asbestos--crocidolite and Mesothelioma

An earlier meta-analysis of mortality studies of asbestos-exposed worker populations, quantified excess mesothelioma and lung cancer risks in relation to cumulative exposure to the three main commercial asbestos types. The aim of this paper was to update these analyses incorporating new data based on increased follow-up of studies previously included, as well as studies of worker populations exposed predominantly to single fibre types published since the original analysis. Mesothelioma as a percentage of expected mortality due to all causes of death, percentage excess lung cancer and mean cumulative exposure were abstracted from available mortality studies of workers exposed predominantly to single asbestos types. Average excess mesothelioma and lung cancer per unit of cumulative exposure were summarised for groupings of studies by fibre type; models for pleural and peritoneal mesothelioma risk and lung cancer risk in terms of cumulative exposure for the different fibre types were fitted using Poisson regression. The average mesothelioma risks (per cent of total expected mortality) per unit cumulative exposure (f/cc.yr), R

Topics: Asbestos; Asbestos, Amosite; Asbestos, Amphibole; Asbestos, Crocidolite; Asbestos, Serpentine; Humans; Lung Neoplasms; Mesothelioma; Microscopy, Phase-Contrast; Occupational Diseases; Occupational Exposure

The term asbestos collectively refers to a group of naturally occurring fibrous minerals which have been exploited in numerous commercial and industrial settings and applications dating to antiquity. Its myriad uses as a "miracle mineral" owe to its remarkable properties of extreme resistance to thermal and chemical breakdown, tensile strength, and fibrous habit which allows it to be spun and woven into textiles. Abundant in nature, it has been mined considerably, and in all continents save Antarctica. The nomenclature concerning asbestos and its related species is complex, owing to the interest held therein by scientific disciplines such as geology, mineralogy and medicine, as well as legal and regulatory authorities. As fibrous silicates, asbestos minerals are broadly classified into the serpentine (chrysotile) and amphibole (crocidolite, amosite, tremolite, anthophyllite, actinolite) groups, both of which may also contain allied but nonfibrous forms of similar or even identical chemical composition, nonpathogenic to humans. Recently, fibrous amphiboles, not historically classified or regulated as asbestos (winchite, richterite), have been implicated in the causation of serious disease due to their profusion as natural contaminants of vermiculite, a commercially useful and nonfibrous silicate mineral. Although generally grouped, classified, and regulated collectively as asbestos, the serpentine and amphibole groups have different geologic occurrences and, more importantly, significant differences in crystalline structures and chemical compositions. These in turn impart differences in fiber structure and dimension, as well as biopersistence, leading to marked differences in relative potency for causing disease in humans for the group of minerals known as asbestos.

Topics: Asbestos; Asbestos, Amosite; Asbestos, Crocidolite; Asbestos, Serpentine; Asbestosis; Humans; Mesothelioma; Mineral Fibers

Mesothelioma is a "new" malignant disease strongly associated with exposure to amphibole asbestos exposure (amosite and crocidolite) environmentally and in the work place. Nonetheless, in recent years, we have learned that many cases of mesothelioma are idiopathic, while some are caused by therapeutic irradiation or chronic inflammation in body cavities. This paper reviews the key epidemiological features of the malignancy in the context of the biological and mineralogical factors that influence mesothelioma development. These tumors challenge the diagnostic pathologist's acumen, the epidemiologist's skill in devising meaningful and definitive studies, the industrial hygienist's knowledge of environmental hazards in diverse occupational settings, and the clinician's skill in managing an intrepid and uniformly fatal malignancy.

Topics: Asbestos, Amosite; Asbestos, Amphibole; Asbestos, Crocidolite; Asbestos, Serpentine; Female; History, 20th Century; Humans; Lung Neoplasms; Male; Mesothelioma; Mining; Occupational Diseases

The strong relationship between mesothelioma and asbestos exposure is well established. The analysis of lung asbestos burden by light and electron microscopy assisted to understand the increased incidence of mesothelioma in asbestos mining and consuming nations.The data on the occupational exposure to asbestos are important information for the purpose of compensation of occupational disease No. 4105 (asbestos-associated mesothelioma) in Germany.However, in many cases the patients have forgotten conditions of asbestos exposure or had no knowledge about the used materials with components of asbestos. Mineral fiber analysis can provide valuable information for the research of asbestos-associated diseases and for the assessment of exposure. Because of the variability of asbestos exposure and long latency periods, the analysis of asbestos lung content is a relevant method for identification of asbestos-associated diseases. Also, sources of secondary exposure, so called "bystander exposition" or environmental exposure can be examined by mineral fiber analysis.Household contacts to asbestos are known for ten patients (1987-2009) in the German mesothelioma register; these patients lived together with family members working in the asbestos manufacturing industry.Analysis of lung tissue for asbestos burden offers information on the past exposure. The predominant fiber-type identified by electron microscopy in patients with mesothelioma is amphibole asbestos (crocidolite or amosite). Latency times (mean 42.5 years) and mean age at the time of diagnose in patients with mesothelioma are increasing (65.5 years). The decrease of median asbestos burden of the lung in mesothelioma patients results in disease manifestation at a higher age.Lung dust analyses are a relevant method for the determination of causation in mesothelioma. Analysis of asbestos burden of the lung and of fiber type provides insights into the pathogenesis of malignant mesothelioma. The most important causal factor for the development of mesothelioma is still asbestos exposure.

Topics: Aged; Asbestos; Asbestos, Amosite; Asbestos, Amphibole; Asbestos, Crocidolite; Asbestos, Serpentine; Female; Germany; Humans; Lung Neoplasms; Male; Mesothelioma; Microscopy, Electron; Middle Aged; Mineral Fibers; Occupational Diseases; Occupational Exposure; Pleural Neoplasms

Asbestos has been recognised as a potential health hazard since the 1940s. Of the two major species of asbestos; white asbestos (chrysotile) and blue asbestos (crocidolite), both of which are hazardous. The workers at extraction facilities are at the greatest risk of exposure to asbestos and, therefore, the development of asbestos-related diseases, commonly mesothelioma. However, other individuals at a high risk of exposure include asbestos-cement workers, insulation workers and ship-yard workers. Environmental exposure to asbestos can occur as a result of living in areas either characterised by natural outcrops of asbestos or asbestos-related materials, or those close to asbestos-producing or -using plants. Unfortunately, man-made fibre alternatives to asbestos, such as rock and slag-wool and glass wool, have also been shown to have a detrimental effect on human health. A characteristic of mesothelioma is that there is a long latency period (20-30 years) before the signs and symptoms of the disease become apparent. In addition, diagnosis of the disease can be difficult. The use of biological markers, such as tissue polypeptide antigen, may play a useful role in the early detection of the disease in individuals at risk.

Topics: Asbestos, Crocidolite; Asbestosis; Environmental Exposure; Humans; Manufactured Materials; Mesothelioma; Mineral Fibers; Occupational Exposure; Risk Factors; Time Factors

In Australia, consumption of asbestos peaked in about 1975 at around 70,000t per year--the majority being used for asbestos cement manufacture. Chrysotile, amphibole and crocidolite have all been mined in Australia and employment records from the single company which mined most of the crocidolite deposits at Wittenoom have formed the basis of an ongoing cohort mortality study of the workforce.

Topics: Asbestos, Crocidolite; Australia; Cohort Studies; Epidemiologic Studies; Humans; Incidence; Mesothelioma; Occupational Exposure; Pleural Neoplasms

Scattered patches of crocidolite, one form of asbestos, were found in the surface soil in the rural county of Da-yao in southwestern China. In 1983, researchers from the West China University of Medical Sciences (WCUMS) discovered that residents of two villages in Da-yao had hyperendemic pleural plaques and excessive numbers of pleural mesotheliomas.. To review and summarise epidemiological studies, along with other relevant data, and to discuss the potential contribution to environmental risk assessment.. This report is based on a review of several clinical/epidemiological studies conducted by WCUMS researchers since 1984, which included one cross sectional medical examination survey, one clinical/pathological analysis of 46 cases of mesothelioma, and three retrospective cohort mortality studies. Additional information acquired from reviewing original data first hand during a personal visit along with an interview of medical specialists from Da-yao County Hospital was also incorporated.. The prevalence of pleural plaque was 20% among peasants in Da-yao over 40 years of age in the cross sectional survey. The average number of mesothelioma cases was 6.6 per year in the 1984-95 period and 22 per year in the 1996-99 period, in a population of 68 000. For those mesothelioma cases that were histology confirmed, there were 3.8 cases/year in the first period and 9 cases/year in the second. Of the 2175 peasants in this survey, 16 had asbestosis. Lung cancer deaths were significantly increased in all three cohort studies. The annual mortality rate for mesothelioma was 85 per million, 178 per million, and 365 per million for the three cohort studies, respectively. The higher exposed peasants had a fivefold increased mesothelioma mortality compared to their lower exposed counterparts. There were no cases of mesothelioma in the comparison groups where no crocidolite was known to exist in the environment. In the third cohort study, almost one of five cancer deaths (22%) was from mesothelioma. The ratio of lung cancer to mesothelioma deaths was low for all three studies (1.3, 3.0, and 1.2, respectively).. The observation of numerous mesothelioma cases at Da-yao was a unique finding, due mainly to their lifetime exposure to crocidolite asbestos. The finding of cases dying at a younger age and the relatively high ratio of mesothelioma cases to lung cancer could also be another unique result of lifetime environmental exposure to crocidolite asbestos. Although the commercial use of crocidolite has been officially banned since 1984, the incidence of mesothelioma has continued to show a steady increase, particularly among peasants. Since the latency of mesothelioma is approximately 30-40 years, the ban had little effect in the 1990s. The increased awareness and changes in diagnosis over time may also contribute to the increase. Furthermore, exposure to asbestos stoves and walls continued. The government implemented reduction of these exposures. However, from a public health standpoint, the most important issue is the complete avoidance of further exposure to asbestos.

Topics: Asbestos, Crocidolite; China; Cohort Studies; Environmental Exposure; Humans; Lung Diseases; Mesothelioma; Pleural Diseases; Residence Characteristics; Retrospective Studies; Risk Assessment; Soil

It has been more than 40 years since occupational crocidolite exposure in South African miners was found to be associated with development of malignant mesothelial tumors 30 to 40 years later. Similar cases were not seen in the amosite and chrysotile miners. Since then, epidemiological and toxicological knowledge have increased enormously, but mortality continues to rise steeply (5% to 10% per year) in most industrialized countries. Even with widespread asbestos abatement efforts, this increase is likely to continue in Western Europe and the United State well into the next century, at least until 2020. Unregulated use of asbestos in less industrialized countries may cause the epidemic to continue throughout the next century in those regions. Asbestos abatement seems to be successful as evidenced by a decline in the proportion of patients with peritoneal tumors, which are the most common malignancies in heavily exposed individuals. Whereas in the 1960s peritoneal tumors comprised up to 30% of the total, in recent years the proportion has fallen to about 10%, This changing ratio could also be due to the steady increase in pleural tumors. The difficulty in formulating the connection as to the etiology of mesothelioma resulted from an unforeseeable difference in the carcinogenicity of various asbestos and mineral fiber types and was compounded by the very long latency of the disease. Unfortunately, the use of a single term, "asbestos," to describe at least five fibrous silicate minerals, each with unique physical, chemical, and biological properties and not infrequently and naturally admixed, severely hampered scientific investigation into the occupational health risks. The field became confused and filled with debate. At the heart of the fiber type controversy lies a fundamentally differing view of the importance of biopersistence of various asbestos fibers in carcinogenesis. This review will deal with the epidemiology of mesothelioma with particular attention to the studies that elucidate the impact of various asbestos fiber types on the etiology of the disease.

Topics: Asbestos; Asbestos, Amphibole; Asbestos, Crocidolite; Case-Control Studies; Cohort Studies; Global Health; Humans; Lung Neoplasms; Mesothelioma; Occupational Diseases; Occupational Exposure; Pleural Neoplasms

Primary malignant mesothelial tumours were recognized by pathologists before asbestiform minerals (chrysotile, crocidolite and amosite) were mined commercially. The discovery, 40 yrs ago, of a causal link with crocidolite and the wide-ranging epidemiological studies which followed are the subject of this review. Early case-control and descriptive surveys, supplemented by cohort studies in insulation workers and chrysotile miners, quickly demonstrated major occupational and geographical differences, with high risk in naval dockyard areas and in the heating trades. In the 1980s, reliable cohort surveys showed that in mining and in the manufacture of asbestos products the mesothelioma risk was much higher when exposure included crocidolite or amosite than chrysotile alone. However, qualitative and quantitative information on exposure was too often inadequate for this evidence to be conclusive. Well-controlled lung fibre analyses have reduced these deficiencies and demonstrated the probable implications of the greater biopersistence of amphibole fibres. Chrysotile for industrial use often contains low concentrations of fibrous tremolite, which may well explain the few cases of mesothelioma associated with this type of asbestos. Progress in this field has been much retarded by controversy, for which the 20 year gap between the availability of reliable estimates of risk for the mining of chrysotile and that for crocidolite or amosite may have been largely responsible.

Topics: Asbestos; Asbestos, Amosite; Asbestos, Amphibole; Asbestos, Crocidolite; Asbestos, Serpentine; Carcinogens; Case-Control Studies; Cohort Studies; Female; History, 20th Century; Humans; Lung Neoplasms; Male; Mesothelioma; Mineral Fibers; Mining; Occupational Diseases; Reproducibility of Results; Risk Factors

Malignant mesothelioma occurred in a female Aborigine after environmental exposure to asbestos. All known cases of the disease in Aborigines in Western Australia were reviewed; all occurred in Pilbara residents. Most were exposed while involved in the transport of asbestos from the Wittenoom crocidolite operation. Based on recent estimates of the size of the Aboriginal population in the Pilbara region, their incidence of this disease (250 per million for ages 15 and over) is one of the highest population-based rates recorded.

Topics: Adult; Aged; Asbestos, Crocidolite; Carcinogens; Female; Humans; Lung Neoplasms; Male; Mesothelioma; Middle Aged; Mining; Native Hawaiian or Other Pacific Islander; Occupational Exposure; Western Australia

The authors briefly reviewed the literature concerning the risk factors for primary pleural tumors in humans. The results from the most relevant studies emphasize the fact that the large majority of mesotheliomas are associated with exposure to asbestos or asbestiform fibers. Exposure to asbestos is mainly through industrial use, and mesotheliomas result from occupational, para-occupational, or environmental exposure. Fibers of crocidolite, amosite, and chrysotile appear to be, in descending order, more carcinogenic for pleural tissues. The authors summarize the available data on consumption of asbestos and asbestos-based products in Italy. The chrysotile-asbestos mine in Balangero (Piedmont) stimulated the industrial production of asbestos-cement; asbestos has been largely sprayed among shipyards and user for insulating railroad coaches and carriages. Italy had the greatest consumption of crocidolite in Europe, which was not banned until 1986. The authors discuss the major findings derived from descriptive epidemiological data presented in previous papers dealing with this issue. In addition, standardized mortality rates of primary pleural tumors for European countries are shown. A clearly increasing trend for mortality is observed in Italy, which has also the provinces with the highest mortality rates in Europe. Among Italian provinces, the mortality rates are consistent with the number of asbestosis cases receiving workman's compensation. The authors present the results of both cohort and case-control analytical studies performed in Italy, and provide suggestions for further research.

Topics: Asbestos; Asbestos, Amosite; Asbestos, Crocidolite; Asbestos, Serpentine; Asbestosis; Construction Materials; Europe; Female; Humans; Italy; Lung Neoplasms; Male; Mesothelioma; Occupational Diseases; Pleural Neoplasms; Prevalence; Risk Factors

Topics: Asbestos; Asbestos, Amosite; Asbestos, Crocidolite; Asbestos, Serpentine; Canada; Humans; Lung Neoplasms; Maximum Allowable Concentration; Mesothelioma; New Zealand; Occupational Diseases; Risk; South Africa; United Kingdom; United States

Our aim was to describe a vitamin A-based cancer prevention program for former asbestos workers and to check for possible harmful effects by comparing rates of disease and death in study subjects with subjects who chose not to join. All subjects had been occupationally exposed to crocidolite at Wittenoom Gorge between 1943 and 1966; 1,677 subjects indicated interest in the program and 1,203 joined between June 1990 and May 1995. Comparison subjects consisted of 996 former workers known to be alive in Western Australia in 1990 who did not join the program. Program subjects were provided with annual supplies of vitamin A (either synthetic beta-carotene or retinol), help in quitting smoking and dietary advice. The comparison group received only mail contact. Both groups were followed up to December 1994 for vital status and cancer information, and rates of cancer and death from various causes were compared. Mortality in both groups was higher than expected (standardised mortality ratio 1.23 in program subjects and 1.67 in comparison subjects). After adjustment for age, smoking and asbestos exposure, the relative rates in participants compared with non-participants was below I for all examined cancers and causes of death. For mesothelioma and lung cancer, group differences increased with time from entry, whereas other differences dissipated with time. No significant side effects were reported. In conclusion, program participants had significantly lower mortality than non-participants, but the rates of the 2 groups converged with time.

Topics: Adult; Aged; Aged, 80 and over; Anticarcinogenic Agents; Asbestos, Crocidolite; Female; Humans; Lung Neoplasms; Male; Mesothelioma; Middle Aged; Myocardial Ischemia; Occupational Exposure; Vitamin A

Former blue asbestos workers known to be at high risk of asbestos-related diseases, particularly malignant mesothelioma and lung cancer, were enrolled in a chemo-prevention program using vitamin A. Our aims were to compare rates of disease and death in subjects randomly assigned to beta-carotene or retinol. Subjects were assigned randomly to take 30 mg/day beta-carotene (512 subjects) or 25,000 IU/day retinol (512 subjects) and followed up through death and cancer registries from the start of the study in June 1990 till May 1995. Comparison between groups was by Cox regression in both intention-to-treat analyses and efficacy analyses based on treatment actually taken. Median follow-up time was 232 weeks. Four cases of lung cancer and 3 cases of mesothelioma were observed in subjects randomised to retinol and 6 cases of lung cancer and 12 cases of mesothelioma in subjects randomised to beta-carotene. The relative rate of mesothelioma (the most common single cause of death in our study) for those on retinol compared with those on beta-carotene was 0.24 (95% CI 0.07-0.86). In the retinol group, there was also a significantly lower rate for death from all causes but a higher rate of ischaemic heart disease mortality. Similar results were found with efficacy analyses. Our results confirm other findings of a lack of any benefit from administration of large doses of synthetic beta-carotene. The finding of significantly lower rates of mesothelioma among subjects assigned to retinol requires further investigation.

Topics: Adult; Aged; Aged, 80 and over; Anticarcinogenic Agents; Asbestos, Crocidolite; beta Carotene; Female; Humans; Incidence; Lung Neoplasms; Male; Mesothelioma; Middle Aged; Myocardial Ischemia; Occupational Exposure; Patient Compliance; Risk Factors; Smoking; Vitamin A

While all forms of asbestos have been determined to be carcinogenic to humans by the International Agency for Research on Cancer (IARC) as well as other authoritative bodies, the relative carcinogenic potency of chrysotile continues to be argued, largely in the context of toxic tort litigation. Relatively few epidemiologic studies have investigated only a single form of asbestos; however, one study that included an asbestos textile plant located in Marshville, North Carolina that processed chrysotile asbestos was used by the United States Environmental Protection Agency (EPA) in 2020 to help inform the agency's chrysotile asbestos risk assessment. During the EPA proceedings toxic tort defense consultants submitted comments to the EPA docket and made public presentations asserting that the Marshville plant had processed amphibole asbestos types and should not be used for the chrysotile risk assessment. A detailed evaluation of defense consultant assertions and supporting information and a full assessment of the available information concerning asbestos types used at the Marshville plant was undertaken. The preponderance of evidence continues to support the conclusion that neither amosite nor crocidolite were likely to have been processed in the Marshville textile plant. Defense consultants' assertions about chrysotile use are not supported by the preponderance of evidence and constitute an example of manipulation of information to cast uncertainty and doubt rather than to seek truth and contribute to the body of scientific evidence.

Topics: Asbestos; Asbestos, Amphibole; Asbestos, Crocidolite; Asbestos, Serpentine; Humans; Lung Neoplasms; Mesothelioma; Risk Assessment; United States; United States Environmental Protection Agency

The South African National Institute for Occupational Health (NIOH), formerly the Pneumoconiosis Research Unit, has previously milled about 544 kg of anthophyllite, crocidolite, amosite and chrysotile asbestos fibre materials. This endeavour came about in an attempt to address a recommendation, made by the International Union Against Cancer (UICC), to make asbestos standard reference samples available for research. Some of these reference samples, as well as the bulk, unprocessed materials are still within the care of the NIOH and can be obtained for the purpose of Public Health research under strict terms and conditions. Considering the hazardous nature of asbestos and regulated prohibitions imposed on this mineral, the NIOH asbestos storage facility is being subjected to various occupational and environmental control measures to ensure that any potential fibre release, and subsequent risk of exposure, are prevented.

Topics: Academies and Institutes; Asbestos; Asbestos, Crocidolite; Humans; Mesothelioma; Occupational Exposure

Prior to its termination, asbestos mining in South Africa was centred on the large crocidolite fields of the present day Northern Cape, the amosite (grunerite)-crocidolite fields of Limpopo, and chrysotile fields of Mpumalanga provinces. The legacy of these activities continues to affect surrounding communities in contemporary South Africa. The asbestos fields of Limpopo host two important former mining areas at Penge and at the Bewaarkloof near Chuenespoort. A large abandoned site is located southeast of Penge at Weltevreden, where there is no evidence of any rehabilitation. Two former mines, Lagerdraai and Uitkyk, are rehabilitated sites in an extensive string of closed mines that operated in the southern Bewaarkloof. Samples from the abandoned and rehabilitated mine sites were studied using semi-quantitative X-ray powder diffraction (XRD) to determine asbestos contamination levels in soils, and to assess distribution patterns of asbestos mineral species in the surrounding soils. Only where below detection (typically 1-3 mass%) from XRD, samples were assessed optically. The Weltevreden site, with no observable rehabilitation efforts, contrasts with the rehabilitated sites at Lagerdraai and Uitkyk. The predominant asbestiform mineral species at each site were successfully identified, with underlying geological asbestos mineral distribution trends recognised in the soils at the Bewaarkloof. Trace amounts of asbestiform minerals were identified in soils downstream of the Weltevreden mine, as well as in surrounding hillsides. The results indicate that XRD is a potentially useful tool for benchmarking sites yet to be rehabilitated as well as monitoring the effectiveness of previous rehabilitation efforts. The method is also a suitable first-pass for target areas that may require more detailed, time-consuming, and costly analysis.

Topics: Asbestos; Asbestos, Amosite; Asbestos, Crocidolite; Asbestos, Serpentine; Humans; Mesothelioma; Soil; South Africa

Asbestos mining operations have left South Africa with a legacy of asbestos contamination and asbestos-related diseases continue to be a problem. The large-scale mining of three types of asbestos presents a unique opportunity to study malignant mesothelioma of the pleura (mesothelioma) in South Africa. This study aimed to describe the demographics of deceased individuals diagnosed with mesothelioma and explore any associations between the histological morphology of mesothelioma and asbestos characteristics. We reviewed the records of all deceased miners and ex-miners from the Pathology Automation System (PATHAUT) database of the National Institute of Occupational Health (NIOH) that were histologically diagnosed with mesothelioma in the period from January 2006-December 2016 (11 years). The study population does not include all cases of mesothelioma in South Africa but rather those that reached the compensation system. Crocidolite asbestos fibres were identified in the majority of mesothelioma cases (

Topics: Asbestos; Asbestos, Crocidolite; Female; Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Mining; Occupational Diseases; Occupational Exposure

Early events in an experimental model of mesothelioma development include increased levels of editing in double-stranded RNA (dsRNA). We hypothesised that expression of endogenous retroviruses (ERV) contributes to dsRNA formation and type-I interferon signaling. ERV and interferon stimulated genes (ISGs) expression were significantly higher in tumor compared to non-tumor samples. 12 tumor specific ERV ("MesoERV1-12") were identified and verified by qPCR in mouse tissues. "MesoERV1-12" expression was lower in mouse embryonic fibroblasts (MEF) compared to mesothelioma cells. "MesoERV1-12" levels were significantly increased by demethylating agent 5-Aza-2'-deoxycytidine treatment and were accompanied by increased levels of dsRNA and ISGs. Basal ISGs expression was higher in mesothelioma cells compared to MEF and was significantly decreased by JAK inhibitor Ruxolitinib, by blocking Ifnar1 and by silencing Mavs. "MesoERV7" promoter was demethylated in asbestos-exposed compared to sham mice tissue as well as in mesothelioma cells and MEF upon 5-Aza-CdR treatment. These observations uncover novel aspects of asbestos-induced mesothelioma whereby ERV expression increases due to promoter demethylation and is paralleled by increased levels of dsRNA and activation of type-I IFN signaling. These features are important for early diagnosis and therapy.

Topics: Animals; Asbestos, Crocidolite; Asbestosis; Cell Line, Tumor; Disease Models, Animal; DNA Methylation; Endogenous Retroviruses; Gene Expression Regulation, Neoplastic; Host-Pathogen Interactions; Interferon Regulatory Factors; Interferon Type I; Mesothelioma; Mice; Promoter Regions, Genetic; RNA Editing; RNA, Double-Stranded; Signal Transduction

The onset of malignant mesothelioma (MM) is linked to exposure to asbestos fibers. Asbestos fibers are classified as serpentine (chrysotile) or amphibole, which includes the crocidolite, amosite, anthophyllite, tremolite, and actinolite types. Although few studies have been undertaken, anthophyllite has been shown to be associated with mesothelioma, and tremolite, a contaminant in talc and chrysotile, is a risk factor for carcinogenicity. Here, after characterizing the length and width of these fibers by scanning electron microscopy, we explored the cytotoxicity induced by tremolite and anthophyllite in cells from an immortalized human mesothelial cell line (MeT5A), murine macrophages (RAW264.7), and in a rat model. Tremolite and short anthophyllite fibers were phagocytosed and localized to vacuoles, whereas the long anthophyllite fibers were caught on the pseudopod of the MeT5A and Raw 264.7 cells, according to transmission electron microscopy. The results from a 2-day time-lapse study revealed that tremolite was engulfed and damaged the MeT5A and RAW264.7 cells, but anthophyllite was not cytotoxic to these cells. Intraperitoneal injection of tremolite in rats induced diffuse serosal thickening, whereas anthophyllite formed focal fibrosis and granulomas on peritoneal serosal surfaces. Furthermore, the loss of Cdkn2a/2b, which are the most frequently lost foci in human MM, were observed in 8 cases of rat MM (homozygous deletion [5/8] and loss of heterozygosity [3/8]) by array-based comparative genomic hybridization techniques. These results indicate that tremolite initiates mesothelial injury and persistently frustrates phagocytes, causing subsequent peritoneal fibrosis and MM. The possible mechanisms of carcinogenicity based on fiber diameter/length are discussed.

Topics: Animals; Asbestos; Asbestos, Amphibole; Asbestos, Crocidolite; Asbestos, Serpentine; Comparative Genomic Hybridization; Cyclin-Dependent Kinase Inhibitor p15; Cyclin-Dependent Kinase Inhibitor p16; Homozygote; Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Rats; Risk Factors; Sequence Deletion

Multi-walled carbon nanotubes can be divided into two general subtypes: tangled and straight. MWCNT-N (60 nm in diameter) and MWCNT-7 (80-90 nm in diameter) are straight-type MWCNTs, and similarly to asbestos, both are carcinogenic to the lung and pleura when administered to rats via the airway. Injection of straight-type MWCNTs into the peritoneal cavity also induces the development of mesothelioma, however, injection of tangled-type MWCNTs into the peritoneal cavity does not induce carcinogenesis. To investigate these effects in the lung we conducted a 2-year comparative study of the potential carcinogenicities of a straight-type MWCNT, MWCNT-A (approximately 150 nm in diameter), and a tangled-type MWCNT, MWCNT-B (7.4 nm in diameter) after administration into the rat lung. Crocidolite asbestos was used as the reference material, and rats administered vehicle were used as the controls. Test materials were administered by intra-Tracheal Intra-Pulmonary Spraying (TIPS) once a week over a 7 week period (8 administrations from day 1 to day 50), followed by a 2-year observation period without further treatment. Rats were administered total doses of 0.5 or 1.0 mg MWCNT-A and MWCNT-B or 1.0 mg asbestos.. There was no difference in survival between any of the groups. The rats administered MWCNT-A or asbestos did not have a significant increase in bronchiolo-alveolar hyperplasia or tumors in the lung. However, the rats administered MWCNT-B did have significantly elevated incidences of bronchiolo-alveolar hyperplasia and tumors in the lung: the incidence of bronchiolo-alveolar hyperplasia was 0/20, 6/20, and 9/20 in the vehicle, 0.5 mg MWCNT-B, and 1.0 mg MWCNT-B groups, respectively, and the incidence of adenoma and adenocarcinoma combined was 1/19, 5/20, and 7/20 in the vehicle, 0.5 mg MWCNT-B, and 1.0 mg MWCNT-B groups, respectively. Malignant pleural mesothelioma was not induced in any of the groups.. The results of this initial study indicate that tangled-type MWCNT-B is carcinogenic to the rat lung when administered via the airway, and that straight-type MWCNT-A did not have higher carcinogenic potential in the rat lung than tangled-type MWCNT-B.

Topics: Air Pollutants; Animals; Asbestos, Crocidolite; Carcinogenicity Tests; Inhalation Exposure; Lung; Lung Neoplasms; Mesothelioma; Nanotubes, Carbon; Rats; Trachea

Rare biallelic

Topics: Adult; Aged; Animals; Asbestos, Crocidolite; Asbestosis; Family; Female; Genetic Predisposition to Disease; Genomic Instability; Germ-Line Mutation; Heterozygote; Humans; Incidence; Inflammation; Male; Mesothelioma; Mice; Middle Aged; RecQ Helicases

Occupational asbestos exposure occurs in many workplaces and is a well-known cause of mesothelioma and lung cancer. However, the association between nonoccupational asbestos exposure and those diseases is not clearly described. The aim of this study was to investigate cause-specific mortality among the residents of Amagasaki, a city in Japan with many asbestos factories, and evaluate the potential excess mortality due to established and suspected asbestos-related diseases. The study population consisted of 143 929 residents in Amagasaki City before 1975 until 2002, aged 40 years or older on January 1, 2002. Follow-up was carried out from 2002 to 2015. Standardized mortality ratio (SMR) with its 95% confidence interval (CI) was calculated by sex, using the mortality rate of the Japanese population as reference. A total of 38 546 deaths (including 303 from mesothelioma and 2683 from lung cancer) were observed. The SMRs in the long-term residents' cohort were as follows: death due to all causes, 1.12 (95% CI, 1.10-1.13) in men and 1.07 (95% CI, 1.06-1.09) in women; lung cancer, 1.28 (95% CI, 1.23-1.34) in men and 1.23 (95% CI, 1.14-1.32) in women; and mesothelioma, 6.75 (95% CI, 5.83-7.78) in men and 14.99 (95% CI, 12.34-18.06) in women. These SMRs were significantly higher than expected. The increased SMR of mesothelioma suggests the impact of occupational asbestos exposure among men and nonoccupational asbestos exposure among women in the long-term residents' cohort. In addition, the high level of excess mortality from mesothelioma has persisted, despite the mixture of crocidolite and chrysotile no longer being used for three or four decades.

Topics: Adult; Aged; Aged, 80 and over; Asbestos; Asbestos, Crocidolite; Asbestos, Serpentine; Cohort Studies; Humans; Japan; Lung Neoplasms; Male; Mesothelioma; Mesothelioma, Malignant; Middle Aged; Occupational Diseases; Occupational Exposure; Pleural Neoplasms

Topics: Adult; Asbestos, Crocidolite; Child; Humans; Lung Neoplasms; Mesothelioma

Topics: Adult; Asbestos, Crocidolite; Child; Humans; Lung Neoplasms; Mesothelioma

Multi-walled carbon nanotube-7 (MWCNT-7) fibers are biopersistent and have a structure similar to asbestos. MWCNT-7 has been shown to induce malignant mesothelioma when administered by intrascrotal or intraperitoneal injection in rats and mice, and an inhalation study demonstrated that rats exposed to respirable MWCNT-7 developed lung tumors. MWCNT-N, which is similar to MWCNT-7, was shown to induce both lung tumors and malignant mesothelioma in rats when administered by trans-tracheal intrapulmonary spraying (TIPS). The present study was performed to investigate the carcinogenicity of MWCNT-7 when administered by the TIPS method. Ten-week-old male F344/Crj rats were divided into 3 groups and administered 0.5 mL vehicle, 0.250 μg/mL MWCNT-7 or 0.250 μg/mL crocidolite once a week for 12 weeks (total doses of 1.5 mg/rat) and then observed for up to 104 weeks. Rats in the MWCNT-7 group began to die from pathologies associated with the development of malignant mesothelioma 35 weeks after the final TIPS administration. Overall, the incidence of malignant mesothelioma in the MWCNT-7 group was significantly higher than in the vehicle or crocidolite groups.

Topics: Animals; Asbestos, Crocidolite; Injections, Intraperitoneal; Lung; Lung Neoplasms; Male; Mesothelioma; Mesothelioma, Malignant; Nanotubes, Carbon; Pleural Neoplasms; Rats; Rats, Inbred F344; Trachea

Topics: Asbestos, Amphibole; Asbestos, Crocidolite; Asbestos, Serpentine; Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Mineral Fibers; Models, Biological

Three hundred and thirty thousand Italians arrived in Australia between 1945 and 1966, many on assisted passage schemes where the worker agreed to a 2-year unskilled employment contract. Italians were the largest of 52 migrant groups employed at the Wittenoom blue asbestos mining and milling operation. We compare mortality from asbestos-related diseases among Italian and Australian workers employed at Wittenoom.. A cohort of 6500 male workers was established from employment records and followed up at state and national mortality and cancer registries. SMRs were calculated to compare mortality with the Western Australian male population. Time-varying Cox proportional hazards models compared the risk of mesothelioma between Australian and Italian workers.. 1031 Italians and 3465 Australians worked at Wittenoom between 1943 and 1966. Duration of employment was longer for the Italian workers, although the concentration of exposure was similar. The mesothelioma mortality rate per 100 000 was higher in Italians (184, 95% CI 148 to 229) than Australians (128, 95% CI 111 to 149). The risk of mesothelioma was greater than twofold (HR 2.27, 95% CI 1.43 to 3.60) in Italians at the lowest asbestos exposure category (<10 fibre years/per mL).. A hierarchy in migration, isolation and a shortage of workers led to Italians at Wittenoom incurring higher cumulative exposure to blue asbestos and subsequently a greater rate of malignant mesothelioma than Australian workers.. Poor working conditions and disparities between native and foreign-born workers has had a detrimental and differential impact on the long-term health of the workforce.

Topics: Adult; Asbestos; Asbestos, Crocidolite; Asbestosis; Cohort Studies; Emigrants and Immigrants; Employment; Ethnicity; Female; Humans; Italy; Lung Neoplasms; Male; Manufacturing Industry; Mesothelioma; Mesothelioma, Malignant; Mining; Occupational Exposure; Proportional Hazards Models; Transients and Migrants; Western Australia; Young Adult

Malignant mesothelioma (MM) is a rare but socially important neoplasm due to its association with asbestos exposure. Malignant mesothelioma is difficult to diagnose at an early stage, yet there are no particularly effective treatments available at the advanced stage, thus necessitating efficient strategies to prevent MM in individuals already exposed to asbestos. We previously showed that persistent oxidative damage caused by foreign body reaction and affinity of asbestos both to hemoglobin and histones is one of the major pathogeneses. Accordingly, as an effective strategy to prevent asbestos-induced MM, we undertook the use of an iron chelator, deferasirox, which decreased the epithelial-mesenchymal transition in a crocidolite-induced rat MM model. However, this agent may show adverse effects. Here, we studied the effects of iron removal by phlebotomy as a realistic measure on the same rat model. We injected a total of 5 mg crocidolite i.p. to F1 hybrid rats between the Fischer-344 and Brown-Norway strains at the age of 6 weeks. We repeated weekly or biweekly phlebotomy of 6-8 mL/kg/time from 10 to 60 weeks of age. The animals were observed until 120 weeks. In male rats, phlebotomy significantly decreased the weight and nuclear grade of MM, and modestly reduced the associated ascites and the fraction of more malignant sarcomatoid subtype. Weekly phlebotomy prolonged long-term survival. Our results indicate that appropriate phlebotomy may be a practical preventive measure to attenuate the initiation and promotion capacity of asbestos towards MM by reducing iron in individuals exposed to asbestos.

Topics: Animals; Asbestos, Crocidolite; Disease Models, Animal; Iron; Lung Neoplasms; Male; Mesothelioma; Mesothelioma, Malignant; Phlebotomy; Rats; Survival Analysis; Treatment Outcome; Tumor Burden

Chronic exposure to intraperitoneal asbestos triggered a marked response in the mesothelium well before tumor development. Macrophages, mesothelial precursor cells, cytokines, and growth factors accumulated in the peritoneal lavage. Transcriptome profiling revealed YAP/TAZ activation in inflamed mesothelium with further activation in tumors, paralleled by increased levels of cells with nuclear YAP/TAZ. Arg1 was one of the highest upregulated genes in inflamed tissue and tumor. Inflamed tissue showed increased levels of single-nucleotide variations, with an RNA-editing signature, which were even higher in the tumor samples. Subcutaneous injection of asbestos-treated, but tumor-free mice with syngeneic mesothelioma tumor cells resulted in a significantly higher incidence of tumor growth when compared to naïve mice supporting the role of the environment in tumor progression.

Topics: Adaptor Proteins, Signal Transducing; Animals; Asbestos, Crocidolite; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Intracellular Signaling Peptides and Proteins; Lung Neoplasms; Macrophage Activation; Mesothelioma; Mesothelioma, Malignant; Mice; Mutation; Phosphoproteins; Polymorphism, Single Nucleotide; RNA Editing; Trans-Activators; Transcription Factors; Transcriptional Activation; Transcriptional Coactivator with PDZ-Binding Motif Proteins; YAP-Signaling Proteins

The presence of asbestos in public buildings is a legacy of past asbestos use in many developed countries. Of particular concern is the amount and current condition in schools and the vulnerability of children to mesothelioma. Our aim was to compare the risk of mesothelioma between those exposed to blue asbestos as children and as adults at Wittenoom.. Public sources were used to establish the Wittenoom residents' cohort. Mesothelioma incidence rates per 100 000 person-years at risk were derived for those first exposed to asbestos at Wittenoom as children (<15 years) or adults separately. Proportional hazards survival models examined the slope of the exposure-response relationship between asbestos exposure and incidence of mesothelioma in different sex and age groups.. The mesothelioma rate was lower among those first exposed as children (76.8 per 100 000) than those first exposed as adults (121.3 per 100 000). Adjusting for cumulative exposure to asbestos and sex, those exposed as adults had a greater risk of mesothelioma (adjusted HR 2.5, 95% CI 1.7 to 3.7). The slope of the exposure-response relationship did not differ between those exposed as children and those exposed as adults.. We found no greater susceptibility to mesothelioma among those first exposed to asbestos as children than those first exposed as adults. However, given the long latency of mesothelioma, and the greater years of life yet to be lived by the Wittenoom children, it is likely that there will be more cases of mesothelioma in the future among those first exposed as children.

Topics: Adolescent; Adult; Age Distribution; Asbestos, Crocidolite; Child; Child, Preschool; Environmental Exposure; Female; Humans; Incidence; Infant; Male; Mesothelioma; Middle Aged; Proportional Hazards Models; Sex Distribution; Western Australia; Young Adult

Exposure to asbestos fiber is central to mesothelial carcinogenesis, for which iron overload in or near mesothelial cells is a key pathogenic mechanism. Alternatively, iron chelation therapy with deferasirox or regular phlebotomy was significantly preventive against crocidolite-induced mesothelial carcinogenesis in rats. However, the role of iron transporters during asbestos-induced carcinogenesis remains elusive. Here, we studied the role of divalent metal transporter 1 (DMT1; Slc11a2), which is a Fe(II) transporter, that is present not only on the apical plasma membrane of duodenal cells but also on the lysosomal membrane of every cell, in crocidolite-induced mesothelial carcinogenesis using DMT1 transgenic (DMT1Tg) mice. DMT1Tg mice show mucosal block of iron absorption without cancer susceptibility under normal diet. We unexpectedly found that superoxide production was significantly decreased upon stimulation with crocidolite both in neutrophils and macrophages of DMT1Tg mice, and the macrophage surface revealed higher iron content 1 h after contact with crocidolite. Intraperitoneal injection of 3 mg crocidolite ultimately induced malignant mesothelioma in ∼50% of both wild-type and DMT1Tg mice (23/47 and 14/28, respectively); this effect was marginally (p = 0.069) delayed in DMT1Tg mice, promoting survival. The promotional effect of nitrilotriacetic acid was limited, and the liver showed significantly higher iron content both in DMT1Tg mice and after crocidolite exposure. The results indicate that global DMT1 overexpression causes decreased superoxide generation upon stimulation in inflammatory cells, which presumably delayed the promotional stage of crocidolite-induced mesothelial carcinogenesis. DMT1Tg mice with low-stamina inflammatory cells may be helpful to evaluate the involvement of inflammation in various pathologies.

Topics: Animals; Asbestos, Crocidolite; Carcinogenesis; Cation Transport Proteins; Epithelial Cells; Gene Expression Regulation, Neoplastic; Humans; Iron; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Mice; Mice, Transgenic

The mining of crocidolite at Wittenoom from 1943 to 1966 is infamous due to the adverse health outcomes in the mining and milling workforce and the non-mining residents and families. Proportional latency risk analysis provided estimates that 6% of the mine workforce along with 1.9% of women and 1.1% of children residents who were environmentally exposed, have or will die from mesothelioma. The absence of environmental exposure data relevant to the period restricts the extrapolation of these historical risk outcomes being applied to the low level exposures from natural contaminant crocidolite and other amphibole fibres experienced in contemporary mining practices in the Pilbara region.

Topics: Adult; Asbestos; Asbestos, Crocidolite; Australia; Child; Dust; Environmental Exposure; Female; Humans; Industry; Inhalation Exposure; Lung Neoplasms; Male; Mesothelioma; Mining; Occupational Exposure; Risk Assessment; Workforce

Germline BAP1 mutations predispose to several cancers, in particular malignant mesothelioma. Mesothelioma is an aggressive malignancy generally associated with professional exposure to asbestos. However, to date, we found that none of the mesothelioma patients carrying germline BAP1 mutations were professionally exposed to asbestos. We hypothesized that germline BAP1 mutations might influence the asbestos-induced inflammatory response that is linked to asbestos carcinogenesis, thereby increasing the risk of developing mesothelioma after minimal exposure. Using a BAP1(+/-) mouse model, we found that, compared with their wild-type littermates, BAP1(+/-) mice exposed to low-dose asbestos fibers showed significant alterations of the peritoneal inflammatory response, including significantly higher levels of pro-tumorigenic alternatively polarized M2 macrophages, and lower levels of several chemokines and cytokines. Consistent with these data, BAP1(+/-) mice had a significantly higher incidence of mesothelioma after exposure to very low doses of asbestos, doses that rarely induced mesothelioma in wild-type mice. Our findings suggest that minimal exposure to carcinogenic fibers may significantly increase the risk of malignant mesothelioma in genetically predisposed individuals carrying germline BAP1 mutations, possibly via alterations of the inflammatory response.

Topics: Animals; Asbestos, Crocidolite; Ascitic Fluid; Chemokines; Cytokines; Dose-Response Relationship, Drug; Female; Genetic Predisposition to Disease; Germ-Line Mutation; Heterozygote; Leukocytes; Macrophages, Peritoneal; Male; Mesothelioma; Mice; Mice, Inbred C57BL; Mineral Fibers; Peritoneal Neoplasms; Peritonitis; Random Allocation; Tumor Suppressor Proteins; Ubiquitin Thiolesterase

Malignant mesothelioma (MM), linked to asbestos exposure, is a highly lethal form of thoracic cancer with a long latency period, high mortality and poor treatment options. Chronic inflammation and oxidative tissue damage caused by asbestos fibers are linked to MM development. Flaxseed lignans, enriched in secoisolariciresinol diglucoside (SDG), have antioxidant, anti-inflammatory and cancer chemopreventive properties. As a prelude to chronic chemoprevention studies for MM development, we tested the ability of flaxseed lignan component (FLC) to prevent acute asbestos-induced inflammation in MM-prone Nf2(+/mu) mice. Mice (n = 16-17 per group) were placed on control (CTL) or FLC-supplemented diets initiated 7 days prior to a single intraperitoneal bolus of 400 µg of crocidolite asbestos. Three days post asbestos exposure, mice were evaluated for abdominal inflammation, proinflammatory/profibrogenic cytokine release, WBC gene expression changes and oxidative and nitrosative stress in peritoneal lavage fluid (PLF). Asbestos-exposed mice fed CTL diet developed acute inflammation, with significant (P < 0.0001) elevations in WBCs and proinflammatory/profibrogenic cytokines (IL-1ß, IL-6, TNFα, HMGB1 and active TGFß1) relative to baseline (BL) levels. Alternatively, asbestos-exposed FLC-fed mice had a significant (P < 0.0001) decrease in PLF WBCs and proinflammatory/profibrogenic cytokine levels relative to CTL-fed mice. Importantly, PLF WBC gene expression of cytokines (IL-1ß, IL-6, TNFα, HMGB1 and TGFß1) and cytokine receptors (TNFαR1 and TGFßR1) were also downregulated by FLC. FLC also significantly (P < 0.0001) blunted asbestos-induced nitrosative and oxidative stress. FLC reduces acute asbestos-induced peritoneal inflammation, nitrosative and oxidative stress and may thus prove to be a promising agent in the chemoprevention of MM.

Topics: Animals; Antioxidants; Asbestos, Crocidolite; Butylene Glycols; Chromatography, Liquid; Diet; Dietary Supplements; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Flax; Glucosides; Inflammation; Lignans; Mesothelioma; Mice; Mice, Mutant Strains; Oxidative Stress; Peritoneal Lavage; Peritoneum; Precancerous Conditions; Reverse Transcriptase Polymerase Chain Reaction; Seeds; Tandem Mass Spectrometry; Transcriptome

We have conducted a population-based study of pleural mesothelioma patients with occupational histories and measured asbestos lung burdens in occupationally exposed workers and in the general population. The relationship between lung burden and risk, particularly at environmental exposure levels, will enable future mesothelioma rates in people born after 1965 who never installed asbestos to be predicted from their asbestos lung burdens.. Following personal interview asbestos fibres longer than 5 µm were counted by transmission electron microscopy in lung samples obtained from 133 patients with mesothelioma and 262 patients with lung cancer. ORs for mesothelioma were converted to lifetime risks.. Lifetime mesothelioma risk is approximately 0.02% per 1000 amphibole fibres per gram of dry lung tissue over a more than 100-fold range, from 1 to 4 in the most heavily exposed building workers to less than 1 in 500 in most of the population. The asbestos fibres counted were amosite (75%), crocidolite (18%), other amphiboles (5%) and chrysotile (2%).. The approximate linearity of the dose-response together with lung burden measurements in younger people will provide reasonably reliable predictions of future mesothelioma rates in those born since 1965 whose risks cannot yet be seen in national rates. Burdens in those born more recently will indicate the continuing occupational and environmental hazards under current asbestos control regulations. Our results confirm the major contribution of amosite to UK mesothelioma incidence and the substantial contribution of non-occupational exposure, particularly in women.

Topics: Adult; Aged; Asbestos, Amosite; Asbestos, Amphibole; Asbestos, Crocidolite; Asbestos, Serpentine; Asbestosis; Employment; Female; Humans; Lung; Lung Neoplasms; Male; Mesothelioma; Mesothelioma, Malignant; Middle Aged; Mineral Fibers; Occupational Diseases; Occupational Exposure; Pleural Neoplasms; Risk Assessment

In 2013 the International Journal of Surgical Pathology published a case report of intrasplenic malignant mesothelioma (MM) in a 48-year-old man: it was the first report in literature describing a case of primitive intra-splenic MM, described without  a history of asbestos exposure.. To verify the possible past exposure to asbestos, ignored by the patient himself, by studying in depth his environmental and occupational history.. Information about the occupational and non-occupational history of the subject was collected by Experts of the Operational Unit of Occupational Health and Safety Control (UOC PSAL) of the Local Health Unit Umbria 1 - Perugia, using the Italian National Mesothelioma Register (ReNaM) questionnaire and guide lines; an inspection was  carried out at the past canning industry where the patient worked in the period 1982-1990 and material was taken to be analysed by MOCF and SEM.. Samples showed the presence of asbestos  fibres belonging to the amphibole class (amosite and crocidolite) and to the serpentine class (chrysotile).. The survey described the past occupational exposure to asbestos in a canning industry, where  the subject worked in the period 1982-1990,  unknown to the patient himself. The authors strongly confirm the  usefulness of standardized methods, such as the ReNaM Questionnaire, and the importance of technical expertise of the investigator to find and analyse the suspect materials and to demonstrate  possible past occupational exposure to asbestos.

Topics: Asbestos; Asbestos, Amosite; Asbestos, Crocidolite; Asbestos, Serpentine; Carcinogens; Food Packaging; Humans; Lung Neoplasms; Male; Medical History Taking; Mesothelioma; Mesothelioma, Malignant; Middle Aged; Risk Assessment; Splenic Neoplasms

Malignant mesothelioma (MM) is one of the worst cancers in terms of clinical outcome, urging the need to establish and characterize new preclinical tools for investigation of the tumorigenic process, improvement of early diagnosis and evaluation of new therapeutic strategies. For these purposes, we characterized a collection of 27 cell lines established from F344 rats, after 136 to 415 days of induction with crocidolite asbestos administered intraperitoneally. Four mesotheliomas were distinguished from 23 preneoplastic mesothelial cell lines (PN) according to their propensity to generate tumors after orthotopic transplantation into syngeneic rats, their growth pattern, and the expression profile of three genes. PN cell lines were further discriminated into groups / subgroups according to morphology in culture and the expression profiles of 14 additional genes. This approach was completed by analysis of positive and negative immunohistochemical MM markers in the four tumors, of karyotype alterations in the most aggressive MM cell line in comparison with a PN epithelioid cell line, and of human normal mesothelial and mesothelioma cells and a tissue array. Our results showed that both the rat and human MM cell lines shared in common a dramatic decrease in the relative expression of Cdkn2a and of epigenetic regulators, in comparison with PN and normal human mesothelial cells, respectively. In particular, we identified the involvement of the relative expression of the Ten-Eleven Translocation (TET) family of dioxygenases and Dnmt3a in relation to the 5-hydroxymethylcytosine level in malignant transformation and the acquisition of metastatic potential.

Topics: 5-Methylcytosine; Animals; Asbestos, Crocidolite; Biomarkers, Tumor; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p18; DNA (Cytosine-5-)-Methyltransferases; DNA Methyltransferase 3A; Epithelial Cells; Epithelium; Humans; Karyotype; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Mixed Function Oxygenases; Precancerous Conditions; Proto-Oncogene Proteins; Rats; Rats, Inbred F344

To describe the incidence of malignant mesothelioma (MM) in Aboriginal people in Western Australia (WA) and determine the main routes of exposure to asbestos in this population.. All MM cases in Western Australia, as well as the primary source of asbestos exposure, are recorded in the WA Mesothelioma Register. Aboriginal cases up to the end of 2013 were extracted from the register and compared with non-Aboriginal cases with respect to the primary means/source of exposure. Age-standardised incidence rates for each decade from 1980 were calculated for both Aboriginals and non-Aboriginals. Age-standardised mortality rates were calculated for the period 1994-2008 and compared with international rates.. There were 39 cases (77% male) of MM among WA Aboriginal people. Twenty-six (67%) were a direct result of the mining of crocidolite at Wittenoom and the subsequent contamination of the surrounding lands. Of the non-Aboriginal MM cases (n = 2070, 86.3% male), fewer than 25% can be attributed to Wittenoom. Aboriginals had consistently higher 10-year incidence rates than non-Aboriginals and, when compared to world populations, the highest mortality rate internationally.. When incidence rates in Aboriginal people are compared with non-Aboriginal people, the Wittenoom mining operation has had a disproportionate effect on MM incidence in the local Aboriginal population.

Topics: Adult; Aged; Asbestos; Asbestos, Crocidolite; Causality; Female; Humans; Incidence; Lung Neoplasms; Male; Mesothelioma; Mesothelioma, Malignant; Middle Aged; Mining; Native Hawaiian or Other Pacific Islander; Occupational Exposure; Registries; Western Australia

Malignant mesothelioma (MM) has distinct histological subtypes (epithelioid, sarcomatoid and biphasic) with variable behaviour and prognoses. It is well recognised that survival time varies with the histological subtype of MM. It is not known, however, if asbestos exposure characteristics (type of asbestos, degree of exposure) are associated with different histological subtypes.. To determine if the pathological MM subtype is associated with the type of asbestos or the attributes of asbestos exposure.. Cases of MM for the period 1962 until 2012, their main histological subtype and their most significant source of asbestos exposure were collected from the Western Australian Mesothelioma Registry. Exposure characteristics included, degree of asbestos exposure (including total days exposed, years since first exposure and, for crocidolite only, calculated cumulative exposure), source of exposure (occupational or environmental), form of asbestos handled (raw or processed) and type of asbestos (crocidolite only or mixed fibres).. Patients with the biphasic subtype were more likely to have occupational exposure (OR 1.83, 1.12 to 2.85) and exposure to raw fibres (OR 1.58, 1.19 to 2.10). However, differences between subtypes in the proportions with these different exposure characteristics were small and unlikely to be biologically relevant. Other indicators of asbestos exposure were not associated with the histological subtype of mesothelioma.. There was no strong evidence of a consistent role of asbestos exposure indicators in determining the histological subtype of MM.

Topics: Aged; Asbestos; Asbestos, Crocidolite; Humans; Logistic Models; Lung Neoplasms; Male; Mesothelioma; Mesothelioma, Malignant; Middle Aged; Mining; Occupational Diseases; Occupational Exposure; Prognosis; Registries; Surveys and Questionnaires; Western Australia

Malignant mesothelioma (MM) is an aggressive cancer of mesothelial cells of pleural and peritoneal cavities. In 85% of cases both pleural and peritoneal MM is caused by asbestos exposure. Although both are asbestos-induced cancers, the incidence of pleural MM is significantly higher (85%) than peritoneal MM (15%). It has been proposed that carcinogenesis is a result of asbestos-induced inflammation but it is not clear what contributes to the differences observed between incidences of these two cancers. We hypothesize that the observed differences in incidences of pleural and peritoneal MM are the result of differences in the direct response of these cell types to asbestos rather than to differences mediated by the in vivo microenvironment. To test this hypothesis we characterized cellular responses to asbestos in a controlled environment. We found significantly greater changes in genome-wide expression in response to asbestos exposure in pleural mesothelial cells as compared to peritoneal mesothelial cells. In particular, a greater response in many common genes (IL-8, ATF3, CXCL2, CXCL3, IL-6, GOS2) was seen in pleural mesothelial cells as compared to peritoneal mesothelial cells. Unique genes expressed in pleural mesothelial cells were mainly pro-inflammatory (G-CSF, IL-1β, IL-1α, GREM1) and have previously been shown to be involved in development of MM. Our results are consistent with the hypothesis that differences in incidences of pleural and peritoneal MM upon exposure to asbestos are the result of differences in mesothelial cell physiology that lead to differences in the inflammatory response, which leads to cancer.

Topics: Adult; Aged; Asbestos, Crocidolite; Cell Line; Cell Survival; Female; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; High-Throughput Nucleotide Sequencing; Humans; Inflammation; Lung Neoplasms; Male; Mesothelioma; Mesothelioma, Malignant; Middle Aged; Peritoneal Neoplasms; Pleural Neoplasms; Sequence Analysis, RNA

Asbestos-induced mesothelioma is a worldwide problem. Parietal mesothelial cells internalize asbestos fibers that traverse the entire lung parenchyma, an action that is linked to mesothelial carcinogenesis. Thus far, vitronectin purified from serum reportedly enhances the internalization of crocidolite by mesothelial cells via integrin αvβ5. To reveal another mechanism by which mesothelial cells endocytose (phagocytose) asbestos, we first evaluated the effects of serum on asbestos uptake, which proved to be nonessential. Thereafter, we undertook a study to identify proteins on the surface of mesothelial cells (MeT5A) that act as receptors for asbestos uptake based on the assumption that receptors bind to asbestos with physical affinity. To this end, we incubated the membrane fraction of MeT5A cells with crocidolite or chrysotile and evaluated the adsorbed proteins using sodium dodecyl sulfate polyacrylamide gel analysis. Next, we extensively identified the proteins using an in-solution or in-gel digestion coupled with mass spectrometry. Among the identified proteins, annexin A2 (ANXA2) and transferrin receptor protein 1 (TFRC) were distinguished because of their high score and presence at the cell surface. Crocidolite uptake by MeT5A cells was significantly decreased by shRNA (short hairpin RNA)-induced knockdown of ANXA2 and direct blockade of cell surface ANXA2 using anti-ANXA2 antibody. In addition, abundant ANXA2 protein was present on the cell membrane of mesothelial cells, particularly facing the somatic cavity. These findings demonstrate that ANXA2 has a role in the mesothelial phagocytosis of crocidolite and may serve as its receptor.

Topics: Adsorption; Animals; Annexin A2; Antigens, CD; Asbestos, Crocidolite; Asbestos, Serpentine; Blotting, Western; Cell Line, Tumor; Endocytosis; Epithelium; Gene Knockdown Techniques; Humans; Lung Neoplasms; Mass Spectrometry; Membrane Proteins; Mesothelioma; Mesothelioma, Malignant; Rats; Receptors, Transferrin

To analyze asbestos exposure level between 1984 and 2010 in a district of malignant mesothelioma with clustering incidence in Zhejiang Province, in order to improve the recognizing and early diagnosis of malignant mesothelioma, protect the health of workers.. Monitoring data of total asbestos dust concentration in the air of workplace from 1984 to 2010 in asbestos textile enterprises, family hand spinning operation, brake production, and asbestos board production in Zhejiang Province were collected in the local CDC. A total of 766 TWA copies of mass concentration were collected, and 1233 copies of MAC data. Asbestos mass concentration and fibre counting concentration of 29 points of family hand spinning operation were parallel determinated in the same time and the same sampling point. Raw asesbtos materials and dust composition of local asbestos processing corporations were collected and analyzed using X-ray diffraction method.. Raw materials of asbestos used between 1984 and 2010 in this area were chrysotile from Sichuan, Qinghai, Xinjiang, Russia, Zimbabwe, and some were mixed with SiO2, CaCO3 and other impurities. Raw materials used in asbestos board production were blue asbestos. Dust concentration between 1960s and 1980s in asbestos processing plants far exceeded the national standard. After then the dust concentration decreased significantly, but still higher than the national standard. 95.2% of air dust concentrations in the workplaces of asbestos factories exceeded the standard, and dust concentrations of workplaces of raw material, spinning, weaving, carding and labor insurance were above 90% in which carding work had the highest median concentration. 37.9% of dust mass concentrations in hand spinning work exceeded the standard where textile machinery side had the highest value. Beating job in asbestos board manufacturing and grinding job in brake production had higher concentrations.. Most of production technologies in asbestos processing industry exceed the standard level, indicating that the workers were at risk for malignant mesothelioma and other asbestos related diseases, which should draw high attention.

Topics: Asbestos; Asbestos, Crocidolite; Asbestos, Serpentine; China; Dust; Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Occupational Diseases; Silicon Dioxide; Workplace

Simian virus 40 (SV40) has been implicated in the development of several cancers including malignant mesothelioma. A definitive role for the virus in human mesothelioma has not been unequivocally demonstrated but has been rigorously debated. The virus clearly has oncogenic potential: the TAg is one of the most potent transforming proteins known and acts synergistically with crocidolite asbestos to transform mesothelial cells. In this study, we show that SV40 oncogenes alone can cause malignant transformation and that asbestos-induced DNA damage and apoptosis occurs principally in cycling cells. After long-term exposure (up to 100 days) to both SV40 and asbestos, cells become resistant to stress-induced senescence. Significantly, these cells demonstrate resistance to chemotherapy-induced apoptosis. This finding has implications for the development of effective treatment options for patients with mesothelioma.

Topics: Animals; Antigens, Polyomavirus Transforming; Apoptosis; Asbestos, Crocidolite; Blotting, Western; Cell Adhesion; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Cocarcinogenesis; Drug Resistance, Neoplasm; Humans; Immunoenzyme Techniques; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Mice; Mice, Inbred C57BL; Mice, Transgenic; Peritoneum; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

The risk of malignant mesothelioma (MM) increases proportionally to the cumulative exposure, and to the 3rd or 4th power of time since first exposed, to asbestos. However, little is known about the risk of MM after more than 40 years since first exposure because most epidemiological studies do not have follow-up for sufficient periods of time.. The data from six cohort studies of exposed workers and two cohorts with residential exposure have been pooled. A nested case control design matched cases and controls on calendar period and age. Conditional logistic regression modelled the relationship between time since first exposure and risk of MM.. The combined data consisted of 22,048 people with asbestos exposure (5769 women), 707 cases of pleural MM (165 in women) and 155 cases of peritoneal MM (32 in women). Median time since first exposure for pleural MM cases was 38.4 years (IQR 31.3-45.3). Median duration of exposure for pleural MM cases was 3.75 years (IQR 0.7-18.2). The rate and risk of pleural MM increased until 45 years following first exposure and then appeared to increase at a slower power of time since first exposure. The rate of increase in peritoneal MM over the 10-50 years since first exposure continued to increase.. Exposure to asbestos confers a long-term risk of developing pleural and peritoneal mesothelioma which increases following cessation of exposure. While the rate of increase appears to start to level out after 40-50 years no one survives long enough for the excess risk to disappear.

Topics: Adolescent; Adult; Asbestos, Crocidolite; Asbestos, Serpentine; Australia; Child; Child, Preschool; Cohort Studies; Female; Follow-Up Studies; Humans; Inhalation Exposure; Italy; Male; Mesothelioma; Middle Aged; Occupational Exposure; Peritoneal Neoplasms; Pleural Neoplasms; Time Factors; Young Adult

In a mesothelioma lawsuit, the Public Prosecutor commissioned an expert evidence on the legal accountability for the disease, because the patient experienced multiple exposures to asbestos in both occupational and environmental settings.. To collect information on asbestos exposure from all available sources and to quantify the contribution of each source of exposure as a percentage of the total risk.. We retrieved information on jobs done and asbestos exposure from a work colleague and a database maintained by the National Institute for Insurance of Occupational Accidents/Diseases, respectively. Information on environmental exposure was searched through the scientific literature. The contribution of each source of exposure was quantified with a method of risk apportionment, taking into account time elapsed since first and last exposure, intensity and frequency of exposure and carcinogenic potency of asbestos fiber mix.. The subject worked in the maintenance of railway electrification system. The mechanical compression stress induced on the ballast during passage of trains released chrysotile (from fragmented stones) and crocidolite (through abrasive action of crushed gravel on the underbody of rolling stocks insulated with friable crocidolite). Despite the low cumulative exposure (about 2 ff×years/cc), 99% of the mesothelioma risk was attributable to the work done because of the high content of crocidolite of inhaled asbestos.. The report of an uncommon source of occupational asbestos exposure and a scientifically based method to allocate mesothelioma risk among multiple exposure could help to recognize mesothelioma as occupational disease in the workers employed in maintenance of the railway electrification system under the Italian National Railways.

Topics: Aged; Asbestos; Asbestos, Crocidolite; Asbestos, Serpentine; Carcinogens; Fatal Outcome; Humans; Italy; Lung Neoplasms; Maintenance; Male; Mesothelioma; Occupational Exposure; Railroads; Risk Assessment

Topics: Asbestos, Crocidolite; Female; Humans; Mesothelioma; Middle Aged; Pleural Neoplasms

Malignant mesothelioma is a devastating disease with a need for new treatment strategies. In the present study, we showed the importance of extracellular signal-regulated kinase 5 (ERK5) in malignant mesothelioma tumor growth and treatment.. ERK5 as a target for malignant mesothelioma therapy was verified using mesothelial and mesothelioma cell lines as well as by xenograft severe combined immunodeficient (SCID) mouse models.. We first showed that crocidolite asbestos activated ERK5 in LP9 cells and mesothelioma cell lines exhibit constitutive activation of ERK5. Addition of doxorubicin resulted in further activation of ERK5 in malignant mesothelioma cells. ERK5 silencing increased doxorubicin-induced cell death and doxorubicin retention in malignant mesothelioma cells. In addition, shERK5 malignant mesothelioma lines exhibited both attenuated colony formation on soft agar and invasion of malignant mesothelioma cells in vitro that could be related to modulation of gene expression linked to cell proliferation, apoptosis, migration/invasion, and drug resistance as shown by microarray analysis. Most importantly, injection of shERK5 malignant mesothelioma cell lines into SCID mice showed significant reduction in tumor growth using both subcutaneous and intraperitoneal models. Assessment of selected human cytokine profiles in peritoneal lavage fluid from intraperitoneal shERK5 and control tumor-bearing mice showed that ERK5 was critical in regulation of various proinflammatory (RANTES/CCL5, MCP-1) and angiogenesis-related (interleukin-8, VEGF) cytokines. Finally, use of doxorubicin and cisplatin in combination with ERK5 inhibition showed further reduction in tumor weight and volume in the intraperitoneal model of tumor growth.. ERK5 inhibition in combination with chemotherapeutic drugs is a beneficial strategy for combination therapy in patients with malignant mesothelioma.

Topics: Animals; Antineoplastic Agents; Asbestos, Crocidolite; Blotting, Western; Cell Line, Tumor; Cell Survival; Cisplatin; Combined Modality Therapy; Cytokines; Doxorubicin; Enzyme Activation; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Mesothelioma; Mice; Mice, SCID; Mitogen-Activated Protein Kinase 7; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Tumor Burden; Xenograft Model Antitumor Assays

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-1β, 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.

Topics: Animals; Asbestos, Crocidolite; Autocrine Communication; Carrier Proteins; Cell Line, Tumor; Cytokines; Dose-Response Relationship, Drug; Epithelium; Humans; Inflammasomes; Inflammation Mediators; Interleukin 1 Receptor Antagonist Protein; Mesothelioma; Mice; Mice, SCID; NLR Family, Pyrin Domain-Containing 3 Protein; Primary Cell Culture; Receptors, Interleukin-1; RNA, Messenger; Time Factors; Transcription, Genetic; Xenograft Model Antitumor Assays; Zeolites

Asbestos was used worldwide in huge quantities in the past century. However, because of the unexpected carcinogenicity to mesothelial cells with an extremely long incubation period, many countries face this long-lasting social problem. Mesothelioma is often diagnosed in an advanced stage, for which no effective therapeutic protocols are yet established. We previously reported on the basis of animal experiments that the major pathology in asbestos-induced mesothelial carcinogenesis is local iron overload. Here, we undertook to find an effective strategy to prevent, delay, or lower the malignant potential of mesothelioma during asbestos-induced carcinogenesis. We used intraperitoneal injections of crocidolite to rats. We carried out a 16-week study to seek the maximal-tolerated intervention for iron reduction via oral deferasirox administration or intensive phlebotomy. Splenic iron deposition was significantly decreased with either method, and we found that Perls' iron staining in spleen is a good indicator for iron reduction. We injected a total of 10 mg crocidolite at the age of six weeks, and the preventive measures were via repeated oral administration of 25 to 50 mg/kg/d deferasirox or weekly to bimonthly phlebotomy of 4 to 10 mL/kg/d. The animals were observed until 110 weeks. Deferasirox administration significantly increased the fraction of less malignant epithelioid subtype. Although we found a slightly prolonged survival in deferasirox-treated female rats, larger sample size and refinement of the current protocol are necessary to deduce the cancer-preventive effects of deferasirox. Still, our results suggest deferasirox serves as a potential preventive strategy in people already exposed to asbestos via iron reduction.

Topics: Animals; Asbestos, Crocidolite; Benzoates; Cell Transformation, Neoplastic; Deferasirox; Epithelial-Mesenchymal Transition; Female; Iron; Iron Chelating Agents; Male; Mesothelioma; Phlebotomy; Rats; Spleen; Triazoles

Clustering of cases of malignant mesothelioma within families has often been observed, but disentangling genetic and exposure effects has not been done. Former workers and residents exposed to crocidolite at Wittenoom, Western Australia, where many families shared exposure to asbestos, have had high rates of mesothelioma. Our study aimed to estimate the additional risk of mesothelioma in relatives, after allowance for common exposure to crocidolite. More than 11,000 former asbestos workers and residents from Wittenoom have been followed up in cancer and death registries. Levels of exposure for all members of the Wittenoom cohorts have been estimated previously. Relationships between family members of all mesothelioma cases were established from questionnaires, birth and death certificates. Expected numbers of cases of mesothelioma were estimated by fitting a Weibull survival model to all data, based on time from first asbestos exposure, duration and intensity of exposure and age. For each family group, the earliest case was considered the index case. Predicted risk was estimated for each subject from the time of diagnosis of the index case. Familial risk ratios were estimated by dividing observed cases by the sum of risks of all same degree relatives of index cases. There were 369 family groups with at least one case of mesothelioma and a further 25 cases of mesothelioma among relatives in the same families, with 12.9 expected. The risk ratio for blood relatives was 1.9 (95% confidence interval [CI] = 1.3-2.9, p = 0.002). These findings suggest an important, but not large, genetic component in mesothelioma, similar to many other cancers.

Topics: Adult; Aged; Asbestos, Crocidolite; Family; Female; Humans; Male; Mesothelioma; Middle Aged; Occupational Exposure; Risk; Western Australia

To report the number of malignant pleural and peritoneal mesotheliomas that have occurred in former Wittenoom crocidolite workers to the end of 2008, to compare this with earlier predictions, and to relate the mesothelioma rate to amount of exposure.. A group of 6489 men and 419 women who had worked for the company operating the former Wittenoom crocidolite mine and mill at some time between 1943 and 1966 have been followed up throughout Australia and Italy to the end of 2008.. The cumulative number of mesotheliomas up to 2008 was 316 in men (268 pleural, 48 peritoneal) and 13 (all pleural) in women. There had been 302 deaths with mesothelioma in men and 13 in women, which was almost 10% of all known deaths. Mesothelioma rate, both pleural and peritoneal, increased with time since first exposure and appeared to reach a plateau after about 40 to 50 years. The mesothelioma rate increased with amount of exposure and the peritoneal mesotheliomas occurred preferentially in the highest exposure group, 37% compared with 15% overall.. By the end of 2008, the number of mesothelioma deaths had reached 4.7% for all the male workers and 3.1% for the females. Over the past 8 years the numbers were higher than expected. It is predicted that about another 60 to 70 deaths with mesothelioma may occur in men by 2020.

Topics: Asbestos, Crocidolite; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Mesothelioma; Mining; Occupational Exposure; Peritoneal Neoplasms; Pleural Neoplasms; Western Australia

Multi-walled carbon nanotubes have a fibrous structure similar to asbestos and induce mesothelioma when injected into the peritoneal cavity. In the present study, we investigated whether carbon nanotubes administered into the lung through the trachea induce mesothelial lesions. Male F344 rats were treated with 0.5 mL of 500 μg/mL suspensions of multi-walled carbon nanotubes or crocidolite five times over a 9-day period by intrapulmonary spraying. Pleural cavity lavage fluid, lung and chest wall were then collected. Multi-walled carbon nanotubes and crocidolite were found mainly in alveolar macrophages and mediastinal lymph nodes. Importantly, the fibers were also found in the cell pellets of the pleural cavity lavage, mostly in macrophages. Both multi-walled carbon nanotube and crocidolite treatment induced hyperplastic proliferative lesions of the visceral mesothelium, with their proliferating cell nuclear antigen indices approximately 10-fold that of the vehicle control. The hyperplastic lesions were associated with inflammatory cell infiltration and inflammation-induced fibrotic lesions of the pleural tissues. The fibers were not found in the mesothelial proliferative lesions themselves. In the pleural cavity, abundant inflammatory cell infiltration, mainly composed of macrophages, was observed. Conditioned cell culture media of macrophages treated with multi-walled carbon nanotubes and crocidolite and the supernatants of pleural cavity lavage fluid from the dosed rats increased mesothelial cell proliferation in vitro, suggesting that mesothelial proliferative lesions were induced by inflammatory events in the lung and pleural cavity and likely mediated by macrophages. In conclusion, intrapulmonary administration of multi-walled carbon nanotubes, like asbestos, induced mesothelial proliferation potentially associated with mesothelioma development.

Topics: Animals; Asbestos, Crocidolite; Cell Proliferation; Lung; Macrophages, Alveolar; Male; Mesothelioma; Nanotubes, Carbon; Pleural Cavity; Rats; Rats, Inbred F344

A strong link has been established between exposure to asbestos and increased risk for pleural malignant mesothelioma (MM). Adenosine plays a key role in inflammatory processes and cancer, where it is involved in the regulation of cell death and proliferation.. The primary aim of this study was to investigate the presence of adenosine receptors (ARs) in human MM pleura (MMP) and healthy mesothelial pleura (HMP). To shed some light on the interaction between adenosine and MM, the presence and functionality of ARs were explored in human healthy mesothelial cells (HMC) and in malignant mesothelioma cells (MMC).. ARs were analyzed by using reverse transcriptase-polymerase chain reaction, Western blotting, and saturation binding assays. HMC were treated with crocidolite asbestos, which is the principal risk factor for MM. The role of A₃ ARs on these cellular models, evaluating cAMP production, Akt phosphorylation, and nuclear factor (NF)-κB activation, was investigated. The dual effect of A₃AR stimulation on healthy and cancer cell growth was studied by means of proliferation, apoptosis, and cytotoxicity assays.. A₃AR was up-regulated by 2.5-fold (P < 0.01) in MMP when compared with HMP. Stimulation of A₃ARs decreased proliferation and exerted a cytotoxic and proapoptotic effect on MMC and on HMC exposed to asbestos and tumor necrosis factor-α, but not on HMC with an involvement of the deregulation of Akt/NF-κB cell survival pathway.. These new findings suggest that A₃AR could represent a pharmacological target to prevent tumor development after asbestos exposure and to treat full-blown MM.

Topics: Adult; Apoptosis; Asbestos, Crocidolite; Blotting, Western; Cell Proliferation; Cells, Cultured; Female; Humans; Male; Mesothelioma; Middle Aged; NF-kappa B; Pleura; Pleural Neoplasms; Proto-Oncogene Proteins c-akt; Receptor, Adenosine A3; Reverse Transcriptase Polymerase Chain Reaction; Up-Regulation

Asbestos is a naturally occurring fibrous silicate, whose inhalation is highly related to the risk of developing malignant mesothelioma (MM), and crocidolite is one of its most oncogenic types. The mechanism by which asbestos may cause MM is unclear. We have previously observed that crocidolite in human MM (HMM) cells induces NF-κB activation and stimulates the synthesis of nitric oxide by inhibiting the RhoA signaling pathway. In primary human mesothelial cells (HMCs) and HMM cells exposed to crocidolite asbestos, coincubated or not with antioxidants, we evaluated cytotoxicity and oxidative stress induction (lipid peroxidation) and the effect of asbestos on the RhoA signaling pathway (RhoA GTP binding, Rho kinase activity, RhoA prenylation, hydroxy-3-methylglutharyl-CoA reductase activity). In this paper we show that the reactive oxygen species generated by the incubation of crocidolite with primary HMCs and three HMM cell lines mediate the inhibition of 3-hydroxy-3-methylglutharyl-CoA reductase (HMGCR). The coincubation of HMCs and HMM cells with crocidolite together with antioxidants, such as Tempol, Mn-porphyrin, and the association of superoxide dismutase and catalase, prevented the cytotoxicity and lipoperoxidation caused by crocidolite alone as well as the decrease of HMGCR activity and restored the RhoA/RhoA-dependent kinase activity and the RhoA prenylation. The same effect was observed when the oxidizing agent menadione was administrated to the cells in place of crocidolite. Such a mechanism could at least partly explain the effects exerted by crocidolite fibers in mesothelial cells.

Topics: Antioxidants; Asbestos; Asbestos, Crocidolite; Cell Line; Epithelium; Guanosine Triphosphate; Humans; L-Lactate Dehydrogenase; Lipid Peroxidation; Mesothelioma; Microscopy, Fluorescence; NF-kappa B; Oxidative Stress; Reactive Oxygen Species; rhoA GTP-Binding Protein; Signal Transduction

We hypothesized that normal human mesothelial cells acquire resistance to asbestos-induced toxicity via induction of one or more epidermal growth factor receptor (EGFR)-linked survival pathways (phosphoinositol-3-kinase/AKT/mammalian target of rapamycin and extracellular signal-regulated kinase [ERK] 1/2) during simian virus 40 (SV40) transformation and carcinogenesis. Both isolated HKNM-2 mesothelial cells and a telomerase-immortalized mesothelial line (LP9/TERT-1) were more sensitive to crocidolite asbestos toxicity than an SV40 Tag-immortalized mesothelial line (MET5A) and malignant mesothelioma cell lines (HMESO and PPM Mill). Whereas increases in phosphorylation of AKT (pAKT) were observed in MET5A cells in response to asbestos, LP9/TERT-1 cells exhibited dose-related decreases in pAKT levels. Pretreatment with an EGFR phosphorylation or mitogen-activated protein kinase kinase 1/2 inhibitor abrogated asbestos-induced phosphorylated ERK (pERK) 1/2 levels in both LP9/TERT-1 and MET5A cells as well as increases in pAKT levels in MET5A cells. Transient transfection of small interfering RNAs targeting ERK1, ERK2, or AKT revealed that ERK1/2 pathways were involved in cell death by asbestos in both cell lines. Asbestos-resistant HMESO or PPM Mill cells with high endogenous levels of ERKs or AKT did not show dose-responsive increases in pERK1/ERK1, pERK2/ERK2, or pAKT/AKT levels by asbestos. However, small hairpin ERK2 stable cell lines created from both malignant mesothelioma lines were more sensitive to asbestos toxicity than shERK1 and shControl lines, and exhibited unique, tumor-specific changes in endogenous cell death-related gene expression. Our results suggest that EGFR phosphorylation is causally linked to pERK and pAKT activation by asbestos in normal and SV40 Tag-immortalized human mesothelial cells. They also indicate that ERK2 plays a role in modulating asbestos toxicity by regulating genes critical to cell injury and survival that are differentially expressed in human mesotheliomas.

Topics: Asbestos, Crocidolite; Cell Line; Cell Survival; Enzyme Inhibitors; ErbB Receptors; Gene Expression; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Mesothelioma; Mitogen-Activated Protein Kinase 1; Pleural Neoplasms; RNA, Small Interfering; Signal Transduction

Malignant mesothelioma is a rare cancer caused by exposure to asbestos. Current therapies have limited efficacy and the prognosis is dismal. A better understanding of the underlying mechanism of asbestos-induced malignant transformation will help to identify molecular markers that can be used for diagnosis, prognosis or therapeutic targets.. The objectives of this study are (1) to identify altered levels of proteins and phosphoproteins and (2) to establish the interactive network among those proteins in crocidolite-treated benign mesothelial cells and in malignant mesothelial cells.. Total cellular proteins were extracted from benign mesothelial cells, crocidolite-treated mesothelial cells and malignant mesothelial cells. The expression levels of 112 proteins and phosphoproteins were analyzed using a multiplex immunoblot-based assay followed by computational analysis (Protein Pathway Array).. A total of 16 proteins/phosphoproteins (7 down-regulated and 9 up-regulated) were altered after exposure of benign mesothelial cells to crocidolite asbestos and the majority of them are involved in DNA damage repair and cell cycle regulation. In malignant mesothelial cells, 21 proteins/phosphoproteins (5 down-regulated and 16 up-regulated) were dysregulated and majority of them are involved in EGFR/ERK and PI3K/Akt pathways. Within the regulatory network affected by crocidolite, p53 and NF-κB complex are the most important regulators. There was substantial overlap in the regulatory networks between the asbestos-treated cells and malignant mesothelial cells.. Asbestos exposure has extensive effects on regulatory pathways and networks. These altered proteins may be used in the future to identify those with a high risk for developing malignant mesothelioma and as targets for preventing this deadly malignancy.

Topics: Asbestos, Crocidolite; Cell Line; Epithelial Cells; Gene Expression Regulation; Humans; Mesothelioma; Phosphoproteins; Proteins; Signal Transduction

Asbestos is a potent carcinogen associated with increased risks of malignant mesothelioma and lung cancer in humans. Although the mechanism of carcinogenesis remains elusive, the physicochemical characteristics of asbestos play a role in the progression of asbestos-induced diseases. Among these characteristics, a high capacity to adsorb and accommodate biomolecules on its abundant surface area has been linked to cellular and genetic toxicity. Several previous studies identified asbestos-interacting proteins. Here, with the use of matrix-assisted laser desorption ionization-time of flight mass spectrometry, we systematically identified proteins from various lysates that adsorbed to the surface of commercially used asbestos and classified them into the following groups: chromatin/nucleotide/RNA-binding proteins, ribosomal proteins, cytoprotective proteins, cytoskeleton-associated proteins, histones and hemoglobin. The surfaces of crocidolite and amosite, two iron-rich types of asbestos, caused more protein scissions and oxidative modifications than that of chrysotile by in situ-generated 4-hydroxy-2-nonenal. In contrast, we confirmed the intense hemolytic activity of chrysotile and found that hemoglobin attached to chrysotile, but not silica, can work as a catalyst to induce oxidative DNA damage. This process generates 8-hydroxy-2'-deoxyguanosine and thus corroborates the involvement of iron in the carcinogenicity of chrysotile. This evidence demonstrates that all three types of asbestos adsorb DNA and specific proteins, providing a niche for oxidative modification via catalytic iron. Therefore, considering the affinity of asbestos for histones/DNA and the internalization of asbestos into mesothelial cells, our results suggest a novel hypothetical mechanism causing genetic alterations during asbestos-induced carcinogenesis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Asbestos, Amosite; Asbestos, Crocidolite; Asbestos, Serpentine; Chromatin; Cytoskeleton; Deoxyguanosine; DNA; DNA Damage; Hemoglobins; Histones; Iron; Lung Neoplasms; Mesothelioma; Mice; Oxidation-Reduction; Proteins; Rats; Ribosomal Proteins; RNA-Binding Proteins; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Surface Properties

In a rural area widespread pollution of friable and non-friable waste products was present, used to harden dirt tracks, yards, and driveways during 1935-1974. Exposure to environmental asbestos was assessed by a site approach, based on number of polluted sites within postal code areas, and by a household approach, based on number of households in the close vicinity to polluted sites within postal code areas. Based on asbestos soil investigations, 293 sites were identified with asbestos waste material at the surface, of which 77% contained crocidolite fibres as well as chrysotile fibres. The 293 sites-at-risk varied from 5 m(2) to 2722 m(2) and were surrounded by 347 households within 100 m of these sites. Distance to the plant was associated with the number of sites (r=0.36), and with the number of households (r=0.52). However, categorization of postal code areas into low, intermediate or high likelihood of exposure to asbestos showed a modest agreement between the site and household approach. In the site approach a total of 2.3 million person-years at risk were estimated with an average exposure of 1674 fibres/m(3) and an expected 1.8 cases of malignant mesothelioma each year. The household approach resulted in estimates of 1.2 million person-years at risk, and 0.9 cases of malignant mesothelioma per year, respectively. This study illustrates that asbestos waste on the surface of roads and yards in an area with over 130,000 inhabitants may result in long-term exposure to asbestos that will cause several cases of malignant mesothelioma each year. Although distance to plant, number of polluted sites and number of exposed household were associated, the modest agreement among these measures of exposure indicate that the exposure assessment strategy chosen in a particular study may result in considerable misclassification. Without detailed information on individual behaviour within the polluted area, it is difficult to show that a more individually oriented approach will perform better than an ecological approach.

Topics: Asbestos; Asbestos, Crocidolite; Asbestos, Serpentine; Environment Design; Environmental Exposure; Environmental Monitoring; Epidemiological Monitoring; Humans; Industry; Mesothelioma; Netherlands; Residence Characteristics; Risk Assessment; Rural Health; Soil Pollutants; Waste Products

Owing to the high rates of malignant mesothelioma in workers exposed to crocidolite earlier at Wittenoom and evidence of protection against cancer by vitamin A, a population-based cancer prevention programme providing retinol supplements (25 000 IU/day) was commenced in 1990. The former workers at Wittenoom known to be alive and living in Western Australia in June 1990 constitute the study population. The participants were classified into two groups: those who received supplemental retinol (intervention group) and those who received none (comparison group). The relative rate of mesothelioma for those receiving retinol was estimated using Cox regression, adjusting for cumulative asbestos exposure and age at first exposure to asbestos. Nine hundred and twenty-eight former Wittenoom workers received retinol at some stage of the programme, whereas 1471 workers never received retinol (comparison group). Those who received retinol were younger, had a greater exposure to asbestos and smoked less than the comparison group. There were 65 cases of mesothelioma in the retinol group and 88 in the comparison group. After adjustment, the hazard ratio was 0.99 (95% confidence interval=0.70-1.41). This result did not alter when the participants who received only retinol once or those who received beta-carotene earlier were excluded from the analysis. In conclusion, this study provides little support for possible preventive effects of retinol against mesothelioma in workers exposed to blue asbestos.

Topics: Asbestos, Crocidolite; Female; Follow-Up Studies; Humans; Incidence; Male; Mesothelioma; Middle Aged; Mining; Occupational Diseases; Occupational Exposure; Program Evaluation; Smoking; Vitamin A; Western Australia

Nearly 3000 women and girls were documented to have lived at the blue asbestos mining and milling town of Wittenoom in Western Australia between 1943 and 1992. Eight per cent of deaths among these women to the end of 2004 have been from malignant mesothelioma of the pleura.. To predict future mortality from mesothelioma to 2030 in this cohort.. Mesothelioma mortality rates incorporating parameters for cumulative exposure, a power of time since first exposure and annual rates of fibre clearance from the lung were calculated from maximum likelihood estimates. These rates plus age specific mortality rates for Western Australian females incorporating an excess lung cancer risk were then applied to all Wittenoom cohort women surviving to the end of 2004, in yearly increments, to predict the future numbers of cases of mesothelioma to 2030.. There were 40 deaths from mesothelioma among the Wittenoom women to the end of 2004. Using a range of models that incorporate time since first exposure, competing risks from other diseases, latency periods and clearance of mesothelioma from the lungs we predict 66 (lowest estimate) to 87 (highest estimate) deaths from mesothelioma until 2030. This represents one and a half to two and a half times the number of deaths that have already occurred to the end of 2004.. The high toll from mesothelioma in this cohort of women and girls will continue well into the future.

Topics: Adult; Aged; Air Pollution; Asbestos, Crocidolite; Carcinogens; Cohort Studies; Environmental Monitoring; Female; Forecasting; Humans; Likelihood Functions; Lung Neoplasms; Mesothelioma; Middle Aged; Occupational Diseases; Occupational Exposure; Pleural Neoplasms; Risk Assessment; Western Australia

A cohort of 1,154 employees, mainly women, who had worked 1940-1945 on the manufacture of military gas masks using filter pads containing 20% crocidolite, was traced through 2003, by which time 65 were known to have died from mesothelioma. The last known death with mesothelioma was in 1994, whereas a further 5 cases would have been expected in those with known duration of exposure. Lung tissue samples, from 50 deaths from mesothelioma and 20 other causes, had been analyzed for mineral fiber content. For ten of the mesothelioma cases data on fiber size were collected. Crocidolite fiber concentrations were analyzed in relation to exposure by time and duration. Fiber concentrations overall fell fairly steadily by decade of death, and increased with length of exposure up to 36 months and then fell sharply. The annual rate of elimination estimated by regression was 7.5% corresponding to a half life of 9.2 years. The proportion of fibers longer than 6 mum increased over time implying that the shorter fibers were eliminated more rapidly than the longer ones. The decline in concentrations with time confirms the hypothesis that crocidolite and, by inference, other amphibole fibers are slowly removed from the lung, but since the longer more carcinogenic fibers were cleared more slowly it is unclear to what extent this clearance explains the slowing down of the increase in mesothelioma mortality from about 40 years from the most recent exposure. The exact biostatistical models which most closely conform with the data remain open to question.

Topics: Air Pollutants, Occupational; Asbestos, Crocidolite; Body Burden; Cohort Studies; England; Female; Humans; Inhalation Exposure; Lung; Lung Neoplasms; Male; Mesothelioma; Particle Size; Respiratory Protective Devices

The present study assessed a carcinogenic hazard of multi-wall carbon nanotube (MWCNT) in intact (not genetically modified) rodents. MWCNT (1 mg/kg body weight, 7 animals), crocidolite (2 mg/kg body weight, 10 animals) or vehicle (2% carboxymethyl cellulose, 5 animals) was administered to male Fischer 344 rats (12 weeks old) by a single intrascrotal injection. Rats were autopsied immediately after death, when becoming moribund or at the end of the maximal observation period scheduled to be 52 weeks. After 37-40 weeks, however, 6 MWCNT-treated animals died or became moribund due to intraperitoneally disseminated mesothelioma (6/7, 85.7%) with bloody ascites. Peritoneal mesothelium was generally hypertrophic, and numerous nodular or papillary lesions of mesothelioma and mesothelial hyperplasia were developed. While mesothelioid cells were predominant in relatively early stage tumors, advanced stage mesotheliomas were constituted by 2 portions occupied by mesothelioid cells on the surface and spindle-shaped sarcomatous cells in the depth. In the latter, the histological transition was apparently observed between these 2 portions. Mesotheliomas were invasive to adjacent organs and tissues, and frequently metastasized into the pleura. Only 1 rat survived for 52 weeks in the MWCNT-treated group, and similar findings except mesothelioma were observed. All 10 crocidolite-treated and 5 vehicle-treated rats survived for 52 weeks without any particular changes except deposition of asbestos in the former case. It is thus indicated that MWCNT possesses carcinogenicity causing mesothelioma at a high rate in intact male rats under the present experimental conditions. The present data identifies a carcinogenic hazard of MWCNT and will serve as one of the indispensable evidences to be used for the risk assessment crucial for not only protection and improvement of human health and welfare, but also safe and acceptable development and prevalence of this and similar upcoming materials.

Topics: Anemia; Animals; Asbestos, Crocidolite; Ascites; Autopsy; Carboxymethylcellulose Sodium; Carcinogens; Dose-Response Relationship, Drug; Epithelium; Granuloma; Injections; Liver; Male; Mesothelioma; Nanotubes, Carbon; Particle Size; Peritoneum; Pharmaceutical Vehicles; Rats; Rats, Inbred F344; Scrotum; Suspensions; Time Factors; Tissue Adhesions

Toxicological investigations of carbon nanotubes have shown that they can induce pulmonary toxicity, and similarities with asbestos fibers have been suggested. We previously reported that multiwall carbon nanotubes (MWCNT) induced lung inflammation, granulomas and fibrotic reactions. The same MWCNT also caused mutations in epithelial cells in vitro and in vivo. These inflammatory and genotoxic activities were related to the presence of defects in the structure of the nanotubes. In view of the strong links between inflammation, mutations and cancer, these observations prompted us to explore the carcinogenic potential of these MWCNT in the peritoneal cavity of rats. The incidence of mesothelioma and other tumors was recorded in three groups of 50 male Wistar rats injected intraperitoneally with a single dose of MWCNT with defects (2 or 20 mg/animal) and MWCNT without defects (20 mg/animal). Two additional groups of 26 rats were used as positive (2 mg UICC crocidolite/animal) and vehicle controls. After 24 months, although crocidolite induced a clear carcinogenic response (34.6% animals with mesothelioma vs. 3.8% in vehicle controls), MWCNT with or without structural defects did not induce mesothelioma in this bioassay (4, 0, or 6%, respectively). The incidence of tumors other than mesothelioma was not significantly increased across the groups. The initial hypothesis of a contrasting carcinogenic activity between MWCNT with and without defects could not be verified in this bioassay. We discuss the possible reasons for this absence of carcinogenic response, including the length of the MWCNT tested (< 1 mum on average), the absence of a sustained inflammatory reaction to MWCNT, and the capacity of these MWCNT to quench free radicals.

Topics: Abdominal Neoplasms; Animals; Asbestos, Crocidolite; Biological Assay; Carcinogenicity Tests; Carcinogens; Cell Transformation, Neoplastic; Injections, Intraperitoneal; Male; Mesothelioma; Nanotubes, Carbon; Peritoneal Cavity; Rats; Rats, Wistar; Reference Standards; Risk Assessment; Surface Properties; Time Factors

The calcium-binding protein calretinin has emerged as a useful marker for the identification of mesotheliomas of the epithelioid and mixed types, but its putative role in tumor development has not been addressed previously. Although exposure to asbestos fibers is considered the main cause of mesothelioma, undoubtedly, not all mesothelioma patients have a history of asbestos exposure. The question as to whether the SV40 virus is involved as a possible co-factor is still highly debated. Here we show that increased expression of SV40 early gene products in the mesothelial cell line MeT-5A induces the expression of calretinin and that elevated calretinin levels strongly correlate with increased resistance to asbestos cytotoxicity. Calretinin alone mediates a significant part of this protective effect because cells stably transfected with calretinin cDNA were clearly more resistant to the toxic effects of crocidolite than mock-transfected control cells. Down-regulation of calretinin by antisense methods restored the sensitivity to asbestos toxicity to a large degree. The protective effect observed in clones with higher calretinin expression levels could be eliminated by phosphatidylinositol 3-kinase (PI3K) inhibitors, implying an important role for the PI3K/AKT signaling (survival) pathway in mediating the protective effect. Up-regulation of calretinin, resulting from either asbestos exposure or SV40 oncoproteins, may be a common denominator that leads to increased resistance to asbestos cytotoxicity and thereby contributes to mesothelioma carcinogenesis.

Topics: Antigens, Polyomavirus Transforming; Asbestos, Crocidolite; Blotting, Western; Calbindin 2; Cell Line, Tumor; Cell Transformation, Neoplastic; Gene Expression; Humans; Immunohistochemistry; Mesothelioma; Phosphatidylinositol 3-Kinases; Polyomavirus Infections; Proto-Oncogene Proteins c-akt; Reverse Transcriptase Polymerase Chain Reaction; S100 Calcium Binding Protein G; Signal Transduction; Simian virus 40; Transfection; Tumor Virus Infections; Up-Regulation

Efforts have been made for 25 years to develop asbestos risk assessments that provide valid information about workplace and community cancer risks. Mathematical models have been applied to a group of workplace epidemiology studies to describe the relationships between exposure and risk. EPA's most recent proposed method was presented at a public meeting in July 2008.. Risk assessments prepared by USEPA, OSHA, and NIOSH since 1972 were reviewed, along with related literature.. None of the efforts to use statistical models to characterize relative cancer potencies for asbestos fiber types and sizes have been able to overcome limitations of the exposure data. Resulting uncertainties have been so great that these estimates should not be used to drive occupational and environmental health policy. The EPA has now rejected and discontinued work on its proposed methods for estimating potency factors. Future efforts will require new methods and more precise and reliable exposure assessments. However, while there may be genuine need for such work, a more pressing priority with regard to the six regulated forms of asbestos and other asbestiform fibers is to ban their production and use.

Topics: Asbestos; Asbestos, Crocidolite; Humans; Lung Neoplasms; Mesothelioma; Models, Statistical; Occupational Diseases; Occupational Exposure; Pleural Neoplasms; Risk Assessment; Workplace

Models based on the multistage theory of carcinogenesis predict that the rate of mesothelioma increases monotonically as a function of time since first exposure (TSFE) to asbestos. Predictions of long-term mortality (TSFE >or= 40 years) are, however, still untested, because of the limited follow-up of most epidemiological studies. Some authors have suggested that the increase in mesothelioma rate with TSFE might be attenuated by clearance of asbestos from the lungs. We estimated mortality time trends from pleural and peritoneal cancer in a cohort of 3,443 asbestos-cement workers, followed for more than 50 years. The functional relation between mesothelioma rate and TSFE was evaluated with various regression models. The role of asbestos clearance was explored using the traditional mesothelioma multistage model, generalized to include a term representing elimination over time. We observed 139 deaths from pleural and 56 from peritoneal cancer during the period 1950-2003. The rate of pleural cancer increased during the first 40 years of TSFE and reached a plateau thereafter. In contrast, the rate of peritoneal cancer increased monotonically with TSFE. The model allowing for asbestos elimination fitted the data better than the traditional model for pleural (p = 0.02) but not for peritoneal cancer (p = 0.22). The risk for pleural cancer, rather than showing an indefinite increase, might reach a plateau when a sufficiently long time has elapsed since exposure. The different trends for pleural and peritoneal cancer might be related to clearance of the asbestos from the workers' lungs.

Topics: Asbestos, Crocidolite; Asbestos, Serpentine; Epidemiologic Methods; Female; Humans; Lung; Male; Mesothelioma; Models, Statistical; Occupational Diseases; Occupational Exposure; Peritoneal Neoplasms; Pleural Neoplasms

Little is known about neighborhood exposure to asbestos and mesothelioma risk among residents around an industrial source of asbestos.. To investigate the magnitude of the risk among residents by asbestos exposure levels and to determine the range of the area affected by asbestos.. We calculated standardized mortality ratios of mesothelioma from 1995 to 2006 among the estimated population at risk that lived around a former large asbestos cement pipe plant in Amagasaki City, Japan, between 1957 and 1975, the time when the plant had used crocidolite and chrysotile. The distance between the plant and homes and relative asbestos concentrations obtained by diffusion equations involving meteorological conditions were used to determine asbestos exposure levels among residents.. We identified 73 mesothelioma deaths of 35 men and 38 women who had no occupational exposure to asbestos. Among persons who had lived within a 300-m radius of the plant, the standardized mortality ratio of mesothelioma was 13.9 (95% confidence interval, 5.6-28.7) for men and 41.1 (95% confidence interval, 15.2-90.1) for women. When the study area was divided into five regions by relative asbestos concentration, standardized mortality ratios of mesothelioma declined, for both sexes, in a linear dose-dependent manner with concentration. The regions with a significantly elevated standardized mortality ratio reached 2,200 m from the plant in the same direction in which the wind predominantly blew.. Neighborhood exposure to asbestos can pose a serious risk to residents across a wide area.

Topics: Aged; Air Pollutants; Asbestos, Crocidolite; Asbestosis; Cluster Analysis; Dose-Response Relationship, Drug; Environmental Exposure; Female; Humans; Japan; Male; Mesothelioma; Middle Aged; Pleural Neoplasms; Risk Assessment

Knowledge of mortality patterns following exposure to asbestos has been determined mostly from cohort studies of men who were exposed to asbestos in their workplace. Women are more likely to have obtained their asbestos exposure domestically or from their environment.. 2552 women and girls are documented to have lived in the blue asbestos mining and milling township of Wittenoom between 1943 and 1992 and were not involved in asbestos mining or milling. Quantitative asbestos exposure measurements were derived from periodic dust surveys undertaken in the industry and around the township. Death records were obtained for the period 1950-2004. Standardised mortality ratios (SMRs) were calculated to compare the Wittenoom women's mortality with that of the Western Australian female population.. There were 425 deaths, including 30 from malignant mesothelioma. There was excess mortality for all causes of death (SMR = 1.13), all neoplasms (SMR = 1.42), symptoms, signs and ill defined conditions (SMR = 6.35), lung cancer (SMR = 2.15) and pneumoconiosis (SMR = 11.8). Mortality from cancer of the ovary (SMR = 1.52), upper aerodigestive cancers (SMR = 2.70) and tuberculosis (SMR = 5.38) was increased but not significantly. The risk of death from mesothelioma was increased, but not significantly, in residents known to have lived with or washed the clothes of an Australian Blue Asbestos Company asbestos worker (HR = 2.67, 95% CI 0.77 to 9.21; HR = 2.61, 95% CI 0.85 to 7.99, respectively).. Women who were former residents of Wittenoom, exposed to asbestos in their environment or in their home, have excess cancer mortality, including mesothelioma, compared with the Western Australian female population.

Topics: Adolescent; Adult; Air Pollution, Indoor; Asbestos, Crocidolite; Child; Child, Preschool; Environmental Exposure; Environmental Monitoring; Epidemiologic Methods; Epidemiological Monitoring; Female; Housing; Humans; Mesothelioma; Middle Aged; Mining; Neoplasms; Western Australia

South Africa (SA), a country in which all three commercially important asbestos minerals have been mined and milled, has retained proven cases of mesothelioma linked with environmental exposure to asbestos. This study illustrates the importance of fiber type in the occurrence of environmental mesothelioma. Four studies have reviewed the source of occupational or environmental asbestos exposure in 504 histologically proven cases of mesothelioma in South Africa. One hundred and eighteen cases (23%) were thought to be related to environmental exposure to asbestos. In the vast majority of these cases, exposure was linked to crocidolite mining activities in the Northern Cape Province. Two cases were thought to have occurred in relation to amosite and Transvaal crocidolite exposure in the Limpopo Province. In the balance of cases there was some uncertainty. No cases were reported with exposure to South African chrysotile. Consequently, in the vast majority of cases of mesothelioma, environmental exposure to asbestos occurred in the Northern Cape Province, in proximity to mines, mills and dumps where crocidolite was processed. Crocidolite appears to be far more mesotheliomagenic than amosite, and chrysotile has not been implicated in the disease. This is true for both occupationally and environmentally exposed individuals.

Topics: Asbestos; Asbestos, Amosite; Asbestos, Crocidolite; Asbestosis; Carcinogens; Environmental Exposure; Female; Humans; Male; Mesothelioma; Mineral Fibers; Mining; Occupations; South Africa

Blue asbestos was mined and milled at Wittenoom in Western Australia between 1943 and 1966.. Nearly 7000 male workers who worked at the Wittenoom mine and mill have been followed up using death and cancer registries throughout Australia and Italy to the end of 2000. Person-years at risk were derived using two censoring dates in order to produce minimum and maximum estimates of asbestos effect. Standardised mortality ratios (SMRs) compare the mortality of the former Wittenoom workers with the Western Australian male population.. There have been 190 cases of pleural and 32 cases of peritoneal mesothelioma in this cohort of former workers at Wittenoom. Mortality from lung cancer (SMR = 1.52), pneumoconiosis (SMR = 15.5), respiratory diseases (SMR = 1.58), tuberculosis (SMR = 3.06), digestive diseases (SMR = 1.47), alcoholism (SMR = 2.24) and symptoms, signs and ill defined conditions (SMR = 2.00) were greater in this cohort compared to the Western Australian male population.. Asbestos related diseases, particularly malignant mesothelioma, lung cancer and pneumoconiosis, continue to be the main causes of excess mortality in the former blue asbestos miners and millers of Wittenoom.

Topics: Aged; Asbestos, Crocidolite; Asbestosis; Cause of Death; Follow-Up Studies; Humans; Italy; Lung Neoplasms; Male; Mesothelioma; Mining; Occupational Exposure; Peritoneal Neoplasms; Pleural Neoplasms; Respiratory Tract Diseases; Western Australia

The impact of crocidolite exposure on the health of former Wittenoom miners and millers (largely male) has been well documented. Less is known about the health outcomes of the 2,968 women and girls who lived (N = 2,552) and worked (N = 416) in the blue asbestos milling and mining town of Wittenoom between 1943 and 1992. Quantitative exposure measurements were derived from dust studies undertaken over the lifetime of the mine and mill and the township. Incident cancers were obtained from the Western Australian (WA) Cancer Registry and the National Cancer Clearing House. Standardized incidence ratios (SIRS) compared Wittenoom females with the WA female population. Exposure-response relationships were examined using a matched case-control study design. There were (47) mesothelioma and (55) lung cancer cases among the 437 cancers in the Wittenoom females over the period 1960-2005. When compared to the WA female population, Wittenoom women and girls had higher rates of mesothelioma and possibly lung cancer. Mesothelioma incidence rates are increasing with the incidence rate of 193 per 100,000 in the period 2000-2005 being more than double that for the period 1995-1999 at 84 per 100,000. A significant exposure-response relationship was present for mesothelioma, but not for lung cancer. Forty years after the asbestos mine and mill at Wittenoom were closed, there is a high toll from cancer among the former female residents of the town and company workers.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Aged, 80 and over; Asbestos, Crocidolite; Case-Control Studies; Child; Cohort Studies; Environmental Exposure; Female; Humans; Incidence; Lung Neoplasms; Mesothelioma; Middle Aged; Mining; Occupational Exposure; Surveys and Questionnaires; Western Australia

Human malignant mesothelioma (HMM), which is strongly related to asbestos exposure, exhibits high resistance to many anticancer drugs. Asbestos fibre deposition in the lung may cause hypoxia and iron chelation at the fibre surface. Hypoxia-inducible factor (HIF)-1alpha, which is upregulated by a decreased availability of oxygen and iron, controls the expression of membrane transporters, such as P-glycoprotein (Pgp), which actively extrude the anticancer drugs. The present study aimed to assess whether asbestos may play a role in the induction of doxorubicin resistance in HMM cells through the activation of HIF-1alpha and an increased expression of Pgp. After 24-h incubation with crocidolite asbestos or with the iron chelator dexrazoxane, or under hypoxia, HMM cells were tested for HIF-1alpha activation, Pgp expression, accumulation of doxorubicin and sensitivity to its toxic effect. Crocidolite, dexrazoxane and hypoxia caused HIF-1alpha activation, Pgp overexpression and increased resistance to doxorubicin accumulation and toxicity. These effects were prevented by the co-incubation with the cell-permeating iron salt ferric nitrilotriacetate, which caused an increase of intracellular iron bioavailability, measured as increased activity of the iron regulatory protein-1. Crocidolite, dexrazoxane and hypoxia induce doxorubicin resistance in human malignant mesothelioma cells by increasing hypoxia-inducible factor-1alpha activity, through an iron-sensitive mechanism.

Topics: Antineoplastic Agents; Asbestos; Asbestos, Crocidolite; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Doxorubicin; Drug Resistance, Neoplasm; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Iron; Lung; Lung Neoplasms; Mesothelioma; Razoxane

Blue asbestos was mined and milled at Wittenoom, Western Australia, from 1943 until 1966. Various public records were used to establish a cohort of residents of the nearby township. Mine tailings were distributed throughout the town.. To report the incident number of malignant mesotheliomas that have occurred in residents of the town who did not work at the mine or mill; and to determine if female subjects are more susceptible to asbestos exposure than male subjects, and if children are more susceptible than adults.. A total of 4,768 residents of the town of Wittenoom have been followed up in cancer and death registries.. There were 67 cases of mesothelioma, and 64 deaths with mesothelioma to the end of 2002. The mortality rate with mesothelioma increased with increasing residence duration, time since first exposure, and estimated cumulative exposure. The mesothelioma mortality rate was consistently lower for female subjects when compared with male subjects, but the dose-response curve was steeper for female subjects. The rate was lower in those first exposed as children compared with those first exposed at > or = 15 years of age. The dose-response slope for asbestos exposure and mortality from mesothelioma was not different between those who were first exposed as children than those who were first exposed at > or = 15 years of age.. Former residents of a crocidolite mining town have a high rate of mesothelioma. The rate is higher in male subjects and those > or = 15 years of age at first exposure, but women have a steeper dose-response curve.

Topics: Age Factors; Asbestos, Crocidolite; Carcinogens; Cohort Studies; Environmental Exposure; Female; Humans; Incidence; Male; Mesothelioma; Mining; Residence Characteristics; Sex Factors; Survival Rate; Western Australia

We have observed that in three human malignant mesothelioma cell lines, crocidolite asbestos induced the activation of the transcription factor NF-kappaB and the synthesis of nitric oxide (NO) by inhibiting the RhoA signaling pathway. The incubation with crocidolite decreased the level of GTP-bound RhoA and the activity of Rho-dependent kinase, and induced the activation of Akt/PKB and IkBalpha kinase, leading to the nuclear translocation of NF-kappaB. The effects of crocidolite fibers on NF-kappaB activation and NO synthesis were mimicked by Y27632 (an inhibitor of the Rho-dependent kinases) and toxin B (an inhibitor of RhoA GTPase activity), while they were reverted by mevalonic acid, the product of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase. Furthermore, crocidolite, similarly to mevastatin, inhibited the synthesis of cholesterol and ubiquinone and the prenylation of RhoA: these effects were prevented in the presence of mevalonic acid. This suggests that crocidolite fibers might inhibit the synthesis of isoprenoid molecules at the level of the HMGCoA reductase reaction or of an upstream step, thus impairing the prenylation and subsequent activation of RhoA. Akt can stimulate NO synthesis via a double mechanism: it can activate the inducible NO synthase via the NF-kappaB pathway and the endothelial NO synthase via a direct phosphorylation. Our results suggest that crocidolite increases the NO levels in mesothelioma cells by modulating both NO synthase isoforms.

Topics: Active Transport, Cell Nucleus; Amides; Animals; Asbestos, Crocidolite; Cattle; Cell Line, Tumor; Enzyme Activation; Enzyme Induction; Enzyme Inhibitors; Humans; I-kappa B Kinase; Isoenzymes; Lovastatin; Mesothelioma; Mevalonic Acid; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase; Proto-Oncogene Proteins c-akt; Pyridines; rho GTP-Binding Proteins; Second Messenger Systems; Terpenes

Topics: Adult; Aged; Asbestos, Crocidolite; Causality; Female; Humans; Male; Mesothelioma; Middle Aged; Military Personnel; Models, Statistical; Occupational Diseases; Occupational Exposure; Peritoneal Neoplasms; Pleural Neoplasms; Respiratory Protective Devices; Risk Assessment; Risk Factors; World War II

An unusual cluster of malignant mesothelioma was evidenced in Biancavilla, a Sicily village where no inhabitant had been significantly and professionally exposed to asbestos. Mineralogical and environmental studies led to the identification of a new prismatic amphibole, named fluoro-edenite. We previously reported, by using the human lung epithelial A549 cells, that prismatic fluoro-edenite was unable to induce changes that could be somehow related to cellular transformation, and this was in accordance with studies carried out in vivo. More recently, a fibrous amphibole with a composition very similar to that of prismatic fluoro-edenite, was identified in Biancavilla. This fibrous fluoro-edenite was shown to induce mesothelioma in rats. In keeping with this effect in vivo, in the present work we observed multinucleation and spreading, common features of transformed cells, as well as pro-inflammatory cytokine release in A549 cells. Such cell changes occurred without interfering with the passage of the resulting multinucleated cells through the cell cycle and without condemning cells to death. Hence, in lung epithelial cells, fibrous fluoro-edenite behaved similarly to the unrelated asbestos type crocidolite, whose connection with severe inflammation and cancer of the lung is renowned.

Topics: Asbestos, Amphibole; Asbestos, Crocidolite; Cell Proliferation; Cell Survival; Cells, Cultured; Cytokines; Epithelial Cells; Humans; Inflammation; Interleukin-6; Interleukin-8; Lung; Mesothelioma

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). The relationships between plasma concentrations of retinol, carotene and vitamin E and incidence of mesothelioma and lung cancer in a cohort of people from this town were examined. The relationships were evaluated by survival analyses using data obtained at the first visit, at each visit and with the rate of change of each vitamin during the period of follow-up. Of 1953 study participants, 65 developed mesothelioma during the follow-up, and 47 developed lung cancer. A lower incidence of mesothelioma was related to plasma concentrations of retinol at the first visit [hazard ratio (HR)=0.63, 95% confidence interval=0.41-0.99], and to measurements at each visit (HR=0.71, 95% confidence interval=0.50-1.00). Plasma carotene concentrations at the first measurement, but not during the follow-up period, were associated with lower incidence of lung cancer in men and in workers. No significant associations were found between carotene concentrations and incidence of mesothelioma. Vitamin E concentrations were not significantly associated with mesothelioma or lung cancer incidence. These findings suggest that people with chronically low plasma levels of retinol have increased risk of developing mesothelioma and lung cancer.

Topics: Adult; Aged; Asbestos, Crocidolite; Carcinogens, Environmental; Carotenoids; Cohort Studies; Female; Humans; Incidence; Lung Neoplasms; Male; Mesothelioma; Middle Aged; Occupational Exposure; Smoking; Vitamin A; Vitamin E; Vitamins; Western Australia

Asbestos has had many commercial applications, including its use as a major component in various types of filters. Between 1952 and 1956, crocidolite asbestos was used as a component of filters for cigarettes, reportedly greatly reducing tars and nicotine from mainstream smoke. This case report quantifies asbestos burden in lung and lymph node tissue in a 67-yr-old woman who succumbed to mesothelioma. Her only historically documented exposure to asbestos was from smoking crocidolite asbestos-containing filtered cigarettes between 1952 and 1956. Tissue digestion analysis by analytical transmission electron microscopy (ATEM) identified crocidolite fibers in lungs and thoracic lymph nodes. Combined ATEM data of lung and lymph node tissue clarified the patient's exposure to asbestos and particularly to crocidolite asbestos and thus to the presence of an entity recognized as the causal agent for mesothelioma.

Topics: Aged; Asbestos, Crocidolite; Body Burden; Fatal Outcome; Female; Humans; Lung; Lymph Nodes; Mesothelioma; Microscopy, Energy-Filtering Transmission Electron; Pleural Neoplasms; Smoking

Only a fraction of subjects exposed to asbestos develop malignant mesothelioma (MM), suggesting that additional factors may render some individuals more susceptible. We tested the hypothesis that asbestos and Simian virus (SV40) are cocarcinogens. Asbestos and SV40 in combination had a costimulatory effect in inducing ERK1/2 phosphorylation and activator protein-1 (AP-1) activity in both primary Syrian hamster mesothelial cells (SHM) and primary human mesothelial cells (HM). Ap-1 activity caused the expression and activation of matrix metalloprotease (MMP)-1 and MMP-9, which in turn led to cell invasion. Experiments using siRNA and chemical inhibitors confirmed the specificity of these results. The same effects were observed in HM and SHM. Experiments in hamsters showed strong cocarcinogenesis between asbestos and SV40: SV40 did not cause MM, asbestos caused MM in 20% of hamsters, and asbestos and SV40 together caused MM in 90% of hamsters. Significantly lower amounts of asbestos were sufficient to cause MM in animals infected with SV40. Our results indicate that mineral fibers and viruses can be cocarcinogens and suggest that lower amounts of asbestos may be sufficient to cause MM in individuals infected with SV40.

Topics: Animals; Asbestos, Crocidolite; Carcinogens; Cells, Cultured; Cricetinae; Enzyme Activation; Epithelial Cells; Epithelium; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Matrix Metalloproteinase 1; Matrix Metalloproteinase 9; Mesocricetus; Mesothelioma; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Proto-Oncogene Proteins c-fos; Repressor Proteins; RNA, Small Interfering; Simian virus 40; Transcription Factor AP-1; Transcriptional Activation

Between 1940 and 1944 military gas masks with filter pads containing 20% crocidolite were assembled in a Nottingham factory.. Records supplied by the late Professor Stephen Jones were of 1154 persons, mainly women, who had worked in the factory during this period; they included many deaths from mesothelioma. A systematic effort was therefore made to establish causes of death for the whole cohort.. Of 640 employees with full name and sex recorded, 567 (89%) were traced. Of these, 491 had died, including 65 from mesothelioma, though only 54 were certified as such. After exclusion of these 54, standardised mortality ratios were significantly raised for respiratory cancer (SMR 2.5) and carcinomatosis (SMR 3.2). The pattern of mortality in the remaining 514 employees without full identification was similar, but a low tracing rate (40%) did not justify their further analysis. The first death from mesothelioma was in 1963 (22 years after first exposure) and the last in 1994, whereas a further 5.0 cases would have been expected between 1996 and 2003 (p = 0.0065).. These findings in a cohort followed over 60 years after brief exposure to crocidolite confirm a high and specific risk of mesothelioma (28% peritoneal) and perhaps of lung cancer some 20-50 years later. The statistically significant absence of further mesothelioma cases during the past eight years suggests that crocidolite, though durable, is slowly removed.

Topics: Asbestos, Crocidolite; Cause of Death; Cohort Studies; England; Female; Humans; Male; Mesothelioma; Neoplasms; Occupational Diseases; Occupational Exposure; Respiratory Protective Devices

To explore the risk of developing malignant neoplasm in a cohort with the history of environmental exposure to crocidolite asbestos.. A retrospective cohort and follow-up study covering 15 years (1987 --> 1995 --> 2001) was carrid out in a small town in Yunnan province. The cohort comprised 6254 local inhabitants. The deaths from and the RR of asbestos-related malignant neoplasms were studied.. There were 186 deaths from neoplasms in the observation group, the mortality being 2160.5 per 10(6) person-years (RR=1.293, 95%CI: 1.032-1.618), 20 of those deaths were caused by mesothelioma, with a crude mortality of 232.3 per 10(6) person-years (RR=17.929; 95%CI: 2.406-133.592). The mortalities for men and women were 267.5 and 186.7 per 10(6) person-years respectively. The crude mortality from lung cancer (56 deaths) was 650.5 per 10(6) person-years,there is no significance between the two groups (RR=1.434; 95%CI: 0.968-2.486). The difference in mortality from gastrointestinal cancer between the two groups is not significant, whereas the risk of man intestinal cancer in the observation is significant (RR=3.71; 95%CI: 1.077-13.270).. The risk of developing mesothelioma is significantly increased in the population with environmental exposure to crocidolite. The risk of man intestinal cancer in the town awaits additional studies.

Topics: Adult; Aged; Asbestos, Crocidolite; China; Cohort Studies; Environmental Exposure; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Mesothelioma; Middle Aged; Pleural Neoplasms; Retrospective Studies; Risk Factors

Malignant pleural mesothelioma (MPM) is a fatal neoplasm with no acceptable curative approaches. We used serial analysis of gene expression (SAGE) to compare the gene expression pattern of a surgically resected MPM to the autologous normal mesothelium. Intelectin gene overexpression (>139-fold) was found in the tumor. Online SAGE datasets revealed intelectin to be consistently present in mesothelioma(s), ovarian cancer, and colon cancer. Intelectin mRNA expression was found by RT-PCR in 4 of 5 resected MPM tumors, and Intelectin protein expression was confirmed by immunohistochemistry in 28 of 53 MPM tumors, and in 4 of 4 mesothelioma cell lines studied by Western blot. A marked induction in intelectin gene expression was observed among human primary mesothelial cells as a consequence of crocidolite asbestos exposure and simian virus 40 infection. Intelectin overexpression in mesothelioma could have potential screening, and therapeutic implications.

Topics: Asbestos, Crocidolite; Blotting, Western; Case-Control Studies; Colonic Neoplasms; Cytokines; Databases, Genetic; Female; Gene Expression Profiling; GPI-Linked Proteins; Humans; Immunohistochemistry; Lectins; Mesothelioma; Ovarian Neoplasms; Pleural Neoplasms; Polyomavirus Infections; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured; Tumor Virus Infections

Malignant mesothelioma has been linked to asbestos exposure and generally has a poor prognosis because it is often diagnosed in advanced stages and is refractory to conventional therapy. Human malignant mesotheliomas accumulate multiple somatic genetic alterations, including inactivation of the NF2 and CDKN2A/ARF tumor suppressor genes. To better understand the significance of NF2 inactivation in malignant mesothelioma and identify tumor suppressor gene alterations that cooperate with NF2 loss of function in malignant mesothelioma pathogenesis, we treated Nf2 (+/-) knockout mice with asbestos to induce malignant mesotheliomas. Asbestos-exposed Nf2 (+/-) mice exhibited markedly accelerated malignant mesothelioma tumor formation compared with asbestos-treated wild-type (WT) littermates. Loss of the WT Nf2 allele, leading to biallelic inactivation, was observed in all nine asbestos-induced malignant mesotheliomas from Nf2 (+/-) mice and in 50% of malignant mesotheliomas from asbestos-exposed WT mice. For a detailed comparison with the murine model, DNA analyses were also done on a series of human malignant mesothelioma samples. Remarkably, similar to human malignant mesotheliomas, tumors from Nf2 (+/-) mice showed frequent homologous deletions of the Cdkn2a/Arf locus and adjacent Cdkn2b tumor suppressor gene, as well as reciprocal inactivation of Tp53 in a subset of tumors that retained the Arf locus. As in the human disease counterpart, malignant mesotheliomas from the Nf2 (+/-) mice also showed frequent activation of Akt kinase, which plays a central role in tumorigenesis and therapeutic resistance. Thus, this murine model of environmental carcinogenesis faithfully recapitulates many of the molecular features of human malignant mesothelioma and has significant implications for the further characterization of malignant mesothelioma pathogenesis and preclinical testing of novel therapeutic modalities.

Topics: Animals; Asbestos, Crocidolite; Cocarcinogenesis; Disease Models, Animal; Genes, Neurofibromatosis 2; Genes, p53; Genetic Predisposition to Disease; Humans; Mesothelioma; Mice; Mice, Knockout; Tumor Suppressor Protein p14ARF

Topics: Asbestos; Asbestos, Amosite; Asbestos, Crocidolite; History, 19th Century; History, 20th Century; Mesothelioma; Mining; Occupational Medicine; Pathology; Physicians; Public Health; Research; Research Personnel; Respiratory Tract Diseases; Silicosis; South Africa; Workplace

To report the number of malignant pleural and peritoneal mesotheliomas that have occurred in former Wittenoom crocidolite workers to the end of 2000, and to compare this with earlier predictions.. A group of 6493 men and 415 women who had worked at the former Wittenoom crocidolite mine and mill at some time between 1943 and 1966 have been followed up throughout Australia and Italy to the end of 2000.. The cumulative number of mesotheliomas up to 2000 was 235 in men (202 pleural, 33 peritoneal) and seven (all pleural) in women. There had been 231 deaths with mesothelioma (9% of known deaths).. The number of deaths in men with mesothelioma between 1987 and 2000 was at the low end of the predictions made earlier based on the number of cases to 1986. If this trend continues, it is predicted that about another 110 deaths with mesothelioma will occur in men by 2020.

Topics: Adult; Age of Onset; Aged; Asbestos, Crocidolite; Female; Humans; Male; Mesothelioma; Middle Aged; Mining; Mortality; Occupational Diseases; Occupational Exposure; Peritoneal Neoplasms; Pleural Neoplasms; Survival Analysis; Textile Industry; Western Australia

The cytotoxic effects of asbestos are partly mediated by the production of free radicals, including nitric oxide (NO). SV40 has been suggested to synergize with asbestos in the pathogenesis of malignant mesothelioma. Crocidolite asbestos fibers induced in human mesothelial and malignant mesothelioma cells a significant increase of NO synthase activity and expression, which was absent in SV40-infected cells. Furthermore, SV40 infection prevented the NF kappa B activation elicited by crocidolite in both mesothelial and mesothelioma cells. These data suggest that SV40, by inhibiting the synthesis of NO, could favor the survival of transformed, potentially neoplastic cells.

Topics: Asbestos, Crocidolite; Cells, Cultured; Down-Regulation; Epithelial Cells; Humans; Mesothelioma; NF-kappa B; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Polyomavirus Infections; Simian virus 40; Tumor Virus Infections

In the first half of the twentieth century, asbestos was a controversial mineral because of its association with asbestosis and asbestos-related lung cancer. It has proved no less so since the 1960s, when another asbestos cancer, mesothelioma, was identified. Mesothelioma appeared to be more strongly linked with blue asbestos (crocidolite) than with the other asbestos varieties, brown (amosite) and white (chrysotile). This finding triggered a fierce debate between "chrysophiles" (those who declared chrysotile innocuous) and "chrysophobes" (those who believed it was a mortal hazard). This essay attempts the first history of the chrysotile controversy, which shows that a scientific consensus on the safety of white asbestos was very slow to emerge. This was only partly due to the complexities of scientific research. Political, economic, and social factors have militated against a speedy resolution of the debate, facilitating the continued production and use of asbestos in the developing world.

Topics: Asbestos; Asbestos, Amphibole; Asbestos, Crocidolite; Asbestos, Serpentine; Asbestosis; Global Health; History, 20th Century; Humans; Lung Neoplasms; Mesothelioma; Risk Factors

Lung tissue from 15 women who died from mesothelioma was evaluated for tissue burden of ferruginous bodies and uncoated asbestos fibers. The group contained individuals who had occupational exposure to asbestos and others had family members whose work history included vocations where contact with asbestos containing materials occurred.. Tissue samples from tumor free lung were digested and filtered and then investigated for ferruginous bodies by light microscopy and asbestos and non-asbestos fibers by analytical transmission electron microscopy (ATEM). Size and type of fibers were also analyzed.. Asbestos bodies were found in 13 of the 15 samples and asbestos fibers were found in all cases. The most commonly found uncoated asbestos fiber in these individuals was amosite whereas tremolite was the second most commonly found form. The asbestos fiber burden in these females was often of mixed types.. The asbestos body and fiber burden in these cases show variation in tissue burden. Some cases in this study had appreciable burden, which was attributed to secondhand exposure from occupationally exposed family members. Mesothelioma can occur also in individuals with comparatively low tissue burdens of asbestos.

Topics: Aged; Aged, 80 and over; Asbestos, Amosite; Asbestos, Amphibole; Asbestos, Crocidolite; Asbestosis; Body Burden; Environmental Exposure; Female; Humans; Lung; Lung Neoplasms; Mesothelioma; Microscopy, Electron; Middle Aged; Mineral Fibers; Occupational Exposure; Reproducibility of Results

Desmoplastic mesothelioma is a rare subtype of diffuse malignant mesothelioma, and is often difficult to distinguish from reactive pleural fibrosis because of associated extensive collagen fibrosis. An 82-year-old woman with a severe cough was revealed to have pleural effusion and diffuse pleural thickening on the right side. Antibiotics were ineffective, and a compression fracture of the ninth and tenth thoracic vertebral bodies was recognized on X-ray. Autopsy revealed a diffuse pleural thickening with hyalinized collagen tissue in the central part of the pleura. However, the peripheral part of the fibrous tissue was composed of spindle and polygonal cell proliferation that were immunohistochemically positive for antibodies against cytokeratin and vimentin. In addition, the ninth and tenth thoracic spines were infiltrated by similar cells. The condition was diagnosed as desmoplastic mesothelioma with bone metastases. Asbestos bodies were detected in the thickened pleura and fibrosed alveolar septa, and it was suggested retrospectively that the patient had been exposed to asbestos. Thus, autopsy analyses of fibrous pleurisy are necessary to detect a desmoplastic variant of mesothelioma of the pleura and its association with asbestos exposure.

Topics: Aged; Aged, 80 and over; Asbestos, Crocidolite; Bone Neoplasms; Fatal Outcome; Female; Humans; Keratins; Mesothelioma; Pleural Neoplasms; Radiography, Thoracic; Vimentin

Biallelic NF2 gene inactivation is frequently found in human malignant mesothelioma. In order to assess whether NF2 hemizygosity may enhance susceptibility to asbestos fibres, we investigated the Nf2 status in mesothelioma developed in mice presenting a heterozygous mutation of the Nf2 gene (Nf2(KO3/+)), after intraperitoneal inoculation of crocidolite fibres. Asbestos-exposed Nf2(KO3/+) mice developed tumoural ascites and mesothelioma at a higher frequency than their wild-type (WT) counterparts (P&<0.05). Six out of seven mesothelioma cell lines established from neoplastic ascitic fluids of Nf2(KO3/+) mice exhibited loss of the WT Nf2 allele and no neurofibromatosis type 2 protein expression was found in these cells. The results show the importance of the NF2 gene in mesothelial oncogenesis, the potential association of asbestos exposure and tumour suppressor gene inactivation, and suggest that NF2 gene mutation may be a susceptibility factor to asbestos.

Topics: Animals; Asbestos, Crocidolite; Genes, Neurofibromatosis 2; Genetic Predisposition to Disease; Mesothelioma; Mice; Mice, Nude; Peritoneal Neoplasms; Reverse Transcriptase Polymerase Chain Reaction

Malignant mesothelioma is a cancer with poor prognosis associated with exposures to asbestos. The mechanisms of asbestos-induced mesotheliomas are unclear, and studies are required to find diagnostic tools and therapies to improve the survival rates of patients. After oligonucleotide microarray analysis (Affymetrix array) of normal rat pleural mesothelial (RPM) cells, RPM cells exposed to crocidolite asbestos, and rat mesotheliomas, subsets of genes that changed in expression were categorized, including the highly up-regulated, early response proto-oncogene, fra-1. Increases in fra-1 in both rat and human mesotheliomas and a subset of genes common to both asbestos-exposed RPM cells and mesotheliomas that mimicked fra-1 patterns of expression were subsequently confirmed using real-time quantitative PCR. Using RNA interference technology, fra-1 gene silenced RPM cells were assayed by real-time quantitative PCR for the expression of possible fra-1-regulated genes. Results reveal that induction of cd44 and c-met is causally linked to fra-1 expression, connecting fra-1 with genes governing cell motility and invasion in mesothelioma. These studies suggest that inhibition of fra-1 signaling pathways may be a strategy for therapy of malignant mesothelioma.

Topics: Animals; Asbestos, Crocidolite; Hyaluronan Receptors; Mesothelioma; Neoplasms, Experimental; Oligonucleotide Array Sequence Analysis; Proto-Oncogene Mas; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-met; Rats; Rats, Inbred F344; RNA Interference

Cellulose fibers, along with many other organic fibers, are durable. Therefore, if inhaled, they have the potential to persist within the lung, and may then cause disease. Here we report the effects of injecting high-purity cellulose fibers into the abdominal cavity of rats. A respirable fraction of cellulose fiber was collected from an aerosol of a thermo-mechanically-processed wood pulp. A sample of respirable crocidolite asbestos, known to produce mesotheliomas in rats, was used as a positive control. Total doses of 10(6), 10(7), 10(8), or 10(9) WHO fibers were injected intraperitoneally as 3 weekly aliquots. A negative control was provided by phosphate-buffered saline used to suspend the fibers for injection. There were 50 rats per treatment group except for the 10(8) and 10(9) fibers crocidolite groups which were reduced to 26 rats because of the expectation of high tumor incidence in these groups. The two higher doses of crocidolite asbestos caused greatly reduced survival compared to the saline controls. With cellulose there was a much less marked effect on survival. In the highest dose cellulose group, multiple large nodules (granulomas) and widespread adhesions (bands of new tissue connecting organs to each other and to the abdominal wall) were present in all animals. Granulomas were not observed in the 10(9) fibers crocidolite group. More than 80% of animals in the 10(8) and 10(9) crocidolite asbestos groups had mesotheliomas, a type of tumor sometimes observed in people exposed to asbestos. In contrast, there were only 2 animals in the cellulose groups with mesothelioma tumors, 1 in the 10(7) and 1 in the 10(8) groups. However, 9 (18%) of the 10(9) cellulose group had malignant tumors that, in contrast to the usual pattern of mesothelioma development following treatment with mineral fibers in rats, showed no obvious involvement of mesothelial tissues, were not associated with blood-stained ascites fluid, and were thus classified as sarcomas. This study has demonstrated that a high dose of cellulose fibers is capable of producing tumors when injected into the abdominal cavity of rats.

Topics: Air Pollutants, Occupational; Animals; Asbestos, Crocidolite; Carcinogenicity Tests; Carcinogens; Cellulose; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Male; Maximum Tolerated Dose; Mesothelioma; Mineral Fibers; Particle Size; Peritoneal Neoplasms; Pleural Neoplasms; Rats; Rats, Wistar; Sarcoma, Experimental

Asbestos fibers produce diffuse malignant mesotheliomas in chronic rodent inhalation assays or after direct intrapleural or intraperitoneal injection. In vitro models have provided evidence that asbestos fibers are genotoxic carcinogens that can directly or indirectly generate reactive oxygen- and nitrogen-derived species that cause DNA damage. Heterozygous p53+/- mice show an increased incidence and reduced latency of malignant mesotheliomas induced by weekly intraperitoneal injections of crocidolite asbestos fibers. In this study, we investigated whether loss of heterozygosity (LOH) at the p53 tumor-suppressor gene locus contributes to accelerated tumor progression. LOH was found in 50% of the tumors produced in heterozygous p53+/- mice. In contrast to tumors that arise in p53+/+ mice or those that retained one p53 allele, LOH was associated with large tumor masses with central areas of necrosis, local invasion, and penetration of lymphatics. Increased tumor size was not associated with increased levels of cell proliferation as determined by BrdU incorporation, but it was correlated with a reduction in apoptosis as determined morphologically and by the TUNEL assay. Wild-type p53 protein is essential for cell cycle arrest in response to DNA damage and in maintenance of genomic stability. Cell lines established from tumors that showed LOH at the p53 tumor-suppressor gene locus were nearly tetraploid. These results suggest that p53 haplo-insufficiency sensitizes mice to the clastogenic or aneuploidogenic effects of crocidolite asbestos fibers, resulting in a shorter latent period. As solid tumors develop, spontaneous loss of the wild-type allele accompanied by decreased apoptosis and genetic instability is associated with accelerated tumor growth, invasion, and lymphatic dissemination.

Topics: Animals; Apoptosis; Asbestos, Crocidolite; Disease Progression; DNA, Neoplasm; Genes, p53; Heterozygote; In Situ Nick-End Labeling; Injections, Intraperitoneal; Loss of Heterozygosity; Male; Mesothelioma; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Micronuclei, Chromosome-Defective; Neoplasm Invasiveness; Peritoneal Neoplasms; Pleural Neoplasms; Tumor Cells, Cultured

Asbestos has been used in many applications, but possibly one of the more unique was in the manufacturing of filters for cigarettes. The type of asbestos used in this application was crocidolite. Data from several resources indicate that crocidolite was one of the least utilized types of commercial asbestos in the United States. The present study provides quantitative tissue burden analysis data for two mesothelioma cases where the work histories included manufacturing of cigarette filters that contained crocidolite. The data include the number of asbestos bodies and uncoated fibers per gram of tissue, as well as the dimensions of these structures. The conclusion of the findings indicates that the individuals had an appreciable homogeneous exposure to crocidolite asbestos.

Topics: Aged; Asbestos, Crocidolite; Fatal Outcome; Humans; Male; Mesothelioma; Occupational Exposure; Pleural Neoplasms; Tobacco Industry

The incidence of cancer among employees of a Norwegian asbestos-cement factory was studied in relation to duration of exposure and time since first exposure. The factory was active in 1942-1968. Most of the asbestos in use was chrysotile, but for technical reasons 8% amphiboles was added.. For the identification of cancer cases, a cohort of 541 male workers was linked to the Cancer Registry of Norway. The analysis was based on the comparison between the observed and expected number of cancer cases. Standardized incidence ratios (SIR) and 95% confidence intervals (95% CI) were estimated. Period of first employment, duration of employment, and time since first employment were used as indicators of exposure. Poisson regression analysis was used for the internal comparisons.. The standardized incidence ratio was 52.5 (95% CI 31.1-83.0) for pleural mesothelioma, on the basis of 18 cases. The highest standardized incidence ratio was found for workers first employed in the earliest production period (SIR 99.0, 95% CI 51.3-173). No peritoneal mesothelioma was found. The standardized incidence ratio for lung cancer was 3.1 (95% CI 2.14.3), but no dose-response effect was observed. The ratio of mesothelioma to lung cancer cases was 1:2.. This study showed a high incidence of mesothelioma and a high ratio of mesothelioma to lung cancer among asbestos-cement workers. The high incidence of mesothelioma was probably due to the fact that a relatively high proportion of amphiboles was used in the production process.

Topics: Aged; Asbestos; Asbestos, Amphibole; Asbestos, Crocidolite; Asbestos, Serpentine; Cohort Studies; Follow-Up Studies; Humans; Incidence; Industry; Lung Neoplasms; Male; Mesothelioma; Middle Aged; Neoplasms; Norway; Occupational Exposure; Poisson Distribution; Registries; Risk Factors; Time

To explore the risk factors for mesothelioma so as to provide epidemiological evidences for prevention of this disease and for further study of its pathogenesis.. A 1:1 paired case-control study was carried out in which asbestos exposure, life style and histories of cancer in first-degree relatives of 23 patients who had mesothelioma were compared with those of controls.. The mean age of patients was 57.96 years with a latency period of 52 years. There were no significant differences in mean exposure age, mean exposure periods, and smoking, drinking habits between patients and controls. The mean cumulative exposure of patients was 37.2 x 10(5) f, which was significantly higher than that of controls (32.3 x 10(5) f, P = 0.005). The odds ratio increased with the cumulative exposure. The percentage of cancer in first-degree relative of patients (26.1%) was significantly higher than that of controls [(4.4%, P < 0.05), OR = 7.75 (95% CI: 0.85-71.43)].. There may be a dose-response relationship between mesothelioma and asbestos exposure. A family history of cancer may be a risk factor for mesothelioma, or may indicate an increased susceptibility to mesothelioma under the same level of asbestos exposure.

Topics: Asbestos, Crocidolite; Case-Control Studies; Environmental Exposure; Family; Humans; Life Style; Mesothelioma; Middle Aged; Pleural Neoplasms; Risk Factors

Topics: Asbestos, Crocidolite; Carcinogens; Humans; Lung Neoplasms; Mesothelioma; Occupational Exposure; Risk Assessment

Malignant mesothelioma (MM) is an aggressive tumor usually associated with asbestos exposure. Although it can remain stable for prolonged periods, it has not been described to spontaneously regress. MM tumors are thought to be immunogenic based both on animal studies and on the good responses in some humans treated with immunotherapy. Here we present a case of pleural MM in which a transient spontaneous regression was associated with tumor tissue infiltration with mononuclear cells and serological evidence of anti-MM reactivity. The patient's tumor eventually progressed and with this progression there was evidence of loss of serological reactivity to some, but not all, of her MM antigens. The patient survived for 20 months and, in contrast to her initial biopsy, no significant lymphoid infiltrate was detected in her MM tissue at post mortem examination.

Topics: Antibodies, Neoplasm; Antigens, Neoplasm; Asbestos, Crocidolite; Disease Progression; Fatal Outcome; Female; Follow-Up Studies; Humans; Lung; Lymphocytes, Tumor-Infiltrating; Mesothelioma; Middle Aged; Mineral Fibers; Neoplasm Regression, Spontaneous; Occupational Diseases; Pleural Neoplasms; Tomography, X-Ray Computed; Tumor Cells, Cultured

Human malignant mesotheliomas are induced almost exclusively by fibrous dusts. The nature of interactions between fibers and target cells, and the molecular mechanisms leading to tumorigenesis, are not yet understood. Here, the mRNA expression patterns at different stages of asbestos-induced carcinogenesis in rats were monitored by suppression subtractive hybridization (SSH) and array assay. Several genes were upregulated in pretumorous tissues from asbestos-treated rats, in asbestos-induced tumors and in cells treated with asbestos in vitro. The upregulation of the proto-oncogene c-myc, fra-1 and egfr in fiber-induced carcinogenesis was demonstrated at different stages of carcinogenesis. A possible role of Fra-1 as one of the dimeric proteins generating the AP-1 transcription factor was substantiated by its dose-dependent expression in mesothelial cells treated with asbestos in vitro. The upregulation of osteopontin (an extracellular matrix protein) and of zyxin and integrin-linked kinase (intracellular proteins associated with the focal adhesion contact), indicate that fibers may affect integrin-linked signal transduction and extracellular matrix proteins.

Topics: Animals; Asbestos, Crocidolite; Base Sequence; Carcinogens; Cell Transformation, Neoplastic; DNA Primers; ErbB Receptors; Genes, myc; Mesothelioma; Precancerous Conditions; Proto-Oncogene Mas; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Up-Regulation

To find the risk of developing mesothelioma in a cohort born in 1916-36 in Prieska, Northern Cape Province, South Africa.. A birth cohort mortality study was carried out in a small town in the Northern Cape Province, South Africa, with a history of crocidolite asbestos mining and milling. The cohort comprised all white births registered in the magisterial district of Prieska from 1916 to 1936, inclusive (2390). Causes of death due to mesothelioma and other cancers as recorded on medical certificates of cause of death were investigated. Person-years analysis was used to calculate mortalities due to mesothelioma, other respiratory cancers, and other non-respiratory cancers. Proportional cancer mortalities were also calculated for mesothelioma and other specific neoplasms.. The follow up rate for the cohort was 74.3% in 1995, and 683 traced members (38.6%) had died. Cause of death was unknown for 6.4% of deaths. There were 118 cases of cancer, 28 of them from mesothelioma, giving a cause specific mortality for mesothelioma of 277 (170-384) per 10(6) person-years. The rates for men and women were 366 and 172 per 10(6) person-years, respectively. The mortality for lung cancer (29 deaths) was 287 (135-436) per 10(6) person-years, and that for other non-respiratory cancers (60 deaths) was 593 (442-745). Two cases of laryngeal and four of colon cancer were observed. All cancer mortality, mesothelioma, and lung cancer proportional cancer mortality ratios were increased.. The mortality for mesothelioma in men was twice that in women, probably because men were more likely to have had both occupational and environmental exposure to asbestos. Nevertheless, the mortality in women was still high and is probably indicative of the environmental exposure as white women were rarely employed in the asbestos industry in the Prieska area. Due to the long latency from first exposure to diagnosis of the neoplasm, the cause specific mortality in this cohort could be expected to increase rapidly over the next 10 years.

Topics: Adolescent; Adult; Aged; Asbestos, Crocidolite; Child; Child, Preschool; Cohort Studies; Environmental Exposure; Female; Follow-Up Studies; Humans; Infant; Male; Mesothelioma; Middle Aged; Risk Factors; South Africa

In order to investigate the potential of pleural mesothelioma induced by crocidolite, author collected samples from four county areas (Dayao, Yaoan, Muding and Yanyuan) in China. A suspension of 1 ml containing 20 mg crocidolite fiber was injected into the right pleural cavity of each rat in various test groups and UICC crocidolite group, totally 40 mg. The negative control was given saline. The results showed that the incidence of mesothelioma was 56.0%-68.8% (in which the rate of induction in Yanyuan group was the highest), and the survival time of the first case of mesothelioma was 273-347 days in the test groups, the Yanyuan group had shorter latency, and the mean survival days of the rats with mesothelioma for four groups were 560, 490, 593 and 498 days respectively; the shortest mean survival time was that for Yanyuan group. The major histological type of mesothelioma induced by crocidolite was the fibrous type. The degree of differentiation in all mesotheliomas was mainly intermediate and low. The results suggested that when rats were intrapleurally inoculated with samples of crocidolite and saline, an appreciable proportion of animals developed mesothelioma except those of the saline group. Compared with other groups, the Yanyuan group had stronger potential of crocidolite-induced mesothelioma.

Topics: Animals; Asbestos, Crocidolite; Female; Male; Mesothelioma; Pleural Neoplasms; Random Allocation; Rats; Rats, Wistar

Crocidolite, a carcinogenic asbestos in humans, specifically induces mesothelioma. We investigated the cytogenotoxic effects of crocidolite in a human mesothelioma cell line, MSTO211H, and a human promyelocytic leukemia cell line, HL60. Using confocal laser scanning microscopy, we found that the MSTO211H cells had phagocytotic activity, whereas the HL60 cells did not. In the MSTO211H cells, crocidolite decreased the cell population and increased the numbers of polynucleated cells (PN) and tetraploid cells, and increased the coefficients of variation (CV) of DNA contents in G0/G1 cells and the formation of 8-hydroxydeoxyguanosine. In contrast, crocidolite showed none of these cytogenotoxic effects in HL60 cells. To investigate the importance of phagocytosis in the cytogenotoxicity of crocidolite, we sorted the crocidolite-phagocytosed cells from less-phagocytosed cells by fluorescence-activated cell sorting, and studied the differences in cytogenotoxicity between these two cell groups. We found significant increases in the numbers of PN and tetraploid cells and the CV in the crocidolite-phagocytosed cells compared to the less-phagocytosed cells. These findings indicate that MSTO211H cells are susceptible to the cytogenotoxic effects of asbestos due to their phagocytotic activity, and that the MSTO211H cell line is suitable for the detection of such effects on human cells by asbestos and other materials which need to be phagocytosed to exert their toxicity.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Asbestos; Asbestos, Crocidolite; Cell Division; Deoxyguanosine; Humans; Mesothelioma; Microscopy, Confocal; Mutagenicity Tests; Mutagens; Neutrophils; Phagocytosis; Tumor Cells, Cultured

Topics: Adult; Asbestos, Crocidolite; Asbestos, Serpentine; Asbestosis; Child; Humans; Lung Neoplasms; Mesothelioma; Mining; South Africa

To describe the exposure experiences of South African mesothelioma cases, with emphasis on the contribution made to the caseload by different fibre types, the proportion of subjects with no recall of asbestos exposure and only environmental contact, and the importance of putative causes other than asbestos.. A multi-centred case-control study.. 123 patients with mesothelioma interviewed by trained interviewers in study centres established in Johannesburg, Kimberley, Pretoria, Bloemfontein, Cape Town and Port Elizabeth.. A convincing history of asbestos exposure was obtained in the overwhelming majority of cases (only 5 cases had unlikely asbestos exposure). Twenty-three subjects had worked on Cape crocidolite mines, 3 at Penge (an amosite mine), 3 on mines producing amosite and Transvaal crocidolite and 1 on a Transvaal crocidolite mine. Exclusively environmental exposure accounted for at least 18% of cases; 91% of these cases (20/22 subjects) had had contact with Cape crocidolite. There was a relative paucity of cases linked to amosite and no convincing chrysotile case. Non-asbestos causes occur rarely, if at all, in South Africa.. The preponderance of crocidolite cases, followed by amosite and then chrysotile cases, is consistent with the view that there is a fibre gradient of mesotheliomagenic potential for South African asbestos (crocidolite > amosite > chrysotile).

Topics: Asbestos, Amosite; Asbestos, Crocidolite; Carcinogens; Case-Control Studies; Disease Outbreaks; Female; Humans; Male; Mesothelioma; Middle Aged; Mining; Occupational Exposure; South Africa

This study aimed to estimate exposure-response relationships for mesothelioma and environmental exposure to crocidolite. All 4,659 former residents of Wittenoom, Western Australia (WA) who lived there between 1943 and 1993 for at least 1 mo and were not directly employed in the crocidolite industry, were followed-up through the WA death, cancer and mesothelioma registries, electoral rolls, and telephone books. In 1992, all subjects who should be traced were sent a questionnaire. Exposure levels were estimated from results of periodic environmental surveys and duration of residence. Incidence rates were standardized to the World Population and Cox Regression was used to estimate the effects of exposure on incidence. To the end of 1993, 27 cases of mesothelioma were diagnosed. Mesothelioma cases stayed longer at Wittenoom, had a higher average intensity of exposure, and a higher cumulative exposure to crocidolite than control subjects. The standardized incidence of mesothelioma was 260 per million person-years, and was similar for males and females. The rate increased significantly with time from first exposure, duration of exposure and cumulative exposure. At these levels of crocidolite exposure, there is a significantly increased risk of mesothelioma, which is dose-dependent.

Topics: Adult; Aged; Asbestos, Crocidolite; Carcinogens; Cause of Death; Environmental Exposure; Female; Follow-Up Studies; Humans; Incidence; Male; Mesothelioma; Middle Aged; Population Surveillance; Proportional Hazards Models; Registries; Residence Characteristics; Risk Factors; Surveys and Questionnaires; Time Factors; Western Australia

To assess the risk of lung cancer and mesothelioma after environmental exposure to crocidolite for 20-30 years, a retrospective cohort study was carried out in farmers who had been exposed to crocidolite in environment. 1610 subjects were followed up for 9 years (Jan. 1, 1987 Dec. 31, 1995). The control group consisted of 7646 farmers who resided in the noncrocidolite pollution rural area in the same province. The results showed that the annual mortality rate was 43.75 per 100,000 population for lung cancer, and 36.46 per 100,000 for mesothelioma. Significantly high risks of lung cancer (RR 5.67) and mesothelioma (RR 182.3) were noted. These results demonstrate a strong causal association between lung cancer, mesothelioma and exposure to crocidolite.

Topics: Adult; Aged; Asbestos, Crocidolite; China; Cohort Studies; Environmental Exposure; Female; Humans; Lung Neoplasms; Male; Mesothelioma; Middle Aged; Retrospective Studies; Risk Factors

Exposure of mesothelial cells to asbestos fibers in vitro has been shown to induce DNA damage mediated by oxidants. An early cellular response to DNA damage is increased expression of the p53 protein. This protein induces transcription of genes that activate cell cycle checkpoints or induce apoptosis. A murine mesothelial cell line that spontaneously acquired a point mutation in the p53 gene shows increased sensitivity to DNA damage induced by crocidolite asbestos fibers. It is hypothesized that p53-deficient mice will show increased sensitivity to the genotoxic effects of asbestos and accelerated development of malignant mesotheliomas.

Topics: Alleles; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Asbestos, Crocidolite; Camptothecin; Carcinogens; Chromosomes; Genes, p53; Lung Neoplasms; Mesothelioma; Mice; Mice, Transgenic; Tumor Suppressor Protein p53

Molecular markers such as mutational spectra or mRNA expression patterns may give some indication of the mechanisms of carcinogenesis induced by fibers and other carcinogens. In our study, tumors were induced by application of crocidolite asbestos or benzo[a]pyrene (B[a]P) to rat peritoneum. DNA and RNA of these tumors were subjected to analysis of point mutations and to investigation of mRNA expression patterns. With both assays we found typical features depending on the type of carcinogen applied. The analysis of point mutations in the tumor suppressor gene p53 revealed mutations in the B[a]P-induced tumors. However, in the tumors induced by crocidolite asbestos that were of the same tumor type as those induced by B[a]P, mutations in p53 were not detectable. Every mutation detected on the DNA level causes an amino acid substitution within one of the functional domains of the tumor suppressor protein. Therefore, these mutations seem to be of biological relevance for tumor progression and indicate a difference in the carcinogenesis regarding the type of the carcinogenic substance. An additional specificity of crocidolite-induced tumors was detectable by analyzing the mRNA expression of the tumor suppressor gene WT1, which is known to be expressed in human mesothelial and mesothelioma cells. A relatively high amount of WT1 mRNA was measured by quantitative competitive reverse transcription-polymerase using RNA extracted from crocidolite-induced tumors. However, WT1 seems to be expressed on a rather low level in tumors induced by B[a]P.

Topics: Abdominal Neoplasms; Animals; Asbestos, Crocidolite; Benzo(a)pyrene; Carcinogens; Electrophoresis, Polyacrylamide Gel; Genes, p53; Genetic Markers; Injections, Intraperitoneal; Mesothelioma; Mineral Fibers; Peritoneal Neoplasms; Point Mutation; Polymerase Chain Reaction; Rats; Rats, Wistar; RNA, Messenger; RNA, Neoplasm

A cohort study was carried out in order to evaluate the cancer risk in the asbestos-cement industry workers. The cohort consisted of workers employed in four asbestos-cement plants. One of those plants was established in 1924, the other three in the 1960s and 1970s. Currently only two of these plants continue their production. The plants used mainly chrysotile asbestos as well as crocidolite and amosite. Amphibolite asbestos was used before the mid-nineteen eighties in production of pressure pipes utilising about 15% of the total quantity of asbestos used. The measurements of the asbestos fibre concentration at work-sites have been taken occasionally since the mid 1980s, thus, the determination of a cumulative dose for individual persons in the cohort and the evaluation of the dose-effect relationship were not feasible. It could only be supposed that the concentrations at the preparatory work-site during first years of the plants' operation accounted for several tens fibres/cm3 in the production that employed the dry method. The cohort consisted of workers employed in the plant for at least three months between beginning of the plant during the post-war period, and 1980, that is during the period when amphibolite asbestos was in use. The retrospective observation was completed on 31 December 1991. The analysis of the death risk by causes was based on a standardized mortality ratios (SMRs) calculated using the person-years method. Statistical significance of SMRs was assessed by means of Poisson distribution one-sided test. The general population of Poland was used as the reference population to estimate the death risk. The cohort comprised 4,712 persons (3,563 males and 1,149 females). Of this number 4,500 persons (3,405 males and 1,095 females) were followed. The cohort availability were 95.5%. Male mortality, both total (473 deaths; SMR = 83) and due to malignant neoplasms (108 deaths; SMR = 86) was lower than in the general population. An excess of deaths from neoplasm of the pleura was by about 23 times higher (5 deaths; SMR = 2,288) and from neoplasm of the large intestine by two times higher (7 deaths; SMR = 214). Among females (41 deaths; SMR = 50) death risk was lower than in the reference population. At a low level of total mortality from neoplasms (13 deaths; SMR = 52) a statistically significant excess of deaths from neoplasm of the pleura (2 deaths; SMR = 2,112) was observed. In the plants investigated the analysis revealed a considerably dive

Topics: Aged; Asbestos; Asbestos, Amosite; Asbestos, Crocidolite; Cohort Studies; Environmental Monitoring; Epidemiological Monitoring; Female; Humans; Incidence; Male; Mesothelioma; Middle Aged; Neoplasms; Occupational Diseases; Pleural Neoplasms; Poland; Risk Assessment; Sex Distribution; Survival Rate

Standard asbestos samples to be used for biomedical research were first prepared by the International Union Against Cancer (UICC) in 1966 in the United Kingdom and South Africa. Using modern techniques, X-ray diffractometry, analytical transmission electron microscopy, and thermal analysis, we have now analyzed these UICC samples to determine the mineral compositions (mineral phases) and their respective quantities. UICC chrysotile A (from Zimbabwe) contains 2% fibrous anthophyllite as impurity; chrysotile B (from Canada) does not contain any fibrous impurities, only non-fibrous minerals. UICC amosite and crocidolite are almost pure. UICC anthophyllite has 20-30% talc as impurity. The chemical compositions and fiber size distributions of the UICC asbestos samples have also been determined. The mean widths of the fibers of chrysotile A and B are smaller than those of the amphibole fibers. This agrees well with the earlier results which showed the two chrysotile samples to have a larger respirable fraction than the amphiboles.

Topics: Asbestos, Amosite; Asbestos, Amphibole; Asbestos, Crocidolite; Asbestos, Serpentine; Canada; Carcinogens; Differential Thermal Analysis; Humans; Lung Neoplasms; Mesothelioma; Microscopy, Electron; Mineral Fibers; Occupational Diseases; Reference Standards; X-Ray Diffraction; Zimbabwe

Although the association between asbestos exposure and mesothelioma development has been established for decades, very little is known regarding the molecular mechanism(s) by which asbestos fibers induce this disease. In this series of experiments, the potential for transforming growth factor alpha (TGF-alpha) to act as an autocrine growth factor in transformed mesothelial cells was examined in rats, a model system frequently used to assess the tumorigenic potential of fibrous particulates. Both asbestos-transformed cells and spontaneously transformed cells expressed functional EGF receptors, although only the asbestos-transformed cells expressed TGF-alpha. Expression of TGF-alpha transcripts was correlated with secretion of picogram amounts of growth factor into conditioned medium by the asbestos-transformed cells. In addition, whereas TGF-alpha inhibited the growth of spontaneously transformed mesothelial cells, it stimulated the growth of asbestos-transformed cells. Neutralizing antibody that recognized TGF-alpha secreted by the asbestos-transformed cells was able to inhibit the growth of these cells. Taken together, these data indicate that TGF-alpha acts as an autocrine growth factor for asbestos-transformed rat mesothelial cells. Therefore, in asbestos-transformed mesothelial cells, altered production and responsiveness to TGF-alpha distinguish these cells from spontaneously transformed mesothelial cells. These data suggest that differences in mesothelioma etiology may be reflected in differences in the molecular alterations present in these tumors.

Topics: Animals; Asbestos, Crocidolite; Blotting, Northern; Cell Division; Cell Line; Cell Line, Transformed; Epidermal Growth Factor; ErbB Receptors; Mesothelioma; Peritoneal Neoplasms; Phosphoproteins; Phosphotyrosine; Radioimmunoassay; Rats; Transforming Growth Factor alpha; Tumor Cells, Cultured; Tyrosine

Data from inhalation studies in which AF/HAN rats were exposed to nine different types of asbestos dusts (in 13 separate experiments) are employed in a statistical analysis to determine if a measure of asbestos exposure (expressed as concentrations of structures with defined sizes, shapes and mineralogy) can be identified that satisfactorily predicts the observed lung tumor or mesothelioma incidence in the experiments. Due to limitations in the characterization of asbestos structures in the original studies, new exposure measures were developed from samples of the original dusts that were re-generated and analyzed by transmission electron microscopy using a direct transfer technique. This analysis provided detailed information on the mineralogy (i.e., chrysotile, amosite, crocidolite or tremolite), type (i.e., fiber, bundle, cluster, or matrix), size (length and width) and complexity (i.e., number of identifiable components of a cluster or matrix) of each individual structure. No univariate measure of exposure was found to provide an adequate description of the lung tumor responses observed among the inhalation studies, although the measure most highly correlated with tumor incidence is the concentration of structures > or = 20 microns in length. Multivariate measures of exposure were identified that do adequately describe the lung tumor responses. Structures contributing to lung tumor risk appear to be long (> or = 5 microns) thin (0.4 microns) fibers and bundles, with a possible contribution by long and very thick (> or = 5 microns) complex clusters and matrices. Potency appears to increase with increasing length, with structures longer than 40 microns being about 500 times more potent than structures between 5 and 40 microns in length. Structures < 5 microns in length do not appear to make any contribution to lung tumor risk. This analysis did not find a difference in the potency of chrysotile and amphibole toward the induction of lung tumors. However, mineralogy appears to be important in the induction of mesothelioma with chrysotile being less potent than amphibole.

Topics: Administration, Inhalation; Animals; Asbestos; Asbestos, Amosite; Asbestos, Crocidolite; Asbestos, Serpentine; Dust; Environmental Exposure; Incidence; Information Systems; Likelihood Functions; Lung Neoplasms; Male; Mesothelioma; Microscopy, Electron; Multivariate Analysis; Rats; Rats, Inbred Strains; Risk Factors; Surface Properties

The relationship between occupational or environmental exposure to asbestos and the development of mesothelioma, typically after prolonged latency, has been accepted as one of cause and effect. Most studies have concluded that asbestos is not mutagenic to mammalian cells in vitro. We have studied the potential of crocidolite asbestos to induce mutations in a stable mesothelioma cell line, using a mutation assay that measures mutation at the autosomal HLA-A locus and permits clonal growth of mutant cells. The mesothelioma cell line chosen is more akin to the in vivo target cells of asbestos than human peripheral blood lymphocytes used in previous studies. Exposure of mesothelioma cells in culture to both 200 micrograms/ml and 50 micrograms/ml crocidolite for 72 hr did not result in a statistically significant difference in the mutation frequency (MF) in the HLA-A assay when compared to the spontaneous MF in these cells. Mutations in the mesothelioma cells were classified according to their molecular basis. Notwithstanding the lack of statistically significant change in overall MF, molecular analysis of mutants obtained following exposure of mesothelioma cells to crocidolite demonstrated a statistically significant increase in the class of mutations arising from loss of heterozygosity (LOH) events involving the selection locus (HLA-A) and more distal loci. Mutations following exposure to 200 micrograms/ml and 50 micrograms/ml crocidolite showed a greater frequency of LOH than did spontaneous mutants (P < 0.01 and P < 0.001, respectively). These results correlate with those obtained in an earlier study using lymphocytes. The mesothelioma cell-based assay may be useful in detecting the mutagenicity of other asbestiform fibers and man-made fibers.

Topics: Asbestos, Crocidolite; Cell Line; Cell Survival; Chromosome Deletion; Dose-Response Relationship, Drug; HLA-A Antigens; Humans; Lymphocytes; Mesothelioma; Mutagenesis; Mutagens; Tumor Cells, Cultured

Twenty cases of mesothelioma among miners of the township of Asbestos, Quebec, Canada, have been reported. To further explore the mineral characteristics of various fibrous material, we studied the fibrous inorganic content of postmortem lung tissues of 12 of 20 available cases. In each case, we measured concentrations of chrysotile, amosite, crocidolite, tremolite, talc-anthophyllite, and other fibrous minerals. The average diameter, length, and length-to-diameter ratio of each type of fiber were also calculated. For total fibers > 5 microns, we found > 1,000 asbestos fibers per mg tissue (f/mg) in all cases; tremolite was above 1,000 f/mg in 8 cases, chrysotile in 6 cases, crocidolite in 4 cases, and talc anthophyllite in 5 cases. Among cases with asbestos fibers, the tremolite count was highest in 7 cases, chrysotile in 3 cases, and crocidolite in 2 cases. The geometric mean concentrations of fibers > or = 5 microns were in the following decreasing order: tremolite > crocidolite > chrysotile > other fibers > talc-anthophyllite > amosite. For total fibers < 5 microns, we found > 1,000 fibers per mg tissue (f/mg) in all cases; tremolite was above 1,000 f/mg in 12 cases, chrysotile in 8 cases, crocidolite in 7 cases, and talc-anthophyllite in 6 cases. Tremolite was highest in 8 cases, chrysotile in 2 cases, and crocidolite and amosite in 2 cases. The geometric mean concentrations of fibers < 5 microns were in the following decreasing order: tremolite > other fibers > chrysotile > crocidolite > talc-anthophyllite > amosite. We conclude, on the basis of the lung burden analyses of 12 mesothelioma cases from the Asbestos township of Quebec, that the imported amphibole (crocidolite and amosite) were the dominant fibers retained in the lung tissue in 2/12 cases. In 10/12 cases, fibers from the mine site (chrysotile and tremolite) were found at highest counts; tremolite was clearly the highest in 6, chrysotile in 2, and 2 cases had about the same counts for tremolite and chrysotile. If a relation of fiber burden-causality of mesothelioma is accepted, mesothelioma would be likely caused by amphibole contamination of the plant in 2/12 cases and by the mineral fibers (tremolite and chrysotile) from the mine site in the 10 other cases.

Topics: Aged; Asbestos; Asbestos, Amosite; Asbestos, Amphibole; Asbestos, Crocidolite; Asbestos, Serpentine; Culture Techniques; Humans; Lung Neoplasms; Male; Mesothelioma; Middle Aged; Mining; Occupational Diseases; Quebec; Textile Industry

The aim of the study was to review existing cases, calculate rates, and predict future numbers of occupational and environmental mesotheliomas from Wittenoom.. On the basis of information contained in occupational and environmental histories, Wittenoom cases were extracted from national records collected since 1979. Occupational and residential population estimates were obtained from company and government records. The proportional latency method was used to predict the numbers of mesotheliomas prior to and after the data collection phase. Airborne fiber monitoring was used to calculate risk due to current levels of contamination in the mine and town environments.. During 1979-1994, Wittenoom cases (N = 176) comprised approximately 6% of the mesothelioma cases recorded in Australia. Of these 122 were employed directly in the mining and milling activities, another 18 were involved in the transport of raw fiber or tailings, and 34 were town residents or visitors. Due to past exposures, additional occupational (N = 301) and environmental (N = 83) cases can be expected. Dependent on residential time, existing levels of contamination may result in a risk of between < 1 to 57 per million of the population.. Latency effects will result in considerable numbers of mesotheliomas appearing over the next 10-20 years in Wittenoom. The cessation of mining activities and major clean up of the town will result in reduced mesothelioma cases.

Topics: Adolescent; Adult; Asbestos, Crocidolite; Asbestosis; Child; Environmental Exposure; Female; Humans; Incidence; Lung Neoplasms; Male; Mesothelioma; Middle Aged; Mining; Occupational Diseases; Occupational Exposure; Registries; Risk Assessment; Western Australia

The number, type, and size of retained asbestos fibers were measured by scanning electron microscopy (SEM) in lung tissues of 10 workers who had died from lung cancer or mesothelioma. The levels were 190-3000 x 10(6) fibers/g of dry tissue in three crocidolite sprayers, 6-39 x 10(6) fibers/g of dry tissue in two asbestos product workers and 13-280 x 10(6) fibers/g of dry tissue in five insulators exposed to anthophyllite. The duration of past exposure corresponding to the limit of 1 million fibers/g of dry tissue was 1 to 2 days in spraying, 3 to 10 days at the production plant and 1 to 4 months in insulation work. No long-term clearance of amphibole fibers, > 5 microns in length, could be demonstrated. In one of the sprayers the fiber concentrations of lung parenchyma, visceral and parietal pleura, hilar lymph nodes, and kidney cortex were orders of magnitude higher than in a series of unselected autopsies. The size and aspect ratio of crocidolite fibers in various tissues were similar, indicating that the translocation processes are rather unselective in respect to fiber dimensions.

Topics: Adult; Aged; Asbestos, Amphibole; Asbestos, Crocidolite; Body Burden; Humans; Lung Neoplasms; Male; Mesothelioma; Metabolic Clearance Rate; Middle Aged; Occupational Diseases; Occupational Exposure; Retrospective Studies

The centralized structure of economic affairs in the former German Democratic Republic (East Germany) and the isolation from the free market led to the situation that imported asbestos was almost exclusively chrysotile. More than 90% came from the Kiembay mining area in the Ural Mountains, and about 7% was long-fibre chrysotile from Canada. Sturm and co-workers detected 1082 mesothelioma cases from 1960 to 1990 in the counties of Magdeburg and Halle. In 843 of these cases an exposure to asbestos was evident. Seventy-two cases were exposed to chrysotile only. Suspected exposure to amphiboles imported before World War II or to fibre contained in talc could not be substantiated. Up to now, there have been no analyses of lung fibre burdens from such cases. Reviewing the carcinogenicity studies in rats performed by inhalation or intra-cavitary injection of chrysotile, amosite and crocidolite fibres, the results give no clear indication of a lower carcinogenic potency per chrysotile fibre than per amphibole fibre if equal fibre numbers and fibre sizes are applied, although the chrysotile content of the lungs is relatively low. Also the mesothelioma rates after inhalation exposure to extremely high concentrations of the different asbestos fibre types are similar for chrysotile and the amphiboles and in the region of 5%. Compared with the asbestos-related cancer rates in chrysotile textile workers, rats have to be exposed to a more than 100-fold higher fibre concentration than humans to induce the same lung tumour incidence.

Topics: Animals; Asbestos; Asbestos, Amphibole; Asbestos, Crocidolite; Asbestos, Serpentine; Case-Control Studies; Germany, East; Germany, West; Humans; Lung Neoplasms; Mesothelioma; Multicenter Studies as Topic; Occupational Exposure; Pleural Neoplasms; Rats; Rats, Wistar; Time Factors

Studies of human lungs indicate that, for virtually all types of exposure, the relative proportion of amphibole asbestos retained in the lung far exceeds the proportion in the original dust and, conversely, the relative proportion of chrysotile is far less than that in the original dust. Although amphiboles appear to accumulate in lung in proportion to exposure and chrysotile does not, failure of chrysotile deposition is probably not the reason for the disproportionate retention of amphibole fibres. The available data suggest that chrysotile is deposited in the parenchyma but is cleared extremely rapidly, with the vast bulk of fibres removed from human lungs within weeks to months after inhalation; by comparison, amphibole clearance half-lives are of the order of years to decades. The mechanisms of preferential chrysotile clearance remain uncertain, but fragmentation of chrysotile into short fibres, possibly accompanied by extremely rapid dissolution of such fibres, appears to be important in this process. Chrysotile fibres do penetrate to the periphery of the lung, so that differences in mesothelial pathogenicity of chrysotile and amphiboles in regard to mesothelioma are not caused by failure of chrysotile to reach the pleura. The theory that the tremolite contaminant rather than the chrysotile itself is the cause of 'chrysotile-induced' disease (especially mesothelioma) is consistent with the available human data, but the contrary ideas that disease is caused either by the total transient burden of inhaled chrysotile fibres or by a small, sequestered, long-retained fraction of chrysotile fibres still need to be excluded.

Topics: Animals; Asbestos, Amosite; Asbestos, Amphibole; Asbestos, Crocidolite; Asbestos, Serpentine; Asbestosis; Guinea Pigs; Humans; Lung; Mesothelioma; Mining; Occupational Exposure; Pleura; Pleural Neoplasms; Textile Industry; Time Factors

Topics: Asbestos; Asbestos, Amosite; Asbestos, Crocidolite; Asbestos, Serpentine; Asbestosis; Humans; Mesothelioma; Pleural Neoplasms; Risk Factors

Topics: Asbestos; Asbestos, Amosite; Asbestos, Amphibole; Asbestos, Crocidolite; Asbestos, Serpentine; Asbestosis; Humans; Mesothelioma; Pleural Neoplasms; Risk Factors

This paper reports the relationship between the effect of sodium selenite on blocking mesothelioma induced by crocidolite and the level of serum lipid peroxidation in rats. The result showed that sodium selenite solution (5ppm) might not only block and slow down the formation and growth of mesothelioma but also prevent peroxidation produced by crocidolite. The incidence of mesothelioma and the content of LPO in the Se group were lower than those in the positive control group in different periods (0-430 days and 0-530 days respectively). The survival time (341 days) of the first case of mesothelioma and the death peak period (530-630 days) in the Se group were longer than those (237 days and 430-530 days respectively) in the positive group. There was a good correlation between the change of G value in the Se group and the change of G value in the positive control group in different experimental periods (r = 0.9991). These results will provide scientific bases for recognizing the mechanism of mesothelioma and for furthering the practice in the people exposed to asbestos.

Topics: Animals; Asbestos, Crocidolite; Female; Lipid Peroxides; Male; Mesothelioma; Pleural Neoplasms; Rats; Rats, Wistar; Sodium Selenite

Pulmonary fiber content of both asbestos and nonasbestos types were evaluated in Japanese patients with malignant pleural mesotheliomas.. Pulmonary fiber content was analyzed in 16 patients and 16 case-matched control subjects by transmission electron microscopy with energy-dispersive X-ray analysis using a low-temperature ashing procedure.. The geometric mean content of total asbestos was significantly higher in the patients (22.0 x 10(6) fibers/g dry lung) than in the control subjects (2.24 x 10(6) fibers/g dry lung) (P < 0.01). When the asbestos content was analyzed by fiber type, the geometric means were also consistently and significantly higher among the patients compared with the control subjects (P < 0.01). Results were as follows: (1) amosite: patients 3.94 times 10(6) versus control subjects 0.23 x 10(6); (2) crocidolite: patients 3.56 times 10(6) versus control subjects 0.35 times 10(6); (3) total amphiboles: patients 16.0 times 10(6) versus control subjects 0.77 times 10(6); and (4) chrysotile: patients 3.76 times 10(6) versus control subjects 1.01 times 10(6). However, when individual total asbestos content was considered, 7 of the 16 patients (44%) had levels lower than the highest value noted among the control subjects. Pulmonary fiber content of patients and control subjects also revealed the presence of nonasbestos fibers. The geometric mean of nonasbestos fibers was significantly higher in the patients (87.3 x 10(6)) than in control subjects (33.8 x 10(6)) (P < 0.01). The major type of nonasbestos fibers in both groups was aluminum silicates. The mean of ratios of nonasbestos fiber contents to total asbestos contents in the patients and control subjects was 7.0 and 17.3, respectively.. The results were mainly in agreement with the findings of earlier investigations, but fiber content of both chrysotile and nonasbestos fiber as well as those of amphibole asbestos were significantly higher in the patients than in the control subjects.

Topics: Adult; Aged; Aluminum Silicates; Asbestos; Asbestos, Amosite; Asbestos, Amphibole; Asbestos, Crocidolite; Asbestos, Serpentine; Case-Control Studies; Electron Probe Microanalysis; Female; Humans; Lung; Male; Mesothelioma; Microscopy, Electron; Middle Aged; Occupational Exposure; Pleural Neoplasms; Silicates

Inductions of oxidative DNA damage (oh8dG) in vitro and peritoneal mesothelioma in rats (F344, female) were compared between crocidolite (CR) and de-ironized crocidolite [DCR, washed by HCl and ethylenediamine tetraacetic acid (EDTA)] to verify the hypothesis that reactive oxygen species contribute to carcinogenesis, focusing on the role of iron present inside or outside of the CR. The yield of oh8dG was 14.6 oh8dG/10(5)dG in CR and 30.2 in DCR under simple incubation with DNA. In the incubation systems added several chemicals and H2O2, DCR induced higher levels of oh8dG than CR. Especially, the addition of Fe2O3 and H2O2 to DCR increased oh8dG in DNA depending on the Fe2O3 concentration, however, this tendency was not observed in the same system of CR. Surprisingly, 7 out of 10 rats died within 2 days after the injection of 10 mg of Fe2O3 following the DCR injection (5 mg/rat), showing necroses of hepatocytes from the surface of each lobe where CR and Fe2O3 particles had been deposited together. There was no death in other groups of rats. One year after the i.p. injection of CR (5 mg/rat, single injection), mesotheliomas were found in all rats administered DCR and Fe2O3 (2 mg/rat, once a week, for 35 weeks), in 4 rats of DCR alone (n = 10), in 5 rats of CR alone (n = 10) and in none of the rats administered Fe2O3 alone (n = 10). Therefore, present results indicate that the induction of oxidative DNA damage changed even when the same type of asbestos was washed by chemical treatment, and Fe2O3 promoted the development of mesothelioma which was induced by DCR.

Topics: Animals; Asbestos, Crocidolite; Deoxyguanosine; DNA; DNA Damage; Female; Ferric Compounds; Iron; Mesothelioma; Oxidation-Reduction; Rats; Rats, Inbred F344; Reactive Oxygen Species

Plain chest radiographs from a one in six random sample of the workforce of the asbestos industry at Wittenoom, Western Australia between 1943 and 1966 have been classified for degree of profusion and pleural thickening by two independent observers according to the 1980 UICC-ILO Classification of Radiographs for the pneumoconioses to clarify the effect of degree of radiological abnormality on survival. A total of 1106 subjects were selected. Each subject's age, cumulative exposure to crocidolite, and time since first exposure were determined from employment records, the results of a survey of airborne concentrations of fibres > 5 mu in length conducted in 1966, and an exposure rating by an industrial hygienist and an ex-manager of the mine and mill at Wittenoom. By the end of 1986 193 subjects had died. Conditional logistic regression was used to model the relative risk of death in five separate case-control analyses in which the outcomes were deaths from: (1) all causes, (2) malignant mesothelioma, (3) lung cancer, (4) asbestosis, and (5) other causes excluding cancer and asbestosis. Up to 20 controls per case were randomly chosen from all men of the same age who were not known to have died before the date of death of the index case. After adjustment for exposure and time since first exposure, there were significant and independent effects of radiographic profusion and pleural thickening on all cause mortality. The effect of profusion was largely a result of the effect on mortality from malignant mesothelioma and asbestosis but not lung cancer. The effect of pleural thickening was greatest on mortality from other causes, mainly ischaemic heart disease. This study has shown that degree of radiographic abnormality has an independent effect on mortality from malignant mesothelioma, asbestosis, and all causes even after allowing for the effects of age, degree of exposure, and time since first exposure.

Topics: Asbestos, Crocidolite; Asbestosis; Cause of Death; Cohort Studies; Humans; Male; Mesothelioma; Neoplasms; Occupational Diseases; Occupational Exposure; Pleura; Pleural Diseases; Radiography; Random Allocation; Western Australia

Two hundred and ninety eight rat mesotheliomas induced by chrysotile or crocidolite were studies. The results demonstrated that tumor masses were scattered extensively. The appearance of tumor was polymorphous. According to the microscopic features, the 298 cases of mesothelioma could be histologically classified into three types, i.e. epithelial type, fibrous type and mixed cell type. The malignant mesothelioma is characteristic of its polymorphism and the clear cancernation of mesothelial cells.

Topics: Animals; Asbestos; Asbestos, Crocidolite; Asbestos, Serpentine; Mesothelioma; Pleural Neoplasms; Rats; Rats, Wistar

To determine the magnitude of the population at risk from non-occupational exposure to crocidolite at Wittenoom, Western Australia (WA), a cohort of 4,890 residents who never worked for the mining company Australian Blue Asbestos (ABA) has been assembled from all 18,553 available records: the local school register, hospital attendances, the WA electoral roll, birth certificates, workers who answered a mailed questionnaire in 1979, participants in a cancer-prevention programme using vitamin-A dietary supplements, and other sources. The majority of subjects were relatives and friends of ABA employees, and nearly half the cohort were either born at Wittenoom or first went there as children under 10 years of age. As most residents were at Wittenoom when the mine and mill were in operation during the period 1943 to 1966, 82% were first exposed to crocidolite 20 or more years ago. The proportion of other workers (i.e., not employed by ABA) and their families increased once the mining operations ceased. To date, 24 cases of mesothelioma have been reported in this cohort: 9 males and 15 females. Time from first exposure to diagnosis ranged from 23 to 44 years and residence in Wittenoom ranged from 6 weeks to 11 years.

Topics: Adolescent; Adult; Aged; Asbestos; Asbestos, Crocidolite; Child; Child, Preschool; Demography; Environmental Exposure; Family; Female; Humans; Longitudinal Studies; Male; Mesothelioma; Middle Aged; Occupations; Retrospective Studies; Western Australia

Topics: Animals; Asbestos; Asbestos, Crocidolite; Hyaluronic Acid; Male; Mesothelioma; Peritoneal Neoplasms; Rats; Rats, Wistar

To determine and compare the fiber types and size distributions in the lung tissue of mesothelioma patients in Finland, samples from 29 patients with known work history were analyzed with transmission electron microscopy (TEM) and X-ray microanalysis. Compared with the earlier results using scanning electron microscopy (SEM), the fiber concentrations were about three times as high and ranged from 0.1 million to 5,200 million fibers per gram of dry tissue. In 15 patients (52%), crocidolite/amosite were the dominating fiber types, representing more than 70% of all fibers. Anthophyllite asbestos was the most prevalent fiber type in eight patients (28%), and it was found in the samples of 13 patients (45%). One-half of the anthophyllite fibers were longer than 5 microns, whereas other fiber types were somewhat smaller.

Topics: Adult; Aged; Asbestos; Asbestos, Amosite; Asbestos, Amphibole; Asbestos, Crocidolite; Female; Finland; Humans; Male; Mesothelioma; Microscopy, Electron; Microscopy, Electron, Scanning; Middle Aged; Occupational Diseases

Histological observations were performed on female Syrian hamsters 2 years after the intratracheal administration of amphibole asbestos, amosite, and crocidolite to evaluate the tumorigenicity of six types of fine manmade fibers (reported previously). A mesothelioma and a lung tumor were induced in 20 animals administered amosite, but no tumors were found in the crocidolite group. Because this incidence is not higher than that of manmade fibers, such as basic magnesium sulfate fiber [9 tumor-bearing hamsters in 20 hamsters (9/20)], metaphosphate fiber (5/20), calcium sulfate fiber (3/20), and fiberglass (2/20), it is suggested that some types of manmade fibers have a greater ability than asbestos to induce tumors. Moreover, as a specific observation in manmade fiber groups, tumors were induced at intracelial organs rather than at the pleural cavity. On the other hand, the average thickness of visceral pleura was higher in all asbestos and manmade fiber groups than in the control (2.9 microns), for instance, 36.95 microns in potassium titanate fiber group, 15.90 microns crocidolite group, 13.00 microns basic magnesium sulfate fiber group, and 10.45 microns in the rockwool group. Although both pleural thickening and mesothelioma are known as peculiar lesions in asbestos-exposed people, it might also be suggested that these lesions could be induced by different mechanisms from the result that there was no relation between the pleural thickening and mesothelioma incidence in hamsters.

Topics: Adenoma; Animals; Asbestos; Asbestos, Amosite; Asbestos, Amphibole; Asbestos, Crocidolite; Calcium Sulfate; Carbon; Cricetinae; Female; Glass; Lung Neoplasms; Magnesium Sulfate; Mesocricetus; Mesothelioma; Pleura; Pleural Neoplasms; Silicon Dioxide; Titanium

Topics: Adult; Aged; Animals; Asbestos; Asbestos, Crocidolite; Asbestosis; China; Female; Humans; Lung Neoplasms; Male; Mesothelioma; Middle Aged; Prevalence; Rats; Risk Factors

The clinical characteristics and the results of mineral fibre and cytogenetic analyses were coordinated prospectively for 41 patients with confirmed malignant pleural mesothelioma. A correlation was found between high total fibre concentration, and partial or total loss of chromosomes 1, 4 and 9 and chromosomal rearrangements involving a breakpoint at 1p11-p22. There was also a correlation between crocidolite/amosite as the main fibre type and partial or total loss of chromosomes 1, 3 and 4 and chromosomal rearrangements involving del (3p). Positive prognostic factors were female gender, low total fibre concentration (less than 10(6) fibres per g dried lung tissue), anthophyllite as the main fibre type and normal chromosome 7. In addition, we found 4 patients with malignant mesothelioma who had been exposed mainly to anthophyllite fibres (total lung fibre concentrations of 1.2, 0.4, 0.2 and 0.1 x 10(6) fibres per g dried lung tissue). This would seem to indicate that there may be a carcinogenic role for anthophyllite.

Topics: Adult; Aged; Aged, 80 and over; Asbestos; Asbestos, Amosite; Asbestos, Amphibole; Asbestos, Crocidolite; Chromosome Aberrations; Chromosome Disorders; Chromosomes, Human, Pair 7; Female; Humans; Karyotyping; Male; Mesothelioma; Middle Aged; Pleural Neoplasms; Prognosis; Sex Factors

A cohort was established in 1981 of all 7317 white male employees in the amosite and crocidolite mines in South Africa whose names had appeared in the personnel records (initiated between 1945 and 1955) of the major companies. Some of the men had been employed as early as 1925, but only 8% had had more than 10 years of service. Three subcohorts were defined: 3212 men whose only exposure to asbestos was to amosite; 3430 exposed to crocidolite; and 675 to both amphiboles. No deaths or losses to view occurred before 1946, and 5925 men (81%) were known to be alive at the end of 1980. Losses to view numbered 167 (2%), and there had been 1225 deaths (17%), an excess of 331 over the number of deaths expected on the basis of the mortality of all white South African males. The fibre related excesses were of mesothelioma, lung cancer, and other respiratory diseases, but there were other excesses perhaps mainly related to socioeconomic factors including lifestyle. When cause of death was determined according to "best evidence" (after study of clinical, radiological, biopsy, and necropsy reports in conjunction with the death certificate), there were 30 deaths due to mesothelioma (22 pleural, six peritoneal, two other) and 65 due to cancer of trachea, bronchus, and lung. Various analyses of these deaths showed that crocidolite had higher toxicity than amosite for lung cancer and this was most pronounced for mesothelioma; there can now be no question that crocidolite is far more dangerous than amosite at least in so far as mesothelioma is concerned. Nevertheless, crocidolite induced mesothelioma appeared only in men who had been exposed for long periods, at least 12 months, but on average about 15 years.

Topics: Asbestos; Asbestos, Amosite; Asbestos, Crocidolite; Cause of Death; Cohort Studies; Humans; Incidence; Lung Neoplasms; Male; Mesothelioma; Mining; Neoplasms; Occupational Diseases; Risk Factors; South Africa; Survival Analysis

Metal content in the chemical structure of asbestos and man-made mineral fibres can affect their carcinogenic properties. As the chemical composition (metal content) of man-made silicate substitutes for asbestos can be varied almost at will in the process of their manufacture, the search for potentially least carcinogenic silicates appears to be of utmost importance. This paper presents diffractometric characteristics, dimensional analysis and morphology data for 4 synthetic amphibole fibres with chemical compositions differing from that of natural crocidolite amphibole. Those included the following synthetic amphiboles: Na2Mg6Ge8O22(OH)2; Na2Ni6Si8O22(OH)2; Na2Mg6Si8O22(OH)2; Na2Co6Si8O22(OH)2. The studied amphiboles differed in fibre length and diameter. The magnesium amphibole contained the longest (6.03 microns) fibres, and the nickel amphibole contained the shortest (2.7 microns) fibres, resembling those of crocidolite. The highest content (54.7%) of respirable fibres was found in the magnesium amphibole, and the lowest (15.9%) in the natural crocidolite. The authors suggest that the detected differences in the physical and chemical characteristics of the synthetic amphiboles may affect their biological properties.

Topics: Asbestos; Asbestos, Crocidolite; Asbestosis; Cobalt; Humans; Lung Neoplasms; Magnesium; Mesothelioma; Microscopy, Electron; Nickel; Particle Size; X-Ray Diffraction

This work presents the results of the test performed on rats to evaluate the carcinogenic effect of 4 synthetic amphiboles compared to that of the natural amphibole--crocidolite. The dose of the magnesium amphibole (Na2Mg6Si8(OH)2) administered to the animals contained 240 x 10(6) respirable fibres; the corresponding value for the nickel amphibole (Na2Ni6Si8O22(OH)2) was 339 x 10(6), for the cobalt amphibole (Na2Co6Si8O22(OH)2)--1000 x 16(6) for the geranium amphibole (Na2Mg6Ge8(OH)2)--250 x 10(6), and of the natural crocidolite amphibole (Na2Fe2Fe3Si8O22(OH)2) x 380 x 10(6) respirable fibres. The control animals (rats) received physiological NaCl solution. The number of peritoneal mesotheliomas following single intraperitoneal administration of 20 mg of the dust was adapted to be the measure of the carcinogenic activity of the dust. 3 synthetic (magnesium, cobalt and nickel) amphiboles and crocidolite caused development of malignant peritoneal mesothelioma in 11.1% to 71% rats. The results show that there is a relationship between the chemical composition of the synthetic amphiboles and their carcinogenic effect. Out of 4 investigated synthetic amphiboles, the magnesium amphibole, which contained magnesium and silicon, displayed most severe carcinogenic effect. The synthetic amphiboles containing either silicon and cobalt or silicon and nickel displayed 8.3 and 6.2 times weaker ability to induce peritoneal mesothelioma.

Topics: Animals; Asbestos; Asbestos, Crocidolite; Asbestos, Serpentine; Cobalt; Disease Models, Animal; Female; Injections, Intraperitoneal; Magnesium; Male; Mesothelioma; Nickel; Peritoneal Neoplasms; Rats; Rats, Wistar

All ascertainable cases of malignant mesothelioma in Australia were notified to a national surveillance program in the period January 1, 1980 to December 31, 1985. There were 854 cases obtained and 823 confirmed on clinical (77) or histologic (746) ground. Tumor site was known in 759 cases (685 pleural and 74 peritoneal). Lung fiber content analyses by light microscopy and analytic transmission electron microscopy with energy-dispersive x-ray analysis were done on 226 cases in which postmortem material was available, using the method of Rogers. Cell type was determined by a five-member expert panel of pathologists appointed by the Royal College of Pathologists of Australasia. There was a statistically significant trend between lung fiber content (fibers/g dry lung) and cell type from epithelial (low fiber content) through mixed to sarcomatous (high fiber content). This trend was most apparent for total uncoated fibers (chi-square = 6.8, df = 1, P less than 0.01) and crocidolite (chi-square = 6.7, df = 1, P less than 0.01). Lung fiber content also was associated with tumor site; higher lung fiber content being associated with peritoneal tumors. This relationship was significant for all fiber content measures except chrysotile and was independent of the fiber content-cell type relationship (log-linear analysis). Survival from time of provisional diagnosis was significantly longer for epithelial (mean, 13 months; standard deviation [SD], 12.8) and mixed (mean, 10.2 months; SD, 8.7) types than sarcomatous cell types (mean, 5.8 months; SD, 6.5; P less than 0.0001, by analysis of variance on log10 survival time). Survival time was significantly greater for pleural tumors (mean, 11.4 months; SD, 13.4) than peritoneal tumors (mean, 8.6 months; SD, 12.5) (P less than 0.005, by Student's t test on log10 survival time).

Topics: Asbestos; Asbestos, Amosite; Asbestos, Crocidolite; Asbestos, Serpentine; Humans; Lung; Mesothelioma; Peritoneal Neoplasms; Pleural Neoplasms; Survival Rate

Projections have been made of the number of mesotheliomas, lung cancers, and cases of asbestosis that might occur over the period 1987 to 2020 in former workers at the Wittenoom crocidolite asbestos mine in Western Australia. Predictions were based on the observed mortality to the end of 1986 and modelling of the mesothelioma rate. Elimination of crocidolite from the lungs was included in the model. Between the years 1987 and 2020 it is predicted that between 250 and 680 deaths will occur due to mesothelioma. This wide range is due to uncertainty on the functional form of the relation between mesothelioma rate and time, and insufficient data to estimate the elimination rate of crocidolite from the lungs. The most likely range is the lower half of this total range--that is, between 250 and 500. It is predicted that between 340 and 465 deaths will occur due to lung cancer. About 45% of these deaths would be attributable to exposure to asbestos. It is estimated that currently there are up to 200 cases of undiagnosed asbestosis. Of these about 50 will die of lung cancer or mesothelioma and are therefore also included in the figures above. Up to 60 former workers may develop the first signs of asbestosis in the future but any such cases are likely to progress to more serious disease at a much slower rate than the cases that have already been identified.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Asbestos; Asbestos, Crocidolite; Asbestosis; Cause of Death; Female; Forecasting; Humans; Lung Neoplasms; Male; Mesothelioma; Middle Aged; Mining; Time Factors; Western Australia

Topics: Asbestos; Asbestos, Crocidolite; Dental Casting Technique; Humans; Lung Neoplasms; Male; Mesothelioma; Middle Aged; Occupational Diseases; Periodontal Dressings

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.

Topics: Asbestos; Asbestos, Amosite; Asbestos, Crocidolite; Asbestos, Serpentine; Cell Survival; Cytotoxicity Tests, Immunologic; Female; Humans; In Vitro Techniques; Interleukin-2; Killer Cells, Lymphokine-Activated; Killer Cells, Natural; Male; Mesothelioma; Tumor Cells, Cultured

Lung tissue from 221 definite and probable cases of malignant mesothelioma reported to the Australian Mesothelioma Surveillance Program from January 1980 through December 1985 and from an age-sex frequency matched control series of 359 postmortem cases were examined by light microscopic (LM) and analytical transmission electron microscopic (TEM) analysis and energy dispersive x-ray analysis (EDAX). Concentrations of total fibers (coated and uncoated) (LM), crocidolite, amosite, chrysotile, and unidentified amphibole (TEM) (fibers/g dry lung tissue) were measured. Fiber concentrations less than 10 microns in length and greater than or equal to 10 microns in length were separately quantified. By comparing cases (221) and controls (359 LM, 103 TEM), odds ratios for increasing fiber concentrations compared with less than 15,000 fibers/g (LM) and less than 200,000 fibers/g (TEM) (the respective detection limits) were calculated. Univariate analyses showed statistically significant dose-response relationships between odds ratio and fiber concentration for all fiber concentration measures. The relationship between log(odds ratio) and log(fiber concentration) was linear. Multiple logistic regression analysis showed that a model containing crocidolite greater than or equal to 10 microns, amosite less than 10 microns, and chrysotile less than 10 microns as explanatory variables best described the data. The odds ratios for a X10 increase in fiber concentration (fibers/micrograms) were as follows: crocidolite greater than or equal to 10 microns, 29.4 (95% confidence interval [CI], 3.6 to 241); chrysotile less than 10 microns, 15.7 (95% CI, 6.1 to 40); amosite less than 10 microns, 2.3 (95% CI, 1.0 to 5.3). An additive risk model gave similar results. In a subgroup of cases and controls with only chrysotile in the lungs, a significant trend in odds ratio with increasing fiber content was found.

Topics: Adult; Aged; Aged, 80 and over; Asbestos; Asbestos, Amosite; Asbestos, Crocidolite; Asbestos, Serpentine; Case-Control Studies; Female; Humans; Male; Mesothelioma; Middle Aged; Particle Size

Cases of pleural mesothelioma induced by five species of chrysotile and three species of crocidolite from China in rats are compared. The rate of induction in the chrysotile group (43.1%) was slightly lower than that in the crocidolite group (56.7%). The survival time of the first case of mesothelioma in the chrysotile group was 408 days and in the crocidolite group 377 days. The major histological types of mesothelioma induced by chrysotile were epithelial and mixed, but the major type in the crocidolite group was fibrous. The extent of differentiation in all mesotheliomas, mainly intermediate and low, was nearly the same.

Topics: Animals; Asbestos; Asbestos, Crocidolite; Carcinogenicity Tests; Carcinogens; Mesothelioma; Rats; Rats, Inbred Strains

Crocidolite was found to be ubiquitous in a county in southwestern China. It had been widely used in the making of road pavement, stoves, wall paint, etc. The environmental levels of the asbestos fibers were determined. Of the 2175 local residents examined, 16 had asbestosis and 232 had pleural plaques. These clinical manifestations were noted mainly in patients over 50 years of age.

Topics: Asbestos; Asbestos, Crocidolite; Carcinogens, Environmental; China; Cohort Studies; Humans; Mesothelioma; Pleural Neoplasms; Retrospective Studies; Rural Health

The concentration of airborne fibers longer than 5 microns, thinner than 3 microns, and with an aspect ratio exceeding 3 as counted by phase contrast optical microscopy is the most widely used fiber exposure index. Recently, more adequate, specific exposure indices for asbestosis, lung cancer, and mesothelioma risk have been suggested by Lippmann (1988, Environ. Res., 46, 86-106). The consequences of using these indices are examined on the basis of calculations for a broad range of theoretical and published size distributions. Optical microscopy appears to be a good predictor of the exposure indices for asbestosis and for lung cancer after scaling. Only fibers longer than about 3 microns need to be counted in a transmission electron microscope. The lung cancer index still cannot explain the large differences of risk among chrysotile exposures. Both the mesothelioma exposure index and the ratio mesothelioma to lung cancer index ranks in order of increasing risk: wollastonite, glass and mineral wool, amosite, glass microfibers, chrysotile, and crocidolite. Amosite is thus not ranked according to epidemiological evidence. Detailed size information should be made available so that the size criteria can be adjusted. It may still prove necessary to use fiber type specific concentration limits.

Topics: Asbestos; Asbestos, Amosite; Asbestos, Crocidolite; Asbestos, Serpentine; Asbestosis; Environmental Exposure; Environmental Monitoring; Humans; Lung Neoplasms; Mesothelioma; Microscopy, Electron; Microscopy, Phase-Contrast; Minerals; Risk Factors

Topics: Asbestos; Asbestos, Crocidolite; Asbestosis; Australia; Humans; Incidence; Lung Neoplasms; Mesothelioma; Models, Statistical; Risk; Survival Rate

90 Wistar strain rats were used in this experiment, 56 rats (Group A) were injected intrapleurally with crocidolite fibers suspended in physiological (NaCl) solution. Another 34 rats (Group B), serving as controls, were injected with the same volume of mere NaCl solution. The rats were killed 1, 3, 6, 9, 12, 14 and 16 months respectively after injection. The results showed that the rats of Group B only exhibited reactive proliferation of mesothelial cells caused by inflammation. In Group A, there appeared 9 cases of mesothelioma. The tumorigenic stages of mesothelioma include three processes: (1). reactive proliferation: the mesothelial cells became cuboid. (2). precancerous changes: the atypical proliferation of stratified, nodular or papillary mesothelial cells and of the cell elements around asbestos granulomas. (3). the occurrence of mesothelioma. Ultrastructural observation revealed that in mesothelioma tissue mesenchymal cells directly or indirectly (via transitional cells) differentiated cinto epithelioid cells. The mesenchymal cells may also become fibroblastoid cells. These findings suggest that mesothelioma originates from mesenchymal cells.

Topics: Animals; Asbestos; Asbestos, Crocidolite; Female; Injections; Male; Mesothelioma; Pleura; Pleural Neoplasms; Precancerous Conditions; Rats; Rats, Inbred Strains

A historical prospective cohort study comprised all persons employed from 1950 to 1981 for at least three years in the oldest asbestos cement factory in the world. From 2816 persons eligible for the study, record based estimates and measurements of dust and fibres and histories of smoking based on interviews were used to calculate individual exposures over time. After observation of 51,218 person-years and registration of 540 deaths, underlying causes of death for this cohort were compared with those for the regional population on the basis of death certificates. Deaths from lung cancer in asbestos cement workers were higher (standard mortality ratio (SMR) 1.7), but after adjustment for age and sex specific smoking habits this was not significant (SMR 1.04). The study had a probability of greater than 92% of detecting a smoking adjusted SMR of 1.5 or more. Using the best available evidence (including necropsy records) 52 deaths were assigned to lung cancer and five to mesothelioma. Life table analyses confirmed the predominant influence of smoking on lung cancer. Mesothelioma was associated with the use of crocidolite in pipe production. From present working conditions with much lower concentrations of chrysotile and no crocidolite no more occupational cancers are expected in the asbestos cement industry.

Topics: Asbestos; Asbestos, Crocidolite; Asbestos, Serpentine; Austria; Cohort Studies; Dust; Humans; Life Tables; Lung Neoplasms; Male; Mesothelioma; Occupational Diseases; Occupational Exposure; Prospective Studies; Risk; Smoking; Time Factors

Tumors and activated macrophages release angiogenic factors that stimulate migration and proliferation of capillaries. We studied the development of angiogenesis before the appearance of mesotheliomas in C57B1/6 mice. Weekly i.p. injections of crocidolite asbestos fibers produced mesotheliomas after 30-50 wk. The initial histologic response to asbestos fibers was a nodular lesion on the peritoneal lining composed of clusters of fibers, activated macrophages, and proliferating mesenchymal cells. The earliest visible evidence of angiogenesis was seen surrounding 7% of these lesions 14 days after a single injection of 200 micrograms of crocidolite asbestos fibers. After six weekly injections, 30% of the lesions containing asbestos fibers were surrounded by a capillary network radiating toward the center of the lesion. Other mineral fibers, including chrysotile asbestos and fiberglass, also induced angiogenesis after six weekly injections. In contrast, only 8% of the lesions containing short asbestos fibers (90.6% less than or equal to 2.0 microns) and 9% of the lesions containing silica particles showed evidence of angiogenesis. We conclude that tumorigenic mineral fibers induce angiogenesis in the peritoneal lining, whereas nontumorigenic mineral particles or short asbestos fibers are less effective. Ingrowth of new blood vessels around clusters of asbestos fibers may facilitate the later emergence of mesotheliomas at these sites.

Topics: Animals; Asbestos; Asbestos, Crocidolite; Asbestos, Serpentine; DNA; Endothelium, Vascular; Fibroblasts; Macrophages; Mesothelioma; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Peritoneum

For many years, the main source of asbestos in Cyprus was thought to be the chrysotile mine in the central mountains. When a woman, who had no connection with the mine, developed mesothelioma, it was surprising to discover tremolite asbestos bodies within her lung. However, further studies have shown that tremolite occurs as a contaminant within the chrysotile ore body. In this study we have shown that both chrysotile and tremolite can be found in domestic and environmental samples throughout the mountain region; in particular, numerous fine fibres of both materials are present in stucco. Preliminary radiological studies have shown pleural disease in the village population and 5 out of 13 known cases of mesothelioma have arisen in persons unconnected with the mine. This suggests an environmental contribution to asbestos-related disease on the island.

Topics: Air Pollutants; Animals; Asbestos; Asbestos, Amphibole; Asbestos, Crocidolite; Asbestos, Serpentine; Cyprus; Humans; Lung; Mesothelioma; Mining; Pleural Neoplasms; Radiography; Sheep; Silicic Acid

The lungs from 36 former workers at an East London asbestos factory dying of asbestos-related disease were compared with lung tissue from 56 matched control patients operated on in East London for carcinoma of the lung. The severity of asbestosis and the presence of pulmonary carcinoma or mesothelioma of the pleura or peritoneum were correlated with an asbestos exposure index and with the type and amount of mineral fibre of the lungs. Asbestosis was associated with far heavier fibre burdens than mesothelioma. Moderate or severe asbestosis was more common among those with carcinoma of the lung than in those with mesothelial tumours. Crocidolite and amosite asbestos were strongly associated with asbestosis, carcinoma of the lung and mesothelial tumours, whereas no such correlation was evident with chrysotile or mullite. It is suggested that greater emphasis should be placed on the biological differences between amphibole and serpentine asbestos fibre.

Topics: Aluminum Silicates; Asbestos; Asbestos, Amosite; Asbestos, Crocidolite; Asbestos, Serpentine; Asbestosis; Female; Humans; London; Lung; Lung Diseases; Lung Neoplasms; Male; Mesothelioma; Middle Aged; Occupational Diseases; Pleural Neoplasms

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.

Topics: Air Pollutants; Asbestos; Asbestos, Amosite; Asbestos, Amphibole; Asbestos, Crocidolite; Australia; Humans; Lung; Mesothelioma; North America; Silicon Dioxide; Tissue Distribution; United Kingdom

The separate and combined effects of duration and intensity of exposure to crocidolite on mortality from lung cancer, malignant mesothelioma, and stomach cancer were examined in 6506 male former crocidolite miners and millers at Wittenoom Gorge, Western Australia. Each subject who had died from lung cancer (92), mesothelioma (31), or stomach cancer (17) was matched with up to 20 control subjects of the same age who were not known to have died before the index subject. Relations of dose and time of exposure to crocidolite to risk of death were modelled by conditional logistic regression. For lung cancer, the best fitting multiplicative model was one which estimated a relative risk (RR) of 1.12 (95% CI 1.04-1.20) per year of exposure and 1.01 (95% CI 1.00-1.01) per fibre/ml. This was statistically indistinguishable from an additive model showing an increase in RR of 0.01045 (95% CI 0.008-0.020) per f/ml year. For mesothelioma the best fitting model appeared to be one estimating a RR of 24.9 (95% CI 3.51-1.77) per log year since first exposed and a RR of 10.5 (95% CI 3.12-35.1) if exposed for longer than six months. This was not distinguishable statistically from a model that showed mortality increasing as the fourth power of time since first exposed less the fourth power of time since last exposed. The effect of intensity of exposure on the RR for mesothelioma was only slight. There was no consistent effect of any measure of exposure to crocidolite on death from stomach cancer.

Topics: Asbestos; Asbestos, Crocidolite; Cohort Studies; Humans; Lung Neoplasms; Mesothelioma; Mining; Occupational Diseases; Pleural Neoplasms; Risk Factors; Stomach Neoplasms; Time Factors; Western Australia

To estimate the effects on health of occupational exposure to crocidolite, a highly toxic form of asbestos, we studied a cohort of 33 men who worked in 1953 in a Massachusetts factory that manufactured cigarette filters containing crocidolite fibers from 1951 to 1957. Twenty-eight of the men have died, as compared with 8.3 deaths expected. This increased mortality was attributable to asbestos-associated diseases. Fifteen deaths were caused by cancer, as compared with 1.8 expected (relative risk, 8.2; 95 percent confidence interval, 4.6 to 13.4), including eight from lung cancer, five from malignant mesothelioma, and two from other types of cancer. There were seven deaths from nonmalignant respiratory disease, as compared with 0.5 expected (relative risk, 14.7; 95 percent confidence interval, 5.9 to 30.3), of which five were due primarily to asbestosis. In contrast, the mortality rates from cardiovascular diseases and all other causes were not increased. Four of the five living workers have pulmonary asbestosis; three of them have recently diagnosed cancers, including two additional lung cancers. We conclude that the extremely high morbidity and mortality in these workers were caused by intense exposure to crocidolite asbestos fibers.

Topics: Asbestos; Asbestos, Crocidolite; Asbestosis; Cohort Studies; Humans; Lung Neoplasms; Male; Massachusetts; Mesothelioma; Nicotiana; Occupational Diseases; Plants, Toxic

It is known that 6505 men and 411 women were employed in the mining and milling of crocidolite at Wittenoom in the Pilbara region of Western Australia between 1943 and 1966. Employment was usually brief (median duration four months) and exposure intense (median estimated cumulative exposure 6 fibres/cc years). The vital status of 73% of the men and 58% of the women employed in the industry was known at 31 December 1980, providing 95 264 person-years of follow up with 820 deaths in men and 4914 person-years with 23 deaths in women. The standardised mortality ratio (SMR) for all causes in men was 1.53 (95% confidence interval 1.43 to 1.64). Statistically significant excess death rates were observed in men for neoplasms, particularly malignant mesothelioma (32 deaths), neoplasms of the trachea, bronchus, and lung (SMR 2.64), and neoplasms of the stomach (SMR 1.90); respiratory diseases, particularly pneumoconiosis (SMR 25.5); infections, particularly tuberculosis (SMR 4.09); mental disorders particularly alcoholism (SMR 4.87); digestive diseases, particularly peptic ulceration (SMR 2.46) and cirrhosis of the liver (SMR 3.94); and injuries and poisonings, particularly non-transport accidents (SMR 2.36). The excess mortality from pneumoconiosis, malignant mesothelioma, and respiratory cancers, but not stomach neoplasms, was dependent on time since first exposure and cumulative exposure. There was no increase in mortality from laryngeal cancer (SMR 1.09) or neoplasms other than those listed. The SMR for all causes in women was 1.47 (95% confidence interval 0.98-2.21) and for neoplasms 1.99; there was one death from malignant pleural mesothelioma.

Topics: Adult; Asbestos; Asbestos, Crocidolite; Asbestosis; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Mesothelioma; Mining; Pleural Neoplasms; Western Australia

The mesothelium is a target of the toxic and carcinogenic effects of asbestos fibers. Fibers greater than 8 mu in length and less than 0.25 mu in diameter have been found to be highly tumorigenic in rodents, while shorter asbestos fibers or spherical mineral particles have not been shown to produce mesotheliomas. For investigation of early mesothelial reactions associated with the development of mesotheliomas, C57BL/6 mice were given intraperitoneal injections of 200 micrograms of short or long crocidolite asbestos fibers, toxic silica particles, or nontoxic titanium dioxide particles. At intervals between 3 hours and 21 days after a single injection, the mesothelial surface of the diaphragm was examined by stereomicroscopy, scanning electron microscopy, and autoradiography. Within 6 hours after injection of asbestos fibers, mesothelial cells in the lacunar regions of the diaphragm retracted opening stomata 10.7 +/- 2.3 mu in diameter leading to the submesothelial lymphatic plexus. Short asbestos fibers (90.6% less than or equal to 2 mu in length), silica, or titanium dioxide particles (less than or equal to 5 mu in diameter) were cleared through these stomata without provoking an inflammatory reaction or mesothelial injury. In contrast, long asbestos fibers (60.3% greater than or equal to 2 mu in length) were trapped at the lymphatic stomata in the lacunar regions on the peritoneal surface of the diaphragm. At these sites, an intense inflammatory reaction developed with accumulation of activated macrophages and a 5.5-fold increase in albumin recovered in the peritoneal lavage fluid after 3 days. As early as 12 hours after injection of long asbestos fibers, the adjacent mesothelial cells were unable to exclude trypan blue and lost their surface microvilli, developed blebs, and detached. Recovery of lactate dehydrogenase activity in the peritoneal lavage fluid was increased 5.8-fold after 3 days and returned to normal levels after 14 days. Regenerating mesothelial cells appeared at the periphery of asbestos fiber clusters 3 days after injection. Maximal incorporation of 3H-thymidine by mesothelial cells occurred after 7 days, followed by partial restoration of the mesothelial lining after 14-21 days. As late as 6 months after a single injection of crocidolite asbestos fibers, clusters of fibers remained in the lacunar regions, partially covered by mesothelium but surrounded by macrophages and regenerating mesothelial cells. The anatomic distribution and si

Topics: Animals; Asbestos; Asbestos, Crocidolite; Diaphragm; Epithelium; Inflammation; Lymphatic System; Male; Mesothelioma; Mice; Mice, Inbred C57BL; Microscopy, Electron, Scanning; Microvilli; Peritoneal Cavity; Silicon Dioxide

Mesotheliomas developed in rats in the abdominal cavity 6-23 months after peritoneal introduction of chrysotile and crocidolite asbestos. The tumors were strikingly similar to those occurring in man both with regard to histologic features and growth patterns. The authors have cultured cells from these tumors and established epithelial lines with a variety of karyologic features and doubling times shorter than those of normal mesothelial cells. Lines of diploid or near-diploid tumor cells required serum in the medium to replicate, whereas most aneuploid cell lines were maintained in a serum-free medium. In serum-free medium, the aneuploid line monolayers produced anchorage-independent excrescent masses of cells which "bud" and float free. These spheroids, which strikingly resemble the papillary structures in human mesotheliomas, are composed of mesothelial-like cells that produce hyaluronic acid and have a rich complement of intermediate filaments, predominantly cytokeratins. Aneuploid cells also replicated in soft agar with high efficiency, whereas the diploid and near-diploid cells did not. All but one cultured cell line, regardless of karyotype, produced tumors after subcutaneous or intraperitoneal inoculation (or both). Aneuploid cells caused lung tumors sporadically when introduced intravenously. Comparative analysis of the nuclear DNA of primary tumors and cultured cells demonstrated a high degree of chromosomal instability and selection among cells during early passage in vitro.

Topics: Abdominal Neoplasms; Animals; Asbestos; Asbestos, Crocidolite; Asbestos, Serpentine; Cell Division; Chromosomes; Female; Mesothelioma; Microscopy, Electron; Microscopy, Electron, Scanning; Neoplasms, Experimental; Rats; Rats, Inbred F344; Tumor Cells, Cultured

Topics: Abdominal Neoplasms; Animals; Asbestos; Asbestos, Crocidolite; Ceramics; Cricetinae; Female; Glass; Lung Neoplasms; Male; Mesocricetus; Mesothelioma; Minerals; Rats; Rats, Inbred Strains; Time Factors

Topics: Air Pollutants, Occupational; Asbestos; Asbestos, Crocidolite; Humans; Male; Mesothelioma; Middle Aged; Nicotiana; Occupational Diseases; Peritoneal Neoplasms; Plants, Toxic

Reference cultures derived from a transplantable rat mesothelioma were obtained by cloning cells three times in soft agar. Each line, designated "CARM-Lines", was selected on the basis of their epithelial or fibroblastic phenotype, and their uniform morphology. Three epithelial lines were used for more detailed in vitro studies comparing morphological and biological criteria at early and late passages. All three lines exhibited both epithelial and fibroblastic elements after 10-14 passages in vitro, demonstrating that the dimorphic histology of these tumours could be derived from a single aberrant cell. Morphology and growth characteristics of these cells were density-dependent. Anchorage dependent and independent clonogenic assays did not correlate. Anchorage dependent colony formation was the only parameter which differed markedly from the original parent line in the assays described. In vivo evidence of chondrogenesis and attempted ossification support the concept of a multipotential cell contributing to the diverse primary tumour morphology by cellular modulation or differentiation.

Topics: Animals; Asbestos; Asbestos, Crocidolite; Cell Adhesion; Cell Line; Female; Mesothelioma; Microscopy, Electron; Neoplastic Stem Cells; Rats; Rats, Inbred Strains

The mortality of a complete cohort of 1506 French asbestos cement workers employed for at least five years is related to the time elapsed since first exposure. The mortality from all causes (analysed by the "man-years method") has been found to be above normal only in those subjects employed for more than 20 years, with more than 35 years of follow up. Standardised mortality ratios for cancers of all sites (ICD 140-209) and pulmonary cancer (ICD 162-163.0) have been assessed in subjects whose first exposure dates go back more than 20 years. Mortalities from cancer of all sites and from pulmonary cancer have been detected in excess in workers employed for more than 20 years and originally hired when aged 25 or under.

Topics: Adolescent; Adult; Aged; Asbestos; Asbestos, Crocidolite; Asbestos, Serpentine; Calcium Hydroxide; Chemical Industry; Child; France; Humans; Lung Neoplasms; Male; Mesothelioma; Middle Aged; Neoplasms; Occupational Diseases; Risk; Time Factors

Epidemiological and environmental surveys in the Cappadocian region of Turkey have linked the high incidence of pleural and peritoneal mesothelioma in the occupants of some villages with the zeolite fibres released from the locally occurring volcanic tuff. In view of the low ambient fibre concentrations and the extraordinary incidence of mesothelioma a study to test the hypothesis of high biological activity for the zeolite fibres was required. Experimental studies using both intrapleural inoculation and inhalation techniques have been undertaken with the erionite from this region and from Oregon in the United States. Additionally a non-fibrous zeolite from Japan and a synthetic non-fibrous zeolite of similar chemical composition to erionite have been included in the experiments. In these studies the samples from Oregon and Turkey produced a very high incidence of tumours. All the rats inoculated intrapleurally with Oregon erionite and almost all those inoculated with the Turkish fibre died with a mesothelioma. Inhalation of the Oregon erionite induced a similar effect. No other dusts we have investigated have produced this high incidence of tumours particularly following inhalation. These studies demonstrate that we now have a valuable new fibre for experimental study and a possible hazard to man in regions other then Turkey.

Topics: Aluminum Silicates; Animals; Asbestos; Asbestos, Crocidolite; Asbestos, Serpentine; Female; Male; Mesothelioma; Pleural Neoplasms; Rats; Rats, Inbred F344; Zeolites

Serial plain chest radiographs taken between 1943 and 1982 for 280 claimants for compensation for asbestosis and 32 claimants for malignant pleural mesothelioma from the Wittenoom asbestos industry were reviewed by two observers to identify diffuse pleural thickening and pleural effusion. A pleural effusion which appeared and resolved within two years without radiographic or clinical evidence of underlying malignancy, infection or cardiac failure was seen in 15 cases by reader 1 and 24 cases by reader 2. Eighteen cases of effusion, determined from clinical records to be caused by malignant pleural mesothelioma, were seen by reader 1 and 20 by reader 2. The latent periods between commencing work and the first radiograph showing effusion were much shorter for subjects with benign asbestos pleural effusion than for subjects with effusion due to malignant pleural mesothelioma, although there was considerable overlap in the range. The longest latent period for benign asbestos pleural effusion was 22 years and the shortest period for effusion due to malignant pleural mesothelioma was 12 years. The latent period for benign asbestos pleural effusion was inversely related to total cumulative exposure, whereas that for effusion due to malignant pleural mesothelioma was significantly shorter for subjects who had worked in the mill than for those who had worked in the mine. A long latent period and a history of working in the mill were significant discriminators for a malignant as opposed to a benign basis for an effusion. The appearance of a benign asbestos pleural effusion appeared to be a risk factor for the severity of subsequent diffuse pleural thickening.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Asbestos; Asbestos, Crocidolite; Asbestosis; Diagnosis, Differential; Humans; Male; Mass Chest X-Ray; Mesothelioma; Mining; Pleura; Pleural Effusion; Pleural Neoplasms; Regression Analysis; Time Factors

The pleura is a main target for various reactions related to asbestos exposure. However there are great radiological and clinical differences between the various reactions, and there is also increasing evidence that they have different prognoses. The main reactions are pleural plaques on the one hand and acute pleurisy and diffuse pleural fibrosis on the other. In a population with a low mesothelioma risk, the anthophyllite-exposed population of Northern Karelia in Finland, there are very few reactions of the second type, while plaques are very common. In Turkey, where the exposure is to erionite, the mesothelioma level is extremely high, and reactions of type two are very common in the exposed population. Thus it seems that careful discrimination of the various pleural changes can have prognostic value. There are also indications that plaques do not have any relation to a disturbed immunologic system, while pleurisy and diffuse pleurisy have.

Topics: Aluminum Silicates; Asbestos; Asbestos, Crocidolite; Asbestosis; Finland; Humans; Mesothelioma; Pleural Diseases; Pleural Neoplasms; Pneumoconiosis; Radiography; Risk; Sweden; Turkey; Zeolites

Topics: Animals; Asbestos; Asbestos, Crocidolite; Female; Mesothelioma; Peritoneal Neoplasms; Pleural Neoplasms; Rats; Rats, Inbred Strains

Standard (UICC) crocidolite was subjected to ball milling to reduce the length of the fibre. These milled materials and the original standard sample were injected into the pleural cavity of rats to determine their ability to induce mesothelioma. Previous in vitro work on the same materials had suggested that biological activity was related to fibres greater than 6.5 microns in length and that the material milled for 4 and 8 h did not contain fibres in this range and was biologically inactive. The results of the animal work, however, did not follow this pattern; mesotheliomas occurred in rats in all treatment groups including the 4 and 8 h milled samples. Examination of the tissues and the dust recovered from them showed the presence of fibres greater than the suggested threshold. Attention is drawn to the problems associated with drawing conclusions from size distributions and in vitro studies without considering in vivo mechanisms.

Topics: Animals; Asbestos; Asbestos, Crocidolite; Female; Granuloma; Male; Mesothelioma; Microscopy, Electron; Particle Size; Pleural Diseases; Pleural Neoplasms; Rats; Rats, Inbred F344; Time Factors

Topics: Adult; Aged; Asbestos; Asbestos, Amosite; Asbestos, Crocidolite; Asbestos, Serpentine; Australia; Humans; Lung; Lung Neoplasms; Male; Mesothelioma; Microscopy, Electron; Middle Aged

Numbers and sizes of fibers from the lungs of 10 patients who had an amphibole asbestos-induced malignant pleural mesothelioma were analyzed. Amosite was found in 10 lungs and crocidolite in 9; the average ratio of amosite to crocidolite was approximately 14:1. In the 8 patients who were not long-time asbestos insulators , the mean number of amosite fibers was 2.3 X 10(6) fibers/g dry lung, and of crocidolite fibers, 0.2 X 10(6)/g; these values represent an approximately 250-fold increase over those found in the general population. Crocidolite fibers were significantly narrower than amosite fibers (mean width, 0.13 versus 0.23 mu), were significantly shorter (mean length, 4.0 versus 5.8 mu), and had a significantly higher mean aspect (length to width) ratio (48 versus 34). Aspect ratios in general increased with increasing fiber length and decreasing fiber width, but the highest values were found for thin amosite fibers at about 13 mu in length, and thin crocidolite fibers at 8 or 15-17 mu in length. Comparison with data from other asbestos-exposed populations indicates that mesothelioma can be induced by relatively small numbers of amphibole fibers and also indicates that amosite is an effective mesothelial carcinogen in humans. Comparison of these data with epidemiologic and experimental predictions of carcinogenic size ranges for mesothelioma induction implies that either the carcinogenic size range is much broader than has been claimed (in particular, fibers considerably shorter than 8 mu and broader than 0.05 mu can produce mesothelioma), or, alternately, that extraordinarily small absolute numbers of fibers in certain size ranges can induce tumors in humans.

Topics: Aged; Asbestos; Asbestos, Amosite; Asbestos, Amphibole; Asbestos, Crocidolite; Female; Humans; Lung; Male; Mesothelioma; Middle Aged; Occupational Diseases; Particle Size; Pleural Neoplasms; Silicon Dioxide

Crocidolite was mined and milled at Wittenoom Gorge in Western Australia from 1943 to 1966. Between 1960-1964 and 1980-1982, the estimated incidence of malignant mesothelioma in Western Australia rose from 0.6/100 000 in men and less than 0.1/100 000 in women, aged 35 years or older, to 6.6/100 000 in men and 0.7/100 000 in women in this age group. Overall, 97 (70%) of 138 patients with malignant mesothelioma had definite or probable exposure to asbestos; 76 of these (55%) to Western Australian crocidolite. Of the latter 76 patients, 56 had worked in the mine or mill at Wittenoom and 4 had non-occupational exposure in the Wittenoom area; the remaining 16 had been exposed to crocidolite elsewhere in the State. There were only 4 (3%) patients with malignant peritoneal mesothelioma, of whom three had been exposed to crocidolite.

Topics: Adult; Aged; Asbestos; Asbestos, Crocidolite; Australia; Female; Humans; Male; Mesothelioma; Middle Aged; Occupational Diseases; Peritoneal Neoplasms; Pleural Neoplasms; Time Factors

Up to the end of 1980, 144 confirmed cases of mesothelioma were identified among employees of an organisation using asbestos in manufacturing and insulation. The primary site was peritoneal in 74 cases, pleural in 66, and undetermined in four. All employees had been exposed to amphibole asbestos, and evidence from different factories confirmed the predominant role of crocidolite in the production of mesothelioma. The ratio of pleural to peritoneal sites showed a continuous change when related to the year of first exposure, varying from 5:1 pleural to peritoneal before 1921 to 1:3 after 1950. The strong temporal relationship appeared to reflect progressive dust suppression, including the non-fibrous dusts present in insulation materials and perhaps also the degree to which the fibres had been opened. Other predisposing factors were related to the degree of individual exposure, the peritoneal site being associated preferentially with longer and heavier exposures.

Topics: Asbestos; Asbestos, Crocidolite; Female; Humans; Male; Mesothelioma; Occupational Diseases; Peritoneal Neoplasms; Pleural Neoplasms; Time Factors

This report describes the second in a series of three parallel cohort studies of asbestos factories in South Carolina, Pennsylvania, and Connecticut to assess the effects of mineral fibre type and industrial process on mortality from malignant mesothelioma, respiratory cancer, and asbestosis. In the present plant (in Pennsylvania) mainly chrysotile, with some amosite and a small amount of crocidolite, were used primarily in textile manufacture. Of a cohort of 4137 men comprising all those employed 1938-59 for at least a month, 97% were traced. By the end of 1974, 1400 (35%) had died, 74 from asbestosis and 70 from lung cancer. Mesothelioma was mentioned on the certificate in 14 deaths mostly coded to other causes. All these deaths occurred after 1959, and there were indications that additional cases of mesothelioma may have gone unrecognised, especially before that date. The exposure for each man was estimated in terms of duration and dust concentration in millions of dust particles per cubic foot (mpcf) from available measurements. Analyses were made both by life table and case referent methods. The standardised mortality ratio for respiratory cancer for the whole cohort was 105.0, but the risk rose linearly from 66.9 for men with less than 10 mpcf.y to 416.1 for those with 80 mpcf.y or more. Lines fitted to relative risks derived from SMRs in this and the textile plant studied in South Carolina were almost identical in slope. This was confirmed by case referent analysis. These findings support the conclusion from the South Carolina study that the risk of lung cancer in textile processing is very much greater than in chrysotile production and probably than in the friction products industry. The much greater risk of mesothelioma from exposure to processes in which even quite small quantities of amphiboles were used was also confirmed.

Topics: Adult; Aged; Asbestos; Asbestos, Amosite; Asbestos, Crocidolite; Asbestos, Serpentine; Asbestosis; Dust; Humans; Lung Neoplasms; Male; Mesothelioma; Middle Aged; Occupational Diseases; Textile Industry

The predominant asbestos fibre type used in the production of asbestos cement is chrysotile. The use of asbestos in relation to fibre type in a Norwegian asbestos cement plant during 1942-80 was 91.7% chrysotile, 3.1% amosite, 4.1% crocidolite, and 1.1% anthophyllite respectively. Electron microscopy and x ray microanalysis of lung tissue samples of asbestos cement workers who had died of malignant pleural mesothelioma or bronchogenic carcinoma showed a completely inverse ratio with regard to fibre type. The percentage of chrysotile asbestos in lung tissue varied between 0% and 9% whereas the corresponding numbers for the amphiboles were 76% and 99%. These differences are discussed with respect to the behaviour of different fibre types in the human body and to the occurrence of malignant mesothelioma in this asbestos cement factory.

Topics: Aged; Asbestos; Asbestos, Amosite; Asbestos, Amphibole; Asbestos, Crocidolite; Asbestos, Serpentine; Carcinoma, Bronchogenic; Humans; Lung; Lung Neoplasms; Mesothelioma; Middle Aged; Occupational Diseases; Pleural Neoplasms; Silicon Dioxide

Analysis of the survival of all 81 cases of pathologically confirmed malignant pleural mesothelioma in Western Australia between January 1957 and December 1980 has revealed a median survival from diagnosis of 5.1 months (mean 7.8 months). The average time between presentation and diagnosis was 3.4 months. Survival was better in younger subjects and subjects selected for surgery but was unrelated to sex, symptoms at onset, history of asbestos exposure, tumour morphology, therapy other than surgery or year of presentation. The selection of subjects at earlier clinical stages for surgical intervention is considered to account for their longer survival. The outlook for patients with this disease remains poor and there is still no optimism for future advances in therapy.

Topics: Adult; Aged; Asbestos; Asbestos, Crocidolite; Australia; Environmental Exposure; Female; Humans; Male; Mesothelioma; Middle Aged; Pleural Neoplasms; Retrospective Studies; Smoking

Topics: Asbestos; Asbestos, Crocidolite; Asbestos, Serpentine; Asbestosis; England; Female; Humans; Lung Neoplasms; Mesothelioma; Occupational Diseases; Ovarian Neoplasms; Respiratory Protective Devices; Time Factors

Topics: Abdominal Neoplasms; Animals; Asbestos; Asbestos, Crocidolite; Female; Mesothelioma; Neoplasms, Experimental; Particle Size; Peritoneal Cavity; Rats; Rats, Inbred Strains

Cell lines were established in vitro from five peritoneal mesotheliomas produced in rats by the injection of crocidolite asbestos. These tumours exhibited the previously described diverse range of histological patterns normally associated with mesotheliomas. This diversity of appearance was also evident in culture but cell patterns in vitro did not necessarily correspond to the histology of the original tumour. With increased time in culture most cell lines tended towards a pattern of random orientation associated with the piling up of cells to form discrete masses. Despite this variation in cell pattern in culture, few ultrastructural differences were seen during electron microscope examination. Following varying periods in culture, some cell lines from these tumours were injected into either rats or athymic mice. Only one typical rat mesothelioma was produced but all cell lines produced tumours in athymic mice. The implications of these findings are discussed in relation to the aetiology of asbestos induced mesotheliomas.

Topics: Animals; Asbestos, Crocidolite; In Vitro Techniques; Male; Mesothelioma; Mice; Mice, Nude; Peritoneal Neoplasms; Rats; Rats, Wistar; Tumor Cells, Cultured

Of 199 persons employed in the manufacture and handling of Canadian military gas mask canisters containing pure crocidolite, 1939 to 1942, by the end of 1975, 56 had died, 120 were still alive, and 23 could not be traced. Nine (16%) of the deaths were probably due to malignant mesothelioma, six involving the peritoneum. The risk of mesothelioma after crocidolite exposure appears to be many times greater than that after chrysotile.

Topics: Asbestos; Asbestos, Crocidolite; Asbestos, Serpentine; Canada; Environmental Exposure; Female; Humans; Industry; Lung Neoplasms; Male; Mesothelioma; Mining; Respiratory Protective Devices