin alpha v beta 5.

The mechanism by which pleural mesothelial cells, the likely progenitor cells of asbestos-induced mesothelioma, recognize and internalize crocidolite asbestos is unknown. Because incubation of asbestos fibers with serum increases their association with cells, we asked whether a protein coat on asbestos increased internalization of fibers via specific cellular receptors. Coating crocidolite with citronectin, but not with fibronectin or other proteins, increased fiber internalization by rabbit pleural mesothelial cells, as measured by a new technique using fluorescence confocal microscopy. Receptors for vitronectin, alpha v beta 3 and alpha v beta 5, were identified on mesothelial cells. Inhibiting vitronectin receptors by plating cells on a vitronectin substrate or incubating cells with excess soluble vitronectin reduced internalization of vitronectin-coated crocidolite. Inhibition of alpha v beta 5, but not alpha v beta 3, with blocking antibodies similarly reduced internalization. In addition, alpha v beta 5, but not alpha v beta 3, showed immunocytochemical colocalization with fibers. Of biologic relevance, coating crocidolite with serum also increased internalization via alpha v beta 5, an effect dependent on the vitronectin in serum. We conclude that pleural mesothelial cells recognize and internalize vitronectin- and serum-coated asbestos via the integrin alpha v beta 5. Since integrins initiate some of the same signaling pathways as does asbestos, our findings may provide insights into the mechanisms of asbestos-induced biologic effects.

Amino Acid Sequence↗

PubMedDate not supplied

Scientific controversy and asbestos: making disease invisible.

Despite irrefutable evidence that asbestos causes asbestosis, lung cancer, and mesothelioma, asbestos mining, milling, and manufacturing continue. The authors discuss three scientific debates over the roles of fiber types, viruses, and genetics in the development of mesothelioma. While these controversies might appear internal to science and unconnected to policies of the global asbestos industry, they argue that scientific debates, whether or not fostered by industry, play a central role in shaping conceptualization of the problem of asbestos-related disease. In South Africa, India, and elsewhere, these controversies help to make the disease experience of asbestos-exposed workers and people in asbestos-contaminated communities invisible, allowing the asbestos industry to escape accountability for its practices.

Asbestos↗

PubMedDate not supplied

Canadian asbestos: a global concern.

The impact of the chrysotile (white asbestos) industry at home and abroad was the focus of the first independent conference on asbestos to be held in Canada. In September 2003, Canadian asbestos victims and international experts met to examine a wide range of issues on Capital Hill, Ottawa; victims and their relatives spoke eloquently of the devious means used by asbestos stakeholders to maintain control of the national asbestos agenda. At the conclusion of the conference, Ban Asbestos Canada, a campaigning group to assist victims and raise awareness of Canada's tragic asbestos legacy, was formed.

Asbestos↗

PubMedDate not supplied

Asbestos exposures during reprocessing of automobile brakes and clutches.

Asbestos exposures of workers in three small factories reprocessing automobile brakes and clutches in Japan were investigated. Airborne asbestos was collected on a membrane filter using an air sampler. From 1982 to 1989, asbestos counting was performed on 295 samples (198 personal and 97 stationary), using phase contrast microscopy. Only chrysotile asbestos was detected. Workers who reprocessed automobile brakes and clutches were exposed to asbestos concentrations of 0.025-76.4 fibers/cm3. Geometric mean asbestos concentrations during attaching linings to brake shoes and attaching facings to clutch disks were 0.859 fibers/cm3 and 0.780 fibers/cm3, respectively. Concentrations during stripping worn brake linings and clutch facings were 0.484 fibers/cm3 and 0.382 fibers/cm3, respectively. Machine grinding and leveling of new brake-lining surfaces represent potential sources of heavy asbestos exposures, unless enclosures and local ventilation are efficient.

Asbestos, Serpentine↗

PubMed1996

Relevance of asbestos bodies in sputum.

The presence of asbestos bodies (ABs) in sputum specimens of individuals with occupational asbestos exposure has been well-documented. The aim of this study was to determine their clinical relevance in comparison to the concentration of AB in bronchoalveolar lavage (BAL) and lung tissue. Subjects were included following a well-documented exposure of asbestos history (n = 93) or BAL fluid analysis positive for ABs (n = 42). The subjects with a well documented history of AB exposure were divided into three groups: heavy (Group 1, n = 29); moderate (Group 2, n = 31); or occasional exposure (Group 3, n = 33). BAL fluid was available from all subjects, and lung tissue from 21 subjects. To assess the variability, 10 sputum positive subjects collected subsequent sputum on days 2, 7, 14, 30 and 90. ABs were determined by light microscopy after membrane filtration of specimen digests. The mean sputum AB content was highest in Group 1 (2.4 +/- 5.5 AB.mL-1), lower in Group 2 (0.2 +/- 0.3 AB.mL-1) and lowest in Group 3 (0.1 +/- 0.1 AB.mL-1) suggesting a correlation with cumulative exposure. However, many negative sputum samples were noted, when BAL specimens were positive. The AB content of sputum and BAL specimens did not correlate. ABs were found in sputum of all subjects with a tissue content of > 1,000 AB-cm-3, but in none with contents of < 1,000 AB-cm-3. Substantial variability of ABs was found in the five sequentially collected sputa of 10 initially positive patients (coefficient of variation 28-93%), but only two false negatives were found in these 50 samples. Thus, sputum analysis for asbestos bodies is an insensitive method for assessing the lung asbestos burden, much less sensitive than bronchoalveolar lavage fluid analysis. However, a sputum sample positive for asbestos bodies is suggestive of a high lung asbestos burden.

Aged↗

PubMed2006

Measurements of asbestos burden in tissues.

Asbestos inhaled into the lung is recognized as a potential causal agent for the development of diseases in man. The diseases induced by asbestos include lung cancer, fibrosis of the lung (asbestosis), and extrapulmonary tumors including mesothelioma (a tumor of the serosal membrane), as well as fibrosis and other changes in the pleura linings. The cause of these diseases can often be more specifically linked to asbestos exposure once tissue burden of asbestos is established. The asbestos burden in tissue can be defined as the number of asbestos bodies and/or the numbers and types of asbestos fibers found in the tissue. In either of these cases the quality of information is directly dependent on the preparative techniques and instrumentation used in the analysis. The present article will discuss the significance of findings of tissue burden based on both these variables.

Asbestos↗

PubMed2004

The asbestos cancer epidemic.

The asbestos cancer epidemic may take as many as 10 million lives before asbestos is banned worldwide and exposures are brought to an end. In many developed countries, in the most affected age groups, mesothelioma may account for 1% of all deaths. In addition to mesotheliomas, 5-7% of all lung cancers can be attributed to occupational exposures to asbestos. The asbestos cancer epidemic would have been largely preventable if the World Health Organization (WHO) and the International Labor Organization (ILO) had responded early and responsibly. The WHO was late in recognizing the epidemic and failed to act decisively after it was well under way. The WHO and the ILO continue to fail to address the problem of asbestos mining, manufacturing, and use and world trade of a known human carcinogen. Part of the problem is that the WHO and the ILO have allowed organizations such as the International Commission on Occupational Health (ICOH) and other asbestos industry advocates to manipulate them and to distort scientific evidence. The global asbestos cancer epidemic is a story of monumental failure to protect the public health.

Asbestos↗

PubMed1987

Report on cancer risks associated with the ingestion of asbestos. DHHS Committee to Coordinate Environmental and Related Programs.

This report is an assessment of all available literature that pertains to the potential risk of cancer associated with ingestion of asbestos. It was compiled by a working group to assist policy makers in the Department of Health and Human Services determine if adequate information was available for a definitive risk assessment on this potential problem and evaluate if the weight of evidence was sufficient to prioritize this issue for new policy recommendations. The work group considered the basis for concern over this problem, the body of toxicology experiments, the individual epidemiologic studies which have attempted to investigate this issue, and the articles that discuss components of risk assessment pertaining to the ingestion of asbestos. In the report, the work group concluded: that no direct, definitive risk assessment can be conducted at this time; that further epidemiologic investigations will be very costly and only possess sufficient statistical power to detect relatively large excesses in cancers related to asbestos ingestion; and that probably the most pertinent toxicologic experiments relate to resolving the differences in how inhaled asbestos, which is eventually swallowed, is biologically processed by humans, compared to how ingested asbestos is processed. The work group believes that the cancer risk associated with asbestos ingestion should not be perceived as one of the most pressing potential public health hazards facing the nation. However, the work group does not believe that information was sufficient to assess the level of cancer risk associated with the ingestion and therefore, this potential hazard should not be discounted, and ingestion exposure to asbestos should be eliminated whenever possible.

Animals↗

PubMed1974

Investigation and analysis of asbestos fibers and accompanying minerals in biological materials.

A method is described for isolating asbestos fibers contained in biological tissues. It consists in incinerating the biological material in activated oxygen at 150 degrees C, and attacking the ash by 1N HC1 for 18 hr. The residue is then filtered on a membrane covered with a carbon film. Electron microscope examination of the deposit makes it possible to determine fiber concentrations when the weight or volume of primary material is known, and to make size analyses. By x-ray diffraction, the mineralogical nature of the asbestos is determined by comparison with an aluminum reference diagram. For x-ray diffraction, a micromethod is used, with an ash sample of about 10 mug. These techniques are used for identifying and counting asbestos fibers in small fragments of lungs or other organs. It was found that asbestos fibers generally go along with other minerals which may be abundant. Most fibers found in lung are less than 5 mum long. Counts on lungs of asbestos workers give concentrations often greater than 10(7) particles per gram of dry tissue. The evolution of inhaled chrysotile seems to be different from that of amphiboles. In the case of pleural mesothelioma, a comparison of fibers within the tumor with fibers in the adjacent parenchyma shows only slight differences in the particle sizes, but marked differences in their nature, with a chrysotile enrichment in the pleural zone. Pleural plaques were analyzed in the same way. After decalcification, many small sized asbestos fibers were found. The same technique is now being used for determining ingested particles. A great number of observations concerning fiber counts, their nature and sizes, and the presence of various clays minerals will be necessary to establish the role of the different factors in the formation of lesions caused by the inhalation or the ingestion of asbestos fibers.

Asbestos↗