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[Studies on carcinogenicity of asbestos with special reference to interaction between viruses and cultured cells].

To investigate effects of asbestos on the process of cancer development, the capacity of asbestos which increases cellular uptake of external carcinogens was tested for asbestos-mediated viral RNA transfection in cultured cells. For the transfection, crocidolite, amosite, anthophyllite and chrysotile were placed onto Vero-E6 cells with poliovirus RNA inoculum, respectively. All asbestos samples mediated viral RNA transfection compared with the background including only viral RNA. The transfection was much greater with combined exposure to asbestos and kaolin than with exposure to asbestos alone.

Animals↗

Asbestos fibres inhibit the in vitro activity of lymphokine-activated killer (LAK) cells from healthy individuals and patients with malignant mesothelioma.

Asbestos exposure is associated with an increased incidence of several malignancies, including malignant mesothelioma (MM). This study evaluates the relationship between asbestos exposure and the in vitro generation and function of LAK cells, an immune effector cell population with powerful lytic activity against MM cells. Both serpentine (chrysotile) and amphibole (amosite and crocidolite) forms of asbestos fibres suppress LAK cell generation, viability (by 5-11%, P less than 0.02) and cell recovery (by 13-15%, P less than 0.02). However, the LAK cells generated in the presence of the amphiboles were as effective as unexposed cells in lysing both standard tumour cell targets (K562, 56.4% lysis versus 61.5%, respectively, P greater than 0.5; NS; Daudi, 60.5% lysis versus 64.5% P greater than 0.5; NS), and MM tumour cell targets (mean of three MM cell lines 48.3% versus 46.3%, P greater than 0.5; NS), whereas the function of LAK cells generated in the presence of chrysotile was significantly reduced against three out of the five tumour cell targets tested (P less than 0.03). In the presence of asbestos fibres, LAK cell function was reduced against all five tumour cell targets (P less than 0.01), irrespective of whether the cell donors were healthy individuals or patients with MM. NK cell activity was also suppressed (P less than 0.01). The serpentine form of asbestos, chrysotile, was significantly more suppressive of both effector cell functions than either of the amphiboles (P less than 0.01). These findings suggest that asbestos exposure may suppress the function and in some instances the generation of immune effector cell mechanisms, thereby increasing the risk of disease and malignancy.

Asbestos↗

Involvement of protein kinase C, phospholipase C, and protein tyrosine kinase pathways in oxygen radical generation by asbestos-stimulated alveolar macrophage.

Although asbestos stimulates oxygen radical generation in alveolar macrophages, the exact mechanism is still not clear. The purpose of this study was to compare the ability of three asbestos fibers (amosite, chrysotile, and crocidolite) to generate oxygen radicals in macrophages and examine the mechanism of this action. All asbestos fibers were able to induce chemiluminescence but chrysotile induced maximal chemiluminescence at higher concentrations than amosite and crocidolite. Protein kinase C (PKC) inhibitors (sphingosine and staurosporine) suppressed the ability of asbestos to induce oxygen radical generation. Phospholipase C (PLC) inhibitors (U73122 and neomycin) and protein tyrosine kinase (PTK) inhibitors (erbstatin and genistein) decreased oxygen radical generation of asbestos-stimulated alveolar macrophages. Oxygen radical generation was not suppressed by an adenylate cyclase activator (forskolin), a protein kinase A inhibitor (H-8), and a protein serine-threonine phosphatase inhibitor (okadaic acid). PLC and PTK inhibitors suppressed the increment of phosphoinositide turnover by amosite. These results suggest that asbestos fibers induce the generation of oxygen radicals through PTK, PLC, and PKC pathways in a dose-response pattern.

Animals↗

Mesotheliomas--asbestos exposure and lung burden.

The assessment of asbestos fibres in the lungs at post mortem in groups of mesotheliomas, groups occupationally exposed to asbestos, and controls has shown that all these groups contain significant levels of asbestos as a lung burden. The amounts in each group are dependent on the degree of past exposure, being highest in those cases with a known or extrapolated occupational exposure, less in those cases with recorded neighbourhood or environmental exposure, and less again in those cases with no evidence of exposure to asbestos and in controls. Relative risk estimates and the use of models developed for occupational situations do not provide good estimates of the relevance of environmental fibres in producing mesotheliomas in the general population. This may be the result of differences between the groups in their time periods of exposure and long-term elimination of asbestos from the lungs. The number of mesotheliomas that might be due to low-level environmental exposure to asbestos cannot be determined from lung contents alone, but an assessment based on detailed occupational histories from the Australian Mesothelioma Surveillance Program show that the problem is not one of great importance when compared with other public health issues.

Air Pollutants↗

Biological effects of asbestos: New York Academy of Sciences 1964.

BACKGROUND: In 1964, the New York Academy of Sciences held a conference on asbestos that was to promote the slow decline in the fortunes of asbestos. It brought together a Who's Who of international scientists who had conducted and reported on experimental and human studies of the effects of asbestos. Very little new data were presented at the conference, but by bringing together a compendium of knowledge of the adverse effects of asbestos, it served further notice to asbestos-using industry of the major public health problem that they had created. With the assistance of its employees and certain scientists, industry mounted public relations exercises to counter the adverse publicity of lung cancer and malignant mesothelioma. Attempts were made to minimize the impact of these diseases by suggesting that their alleged associations with asbestos were spurious, and by diversionary ad hominem attacks on Professor Irving J. Selikoff who had played an important role in the organization of the conference. METHODS: Consideration of the contents of the meeting program, other previously published information and documents revealed through legal discovery by Chase Manhattan Bank provide the sources on which this paper is based. CONCLUSIONS: Today, asbestos is no longer seen as a material indispensable on technical grounds and a mainstay of industry and the economy. Its progressive banning in developed countries may be seen as the consequence of the momentum initiated in New York in 1964.

Academies and Institutes↗

Finnish Institute of Occupational Health (FIOH): prevention and detection of asbestos-related diseases, 1987-2005.

BACKGROUND: Between 1987 and 1992, the Finnish Institute of Occupational Health (FIOH) initiated and implemented the Asbestos Program that aimed at reducing asbestos-related risks. It was a cooperative effort between government authorities, labor market organizations, and health care and labor protection personnel. METHODS: During the Program and its follow-up since 1993 several preventive actions were taken, and considerable new legislation and official instructions were issued. RESULTS: Approximately 200,000 people in Finland have been exposed to asbestos in their work. Through the cooperative efforts of government, labor, health care and worker protection programs, the import of asbestos was ceased in 1993 with a few exceptions. Almost all imports ceased in 2005 following European Union directives. Regulation of asbestos abatement companies has been greatly increased. The occupational exposure limit has been reduced from 2.0 fibers/cm(3) to the present 0.1 fibers/cm(3). Asbestos-related diseases are closely monitored and education of health care providers regarding the occupational source of these conditions is now emphasized. CONCLUSIONS: The success of the primary goal of the Program, a reduction in asbestos-related morbidity, will not be fully realized for many decades.

Asbestos↗

Incremental value of oblique chest radiographs in the diagnosis of asbestos-induced pleural disease.

To assess the value of oblique chest radiographs in the diagnosis of asbestos-related pleural disease, we identified 100 asbestos-exposed construction workers and provided separate interpretations of the postero-anterior (PA), left anterior oblique (LAO), and right anterior oblique (RAO) projections using the International Labour Office (ILO) system. We found that the LAO projection identified left-sided pleural thickening more effectively than the PA view and the RAO view improved diagnosis of right-sided disease comparably. Of 62 cases of bilateral pleural thickening, only 43 (68%) were diagnosed by the PA projection alone. The increased diagnostic efficiency of approximately 50% in identifying bilateral pleural thickening appears to justify the routine use of oblique chest films in screening asbestos-exposed populations. Since bilateral pleural thickening among asbestos-exposed workers is an indicator of significant asbestos exposure and increased risk of other asbestos-induced conditions, early detection of this abnormality can lead to interventions designed to reduce asbestos-related morbidity and mortality.

Adult↗

Comparative epidemiology of men exposed to asbestos and man-made mineral fibers.

Comparative analyses are presented of selected studies of long-term reactions to occupational exposures to asbestos and man-made mineral fibers (MMMF), with emphasis on studies with dose-response information and long enough period of follow-up to observe lung cancer excess, if it occurred. Uniform dose estimates based on average number of fibers per milliliter were derived and tabulated with the corresponding standard mortality (or morbidity) ratio (SMR), crude probability for each unfavorable outcome, and the likelihood that at least as many deaths would have occurred as a result of the expected numbers under Poisson assumptions. A dose-response relationship was said to have been indicated when the crude probability increased monotonically with dose and/or the Poisson probability decreased and reached a value of less than 0.05. Some arbitrary assumptions had to be made in estimation of the dose, and they may need to be corrected. Gravimetric dose estimates may have given different results. Studies selected for analysis included Quebec asbestos miners and asbestos cement workers exposed to asbestos, and pooled U.S. and European studies of MMMF workers, as well as a sample of cigarette-smoking fiberglass workers whose X-ray films were evaluated for fine nodular or irregular opacities. The lowest dose capable of showing either a statistically significant excess (single point criterion--SP) or the median dose in an apparent dose-response relationship with cause of death or radiological results is tabulated. Radiological changes show a dose-response relationship for all types, with a median dose for asbestos of 2.8 fibers/ml. For fiberglass workers, the median dose of electron-microscopically detected fibers was two orders of magnitude less. For asbestos SP, exposures of 1.4 to 22 fibers/ml were associated with increased lung cancer, while for mineral wool, the minimal level with significant SP increase in lung cancer was an order of magnitude less. Based on fiber or particle counts, man-made mineral fibers appear to be more potent than asbestos with regard to chronic pulmonary disease.

Asbestos↗

Asbestos fibers in human pulmonary and extrapulmonary tissues.

The association between asbestos fibers in human lung tissues and those in other extrapulmonary organs was studied by analysing three autopsied cases, one of whom had a high pulmonary asbestos burden, one an intermediate burden, and one a low burden. The amount, types and sizes of asbestos fibers in the tissues of lung, liver, spleen, pancreas, kidney, and gastrointestinal tract were identified and measured by transmission electron microscopy equipped with an energy dispersive X-ray analyser. The following results were obtained: 1) The concentrations of asbestos fibers in extrapulmonary organs tended to increase with that in lung tissues. 2) The types of fibers identified in lungs were approximately consistent with those in other organs. 3) A relatively large range of fiber length was observed in both lungs and other organs. The findings extend and support previous light microscopic studies comparing asbestos bodies in various organs, and may imply that persons with high levels of asbestos in their lungs are also likely to have the same types and high levels of asbestos in their other tissues.

Aged↗

Occupational asbestos exposure and mesothelioma risk in Los Angeles County: application of an occupational hazard survey job-exposure matrix.

We evaluated the newly available National Institute for Occupational Safety and Health (NIOSH) National Occupational Hazard Survey (NOHS) job exposure matrix (JEM) by considering mesothelioma risk from asbestos exposure. We applied this system (NOHS-JEM) to the Los Angeles County Cancer Surveillance Program (CSP) to see how many cancer cases could be assigned asbestos exposure and how asbestos exposure affected mesothelioma risk. Using the same CSP data, our "experts" classified asbestos exposure simply by occupation and industry. Both exposure classifications were divided into low and high; the NOHS-JEM by the number of exposed people per couplet, and ours by judgements of intensity. Odds ratios (OR) for mesothelioma risk for low and high asbestos exposure for the NOHS-JEM were 2.0 (95% C.I. 1.2-3.4) and 2.5 (95% C.I. 1.2-4.8). For ours, corresponding risks were 1.6 (95% C.I. 1.1-2.4) and 6.3 (95% C.I. 2.5-15.1). Our system was able to assign more cases to couplets then the NOHS-JEM (35,895 to 22,369). Three limitations of the NOHS-JEM were that many occupation-industry couplets were not classified at all, many couplets associated with past asbestos exposure (before the 1972-1974 NOHS survey) were not classified as asbestos exposure, and no assessment of intensity was made. These limitations may apply to other exposures and should be carefully considered before the NOHS-JEM is applied to other case-control studies.

Adolescent↗

Asbestos-related mesothelioma in Monfalcone, Italy.

The Monfalcone area, in northeastern Italy, is a small industrial territory (population about 60,000), with a large shipyard. Between October 1979 and April 1992, ninety-two malignant mesotheliomas were diagnosed at the Monfalcone Hospital. The series included 84 men and 8 women, aged 42 to 89 years (median age 68 years). There were 89 pleural and 3 peritoneal tumors. Seventy patients (69 men and 1 woman) had worked in the shipyards; six were seamen, and four insulators. Five men had been exposed to asbestos in various industries; six women had histories of domestic exposure, and one woman had a history of possible environmental exposure. The latency periods (intervals between first exposure to asbestos and diagnosis of the tumor) ranged from 20 to 65 years (median 52 years). Latency periods among insulators were significantly lower than among shipyard workers, as well as lower than among the other categories (p < 0.01). Lung asbestos bodies were isolated after chemical digestion in 73 cases at necropsy, and in two cases at surgery. In necropsy cases, asbestos body burdens ranged between 100 and 10,000,000 bodies per gram of dried tissue (median 11,000). Pleural plaques were observed at necropsy in 62 out of 73 cases, and in two cases at surgery. In the time period we considered, the annual incidence rates for pleural mesothelioma were very high among male Monfalcone residents, being 189 per 100,000 among people aged 75 years or more. On the basis of occupational data and of objective signs (lung asbestos bodies, pleural plaques), all the cases of the present series but one (that with possible environmental exposure) were considered as asbestos-related. The role of co-factors in the development of asbestos-related mesothelioma is suggested.

Adult↗

Insulation, asbestos, smoking habits, and lung cancer cell types.

The association between occupational exposure to asbestos and histological type of lung cancer was analyzed in a multicenter hospital-based case-control study (2,871 male cases and 5,240 male controls) conducted from 1981-1991. Twenty-two percent of cases and 18% of controls were employed in asbestos-related occupations for at least 1 year. Most of these asbestos jobs were in the construction field. The odds ratio (OR) among current smokers was 1.0 [95% confidence intervals (CI) 0.9 to 1.3]; for ex-smokers, the OR was 1.4 (95% CI 1.1 to 1.6). In contrast, 10% of cases and 5% of controls self-reported that they were chronically exposed to asbestos for at least 1 year. Self-reported asbestos exposure was significantly related to all lung cancer cell types among smokers and ex-smokers, although a trend in the ORs with duration of self-reported exposure was not found for current smokers. Among 48 cases and 52 controls reporting distinct exposure to building insulation, the OR was 2.2 (95% CI 1.2 to 4.3) for current smokers, and 1.8 (95% CI 0.9 to 3.6) for ex-smokers, compared to subjects who were not exposed to building insulation and asbestos. A nonsignificant association with self-reported exposure to asbestos was observed for a small number of never smokers (eight of 83 nonsmoking cases, OR = 2.0, 95% CI 0.9 to 4.6). When examining these results and their causal implications, possible misclassification and reporting biases need to be considered.

Asbestos↗

Influence of metal ions on flavonoid protection against asbestos-induced cell injury.

Influence of metal ions (Fe2+, Fe3+, Cu2+, Zn2+) on the protective effect of rutin, dihydroquercetin, and green tea epicatechins against in vitro asbestos-induced cell injury was studied. Metals have been found to increase the capacity of rutin and dihydroquercetin to protect peritoneal macrophages against chrysotile asbestos-induced injury. The data presented here show that this effect is due to the formation of flavonoid metal complexes, which turned out to be more effective radical scavengers than uncomplexed flavonoids. At the same time epicatechins and their metal complexes have similar antiradical properties and protective capacities against the asbestos induced injury of macrophages. Metal complexes of all flavonoids were found to be considerably more potent than parent flavonoids in protecting red blood cells against asbestos-induced injury. It was also found that the metal complexes of all flavonoids were absorbed by chrysotile asbestos fibers considerably better than uncomplexed compounds and probably for this reason flavonoid metal complexes have better protective properties against asbestos induced hemolysis. Thus, the results of the present study show that flavonoid metal complexes may be effective therapy for the inflammatory response associated with the inhalation of asbestos fiber. The advantage of their application could be the strong increase in ROS scavenging by flavonoids and finally a better cell protection under the conditions of cellular oxidative stress.

Adsorption↗

Role of transcription factor NF-kappaB in asbestos-induced TNFalpha response from macrophages.

Asbestos exposure in humans is associated with inflammatory, fibrotic, and malignant diseases in the lung. Increasing evidence supports the hypothesis that the production of proinflammatory cytokines such as tumor necrosis factor-alpha (TNFalpha) is an important mediator of the pathologic responses of asbestosis. In this study, we examine the role of nuclear transcription factor-kappaB (NF-kappaB) and free oxygen radicals in asbestos-induced TNFalpha gene and protein expression in lung macrophages. Exposure of the cells to crocidolite asbestos caused a parallel increase in TNFalpha production and NF-kappaB activation, as analyzed by enzyme-linked immunosorbent assay and electrophoretic mobility shift assay. Inhibition of NF-kappaB by SN50, an inhibitor of NF-kappaB nuclear translocation, or by sequence-specific oligonucleotides directed against the NF-kappaB binding site of TNFalpha promoter attenuated the asbestos effect on TNFalpha production. Gene transfection assays using an expression plasmid containing a luciferase reporter gene and a TNFalpha-derived NF-kappaB gene promoter further indicated the dependence of NF-kappaB activation on asbestos-induced gene expression. The effects of asbestos on NF-kappaB and TNFalpha activation were inhibited by oxygen radical scavengers and were enhanced by antioxidant enzyme inhibitors. These results indicate that asbestos-induced TNFalpha gene expression is mediated through a process that involves NF-kappaB activation and free radical reactions.

Animals↗

Early inflammatory response to asbestos exposure in rat and hamster lungs: role of inducible nitric oxide synthase.

Recent studies have suggested that inducible nitric oxide synthase (iNOS) plays a role in the development of asbestos-related pulmonary disorders. The pulmonary reactions of rats and hamsters upon exposure to asbestos fibers are well known to be disparate. In addition, in vitro experiments have indicated that mononuclear phagocytes from hamsters, in contrast to those from rats, lack the iNOS pathway. Therefore, the purpose of this study was to investigate whether rats and hamsters differ in lung iNOS expression in vivo upon exposure to asbestos fibers and whether differences in iNOS induction are associated with differences in the acute pulmonary inflammatory reaction. Body weight, alveolar-arterial oxygen difference, differential cell count in bronchoalveolar lavage fluid, total protein leakage, lung myeloperoxidase activity and lipidperoxidation, wet/dry ratio, iNOS mRNA and protein expression, and nitrotyrosine staining of lung tissue were determined 1 and 7 days after intratracheal instillation of asbestos fibers in CD rats and Syrian golden hamsters. Exposure of rats to asbestos fibers resulted in enhanced pulmonary iNOS expression and nitrotyrosine staining together with an acute inflammation that was characterized by an influx of neutrophils, enhanced myeloperoxidase activity and lipid peroxidation, damage of the alveolar-capillary membrane, edema formation, and impairment of gas exchange. In comparison, instillation of asbestos fibers in hamsters resulted in a significantly milder inflammatory reaction of the lung with no induction of iNOS in pulmonary cells. The data obtained provide important information to understand the underlying mechanisms of species differences in the pulmonary response upon exposure to asbestos fibers.

Animals↗

Hyaluronan (hyaluronic acid) in lung lavage of asbestos-exposed humans and sheep.

The concentration of hyaluronan was measured in the bronchoalveolar lavage fluid (BALF) of 18 control subjects and 27 workers from the asbestos mills and mines of Québec, 9 without asbestosis and 18 with asbestosis. Hyaluronan was also measured in the BALF of 9 control sheep exposed to 100 ml phosphate-buffered saline (PBS) at 10 day intervals for 39 months, and 13 sheep exposed at the same intervals to 100 mg chrysotile in 100 ml PBS for 24 months. At month 24, the asbestos-exposed sheep were classified into 3 groups: (A) 4 sheep exposed to PBS alone, (B) 4 sheep exposed to 10 mg chrysotile asbestos every 10 days, and (C) 5 sheep exposed to 100 mg chrysotile asbestos every 10 days for 15 months. The BALF hyaluronan averaged 53.9 +/- 7.4 ng/ml in human controls, 67.5 +/- 10.3 ng/ml in asbestos-exposed workers without asbestosis, and 206 +/- 83 ng/ml in workers with asbestosis (p less than 0.05 vs. normal). In the control sheep, BALF hyaluronan was 34.7 +/- 6.9 ng/ml, and it was 31.5 +/- 17.8 ng/ml in the low-dosage asbestos-exposed group (A), 83.0 +/- 27.7 ng/ml in the intermediate-dose group (B), and 248.0 +/- 134.7 ng/ml in the high-dosage group (C) (p less than 0.05 vs. controls). In contrast, the release of plasminogen activator, a protease that may play a role in limiting the fibrotic process, was increased in group A, but not in groups B and C. In conclusion, BALF hyaluronan constitutes an indicator of lung interstitial tissue changes that may reflect the activity of the fibrosing alveolitis associated with chronic asbestos exposure.

Adult↗

Asbestos exposure according to different exposure indices among Finnish lung cancer patients.

During a 6-month period all lung cancer patients in a university hospital chest clinic were investigated for asbestos exposure by means of personal interview, bronchoalveolar lavage (BAL), roentgenograms, lung function testing, histology and measurement of fibre concentrations in lung tissue samples using scanning electron microscopy (SEM). About one-third of the patients (33%) were classified as having been exposed to asbestos on the basis of the interview. BAL was performed and AB counts were done in 51 patients. Fourteen (27%) BAL specimens had AB counts of 1 or more AB/ml, which is the conventional limit for non-trivial asbestos exposure. For a subgroup of 25 operated lung cancer patients fibre analysis was also available. In six cases (30%) the asbestos-containing samples had asbestos fibre concentrations equal to or more than 1 million fibres/g dry lung. In eight (32%) of the operated lung cancer patients histopathologically confirmed fibrosis was seen; five of these patients were in the two highest exposure classes. Pleural plaques on X-ray films were seen in six (24%) of the operated cases. With each indicator of exposure about 30% of lung cancer patients were found to have been exposed, confirming the "one-third rule"; however, when all the information was collated there were three cases (12%) in which exposure was most obvious according to the different parameters used in this study. In these three cases the cancer could well be attributed to asbestos. Anthophyllite was present in all asbestos-containing samples and anthophyllite was the main fibre type in 61% of these samples.

Adult↗

Oxidative damage on DNA induced by asbestos and man-made fibers in vitro.

We compared the potential of asbestos and man-made fibers to attack DNA by the determination of the yield of 8-hydroxy-2'-deoxyguanosine (8-OH-dGuo) under several in vitro conditions. Asbestos induced 6.6-99.8 of 8-OH-dGuo per 10(5) dGuo in calf thymus DNA after 20 h of incubation, while the levels of 8-OH-dGuo in man-made fibers were low (3.6-9.4). The amounts of 8-OH-dGuo were strongly stimulated by the addition of H2O2 in asbestos, but not in man-made fibers. However, the yield of 8-OH-dGuo was induced more than that with asbestos by the further addition of FeSO4 in attapulgite, fiberglass, potassium titanate whisker, and metaphosphate polymer. The addition of ethylene diamine tetra-acetic acid (EDTA) promoted the induction of 8-OH-dGuo with asbestos and H2O2. The effects of mannitol (known as a hydroxy radical scavenger) were not dramatic on 8-OH-dGuo induction by all fibers except fiberglass and basic magnesium sulfate whisker, which induced higher amounts after mannitol addition than in these fibers and H2O2. Therefore, it was suggested that asbestos could damage DNA, resulting in 8-OH-dGuo as a cause of point mutation, and also several types of man-made fibers had similar effects to asbestos under certain conditions.

Animals↗