Mesothelioma in immigrants from Turkey: Genes have a minor role.

OBJECTIVE: To examine the incidence and epidemiology of malignant mesothelioma in immigrants from Karain where there is an extraordinarily high incidence of mesothelioma, Cappadocia, Turkey, to Stockholm, Sweden, and their children over 20 years of age born in Stockholm, i.e. two genetically similar populations with and without erionite exposure. METHODS: This survey was conducted as a retrospective cohort study. Standardized average annual mesothelioma incidence rates (AAMIRs) and mesothelioma standardized incidence ratio (mSIR) were calculated. Cox regression analysis was used to determine the importance of different factors related to mesothelioma risk. RESULTS: The cohort consisted of 337 people, 203 of whom were born and/or lived in Karain before immigrating to Sweden (erionite-exposed), and 134 who were born in Stockholm (erionite-unexposed). There were 69 deaths, 42 (61%) due to mesothelioma, and two patients with the disease who were still alive. Of these 44 patients, 22 were men. All mesothelioma patients were in the erionite-exposed group. In the age group 30-49 years, mesothelioma developed in 11 of 38 (29%) with erionite exposure, while there were no cases among 86 persons in the non-exposed group. For men, the AAMIR was 253.9 per 100,000 persons in the whole cohort, and for women, it was 350.9. The mSIR was 71.9 for men and 393.1 for women. Exposure to erionite exceeding 20 years and age over 40 years were associated with increased mesothelioma risk. CONCLUSION: Exposure to erionite is the leading cause of mesothelioma in Karain villagers, and genetic factors are probably of minor importance.

Asbestos and Zeolites: from A to Z via a Common Ion.

Asbestos and zeolites are silicate-based minerals, linked inextricably via paradoxical similarities and differences which have emanated from different geological epochs. Both have been employed in the service of humanity through millennia: asbestos, for its "inextinguishable" quality of being an insulator against heat and fire; zeolite, a "boiling stone" with its volcanic and marine sedimentary rock origins, for its propensity to adsorb water and remove metals and toxins. Serious adverse health effects observed in asbestos miners as long ago as the 1st Century AD did not halt the rising popularity of asbestos. As the miracle material of the 1900s, asbestos production and consumption exploded, culminating in its ubiquity in ships, vehicles, homes, commercial buildings, and over 3000 different industrial and household products. Through the 1940s and 1950s, epidemiological studies concluded that asbestos was a likely cause of asbestosis, lung cancer, and malignant mesothelioma, and it is now banned in many but far from all countries. The long latency between exposure to asbestos and the occurrence of cancer has obscured the deadly consequences of asbestos exposure for centuries. Even today, a considerable part of the world population is insufficiently aware of the dangers of asbestos, and millions of tons of this carcinogen continue to be mined and used worldwide. Zeolites, both natural and synthetic, are microporous aluminosilicate minerals commonly used in a myriad of processes, in the petrochemical industry, in domestic appliances and cleaning agents, as commercial adsorbents and exchangers for toxins and pollutants, and as catalysts. Zeolites are found in agriculture, veterinary science, and human health. More recently, new materials such as carbon nanotubes are being employed in materials requiring durability and thermal and electrical conductivity, yet nanotubes are now joining the ranks of more established particulates such as asbestos and silica, in causing human disease. In this review, we compare and contrast the similarities and differences of these two groups of silicate minerals and their waxing and waning use in the employ of humanity.

Erionite in Auckland bedrock and malignant mesothelioma: an emerging public and occupational health hazard?

Overseas, emerging research has shown that where erionite is present in bedrock as a zeolite, and then subsequently disturbed and blown into the atmosphere, resulting exposure is associated with health effects similar to those caused by asbestos, including malignant mesothelioma (MM). Erionite-induced MM is thought to be particularly prevalent in the construction and quarrying industries, in regions where rock containing erionite is disturbed. In 2015, the then Government Chief Scientist, Sir Peter Gluckman, reported that erionite was a more potent carcinogen than asbestos, and more recent studies have established its presence in the Auckland Region. However, globally at present, there are no established occupational exposure limits for erionite, standard sampling and analytical methods or exposure mitigation guidelines. Given the many major construction projects being carried out in Auckland at the present time, which involve the removal of large quantities of bedrock containing erionite, an assessment of the health risks such activities pose to the public is needed.

Malignant Mesothelioma and Its Non-Asbestos Causes.

CONTEXT: - Although many mesotheliomas are related to asbestos exposure, not all are, and there is increasing information on other causes of mesothelioma. OBJECTIVE: - To provide a review of non-asbestos causes for malignant mesothelioma. DATA SOURCES: - Review of relevant published literature via PubMed and other search engines. CONCLUSIONS: - Currently, most pleural mesotheliomas (70% to 90%) in men in Europe and North America are attributable to asbestos exposure; for peritoneal mesothelioma the proportion is lower. In North America few mesotheliomas in women at any site are attributable to asbestos exposure, but in Europe the proportion is higher and varies considerably by locale. In certain geographic locations other types of mineral fibers (erionite, fluoro-edenite, and probably balangeroite) can induce mesothelioma. Therapeutic radiation for other malignancies is a well-established cause of mesothelioma, with relative risks as high as 30. Carbon nanotubes can also induce mesotheliomas in animals but there are no human epidemiologic data that shed light on this issue. Chronic pleural inflammation may be a cause of mesothelioma but the data are scanty. Although SV40 can induce mesotheliomas in animals, in humans the epidemiologic data are against a causative role. A small number of mesotheliomas (probably in the order of 1%) are caused by germline mutations/deletions of BRCA1-associated protein-1 ( BAP1) in kindreds that also develop a variety of other cancers. All of these alternative etiologies account for a small proportion of tumors, and most mesotheliomas not clearly attributable to asbestos exposure are spontaneous (idiopathic).

Effect of Clinoptilolite and Sepiolite Nanoclays on Human and Parasitic Highly Phagocytic Cells.

Nanoclays have potential applications in biomedicine raising the need to evaluate their toxicity in in vitro models as a first approach to its biocompatibility. In this study, in vitro toxicity of clinoptilolite and sepiolite nanoclays (NC) was analyzed in highly phagocytic cultures of amoebas and human and mice macrophages. While amebic viability was significantly affected only by sepiolite NC at concentrations higher than 0.1 mg/mL, the effect on macrophage cultures was dependent on the origin of the cells. Macrophages derived from human peripheral blood monocytes were less affected in viability (25% decrease at 48 h), followed by the RAW 264.7 cell line (40%), and finally, macrophages derived from mice bone marrow monocytes (98%). Moreover, the cell line and mice macrophages die mainly by necrosis, whereas human macrophages exhibit increased apoptosis. Cytokine expression analysis in media of sepiolite NC treated cultures showed a proinflammatory profile (INFγ, IL-1α, IL-8, and IL-6), in contrast with clinoptilolite NC that induced lees cytokines with concomitant production of IL-10. The results show that sepiolite NC is more toxic to amoebas and macrophages than clinoptilolite NC, mostly in a time and dose-dependent manner. However, the effect of sepiolite NC was comparable with talc powder suggesting that both NC have low cytotoxicity in vitro.

Clinical and prognostic features of erionite-induced malignant mesothelioma.

This review analytically examines the published data for erionite-related malignant pleural mesothelioma (E-MPM) and any data to support a genetically predisposed mechanism to erionite fiber carcinogenesis. Adult patients of age ≥18 years with erionite-related pleural diseases and genetically predisposed mechanisms to erionite carcinogenesis were included, while exclusion criteria included asbestos- or tremolite-related pleural diseases. The search was limited to human studies though not limited to a specific timeframe. A total of 33 studies (31042 patients) including 22 retrospective studies, 6 prospective studies, and 5 case reports were reviewed. E-MPM developed in some subjects with high exposures to erionite, though not all. Chest CT was more reliable in detecting various pleural changes in E-MPM than chest X-ray, and pleural effusion was the most common finding in E-MPM cases, by both tests. Bronchoalveolar lavage remains a reliable and relatively less invasive technique. Chemotherapy with cisplatin and mitomycin can be administered either alone or following surgery. Erionite has been the culprit of numerous malignant mesothelioma cases in Europe and even in North America. Erionite has a higher degree of carcinogenicity with possible genetic transmission of erionite susceptibility in an autosomal dominant fashion. Therapeutic management for E-MPM remains very limited, and cure of the disease is extremely rare.

Molecular pathways: targeting mechanisms of asbestos and erionite carcinogenesis in mesothelioma.

Malignant mesothelioma is an aggressive malignancy related to asbestos and erionite exposure. AP-1 transcriptional activity and the NF-κB signaling pathway have been linked to mesothelial cell transformation and tumor progression. HGF and c-Met are highly expressed in mesotheliomas. Phosphoinositide 3-kinase, AKT, and the downstream mTOR are involved in cell growth and survival, and they are often found to be activated in mesothelioma. p16(INK4a) and p14(ARF) are frequently inactivated in human mesothelioma, and ∼50% of mesotheliomas contain the NF2 mutation. Molecular therapies aimed at interfering with these pathways have not improved the dismal prognosis of mesothelioma, except possibly for a small subset of patients who benefit from certain therapies. Recent studies have shown the importance of asbestos-induced inflammation in the initiation and growth of mesothelioma, and HMGB1 and Nalp3 inflammasome have been identified as key initiators of this process. Asbestos induces cell necrosis, causing the release of HMGB1, which in turn may activate Nalp3 inflammasome, a process that is enhanced by asbestos-induced production of reactive oxygen species. HMGB1 and Nalp3 induce proinflammatory responses and lead to interleukin-1ß and TNF-α secretion and NF-κB activity, thereby promoting cell survival and tumor growth. Novel strategies that interfere with asbestos- and erionite-mediated inflammation might prevent or delay the onset of mesothelioma in high-risk cohorts, including genetically predisposed individuals, and/or inhibit tumor growth. The very recent discovery that germline BAP1 mutations cause a new cancer syndrome characterized by mesothelioma, uveal melanoma, and melanocytic tumors provides researchers with a novel target for prevention and early detection.

Quantitative characterization of the mesothelioma-inducing erionite series minerals by transmission electron microscopy and energy dispersive spectroscopy.

Air-collected erionite series minerals from Cappadocia region of Turkey were characterized quantitatively by using transmission electron microscopy (TEM) equipped with energy dispersive spectroscopy (EDS). Field emission scanning electron microscopy aided identification of fibrous minerals. Quantitative characterization guidelines for positive identification of erionites proposed by Dogan and Dogan (2008) was applied and the modified balance error formula (E%<10) and Mg-content test <0.80 were performed for each analysis. Erionite species computation showed that the mineral is erionite-K and a mean chemical formula is proposed based upon the TEM-EDS results. Among the 60 analyses, 11 passed E% test (18.3%), 33 passed Mg-content test (55.0%), and only 3 passed both E% and Mg-content tests (5.0%). This shows difficulty of quantitative characterization of the erionite series minerals. However, as erionite is the most carcinogenic mineral known and is classified by IARC as a Group-I (human) carcinogen, it requires special attention from the mineralogical community to help establish its true mineralogical properties. Quantitatively characterized erionite data are very scarce in literature. Correctly identified erionite mineral types will be useful to medical researchers in their search to find a possible cure for the deadly disease of mesothelioma.

Erionite exposure in North Dakota and Turkish villages with mesothelioma.

Exposure to erionite, an asbestos-like mineral, causes unprecedented rates of malignant mesothelioma (MM) mortality in some Turkish villages. Erionite deposits are present in at least 12 US states. We investigated whether increased urban development has led to erionite exposure in the United States and after preliminary exploration, focused our studies on Dunn County, North Dakota (ND). In Dunn County, ND, we discovered that over the past three decades, more than 300 miles of roads were surfaced with erionite-containing gravel. To determine potential health implications, we compared erionite from the Turkish villages to that from ND. Our study evaluated airborne point exposure concentrations, examined the physical and chemical properties of erionite, and examined the hallmarks of mesothelial cell transformation in vitro and in vivo. Airborne erionite concentrations measured in ND along roadsides, indoors, and inside vehicles, including school buses, equaled or exceeded concentrations in Boyali, where 6.25% of all deaths are caused by MM. With the exception of outdoor samples along roadsides, ND concentrations were lower than those measured in Turkish villages with MM mortality ranging from 20 to 50%. The physical and chemical properties of erionite from Turkey and ND are very similar and they showed identical biological activities. Considering the known 30- to 60-y latency for MM development, there is reason for concern for increased risk in ND in the future. Our findings indicate that implementation of novel preventive and early detection programs in ND and other erionite-rich areas of the United States, similar to efforts currently being undertaken in Turkey, is warranted.

Erionite series minerals: mineralogical and carcinogenic properties.

Erionite is a human and animal carcinogen and one of the most toxic minerals known. Erionite deposits have been reported in many countries; however, it is only in the area of three villages of Cappadocia, Turkey, that environmental exposure to erionite has been demonstrated to be the cause of an epidemic of the disease mesothelioma. In the USA, no cases of mesothelioma have been reliably proven to be the result of erionite exposure, though the possibility exists. Erionite samples from three villages of the Cappadocia region were characterized mineralogically and compared with three different standards from the USA. Micro morphological details of erionite minerals using a high-resolution field-emission SEM showed that microstructures of "bundles", "fibers", and "fibrils" are important physical properties of fibrous erionite minerals. Typical lung burden of erionite and asbestos fibers were compared in terms of number of fibers. Assuming the lung burden of fibers in a human mesothelioma victim is about 1 mg, and the hazardous fibers are approximately 1 mum in diameter and 10 mum long, that milligram contains approximately 40 million asbestos and 50 million erionite fibers. These microstructures of erionite minerals draw attention to the concepts of surface area or surface-area-to-volume ratio and their relationship to the carcinogenicity of the mineral. The larger surface area creates a wider platform for mineral-cell interaction and thus more possibilities of proliferative transformation of mesothelial cells. Consequently, understanding the exact mineralogical properties will help determination of the true carcinogenic mechanism(s) of the mineral for prevention and possibly treatment of malignant mesothelioma.

Environmental mesothelioma associated with tremolite asbestos: lessons from the experiences of Turkey, Greece, Corsica, New Caledonia and Cyprus.

Mediterranean regions such as Greece, Turkey, Cyprus, Corsica and New Caledonia have experienced epidemics of malignant mesothelioma as a result of non-occupational, "domestic" exposure to tremolite asbestos and fibrous erionite. This exposure to tremolite asbestos and fibrous erionite is typified "domestic" due to its prevalence in regions with natural deposits of tremolite asbestos (or fibrous erionite) where the material from tremolite asbestos or fibrous erionite is used for domestic applications such as whitewashing. However, these exposures may be useful in examining the potential consequences of even small amounts of amphibole asbestos fibers in the ambient air. It can also elucidate the effects of fibers that behave like amphibole asbestos. However, this type of exposure is not useful for studying the potential effects of small amounts of asbestos in the ambient air of big cities due to the differing nature of the fiber types and modes of exposure between the regions.

Topically applied nitric oxide induces T-lymphocyte infiltration in human skin, but minimal inflammation.

Nitric oxide (NO) plays an important role in the cutaneous response to UV radiation and in cutaneous inflammation. The presence of inducible NO synthase protein in a number of inflammatory dermatoses, coupled with the induction of an intense cutaneous inflammatory infiltrate following topical application of the NO donor-acidified nitrite (NO2(-)), has set the paradigm of NO being an inflammatory mediator in human skin. Using zeolite NO (Ze-NO), a chemically inert, pure NO donor, we have shown that NO per se produces little inflammation. Biologically, relevant doses of Ze-NO induce a dermal CD4-positive T-cell infiltrate and IFN-gamma secretion. In contrast acidified nitrite, releasing equal quantities of NO (measured by dermal microdialysis and cutaneous erythema), induces an intense epidermal infiltrate of macrophages with a similar dermal infiltrate of CD3-, CD4-, CD8-, and CD68-positive cells and neutrophils. Suction blisters were created in Ze-NO-treated and control skin. IFN-gamma, but not IL-4, was detected in Ze-NO-treated skin (mean control 0.1+/-0.07 pg mg(-1) protein, mean IFN-gamma 0.6+/-0.4 pg mg(-1) protein). We suggest that the potent inflammation induced by acidified NO2(-) is secondary to the release of additional mediators.

Tissue response to a supplement high in aluminum and silicon.

The objective was to determine the effects of sodium zeolite A (SZA) on mineral metabolism and tissue mineral composition in calves. Twenty calves were placed on study at 3 days of age and were placed into one of two groups: SS, which received 0.05% BW SZA added to their milk replacer, and CO, which received only milk replacer. Blood samples were taken on days 0, 30, and 60 for mineral analysis. Urine and feces were collected on day 30 for mineral metabolism, and on day 60, the calves were euthanized, and samples were taken from numerous organs for mineral analyses. Aluminum retention was increased in the SS calves (p = 0.001). Silicon concentrations were increased in the aorta, spleen, lung, muscle, and kidney of the SS calves, and aluminum was increased in all SS tissues (p < 0.05). Calcium concentrations were increased in aorta, liver, muscle, and tendon; phosphorus concentrations were increased in aorta, but decreased in plasma; magnesium concentrations were increased in aorta, heart, kidney, liver, and pancreas, but decreased in plasma; and iron concentrations were decreased in kidney and liver (p < 0.05). The accumulation of tissue aluminum and therefore potential adverse consequences may preclude any benefits of using SZA as a dietary supplement.

Prospective study of mesothelioma mortality in Turkish villages with exposure to fibrous zeolite.

Mesothelioma incidence is high in certain villages on the Anatolian plateau in Turkey, where environmental exposure includes erionite, a form of zeolite fibers, from the local volcanic tuff. Previous studies of this exposure were cross-sectional or with a follow-up period of only a few years. A prospective study of residents of two exposed and one nearby control village was initiated in 1979 and continued through December 31, 2003. A total of 891 men and women, aged 20 years or older, were included, 230 of them residing in the village without known exposure to erionite. Mortality data were obtained from hospital records and death certificates. During the 23-year follow-up, 372 deaths occurred; 119 of these were from mesothelioma, which was the cause of 44.5% of all deaths in the exposed villages. Seventeen patients had peritoneal mesothelioma; the rest had pleural mesothelioma. Only two cases of mesothelioma, one of each type, occurred in the control village-both in women born elsewhere. When standardized to the world population, the pleural mesothelioma incidence was approximately 700 and 200 cases per 100,000 people annually in the two exposed villages and about 10 cases per 100,000 people in the control village. When we used Danish data for comparison, the standardized pleural mesothelioma mortality rate was 485 (95% confidence interval = 395 to 590). Our results emphasize the severity of the mesothelioma endemic in erionite-exposed areas of Turkey and call for intensified prevention of mesothelioma by limiting environmental exposures to these fibers.

Contested etiology: cancer risk among two Anatolian populations in Turkey and Europe.

This paper discusses the different explanatory models and the contested perceptions of cancer etiology among residents of two Anatolian villages and migrants from these villages in Turkey, Sweden, and Germany. These communities suffer from an endemic, deadly cancer called mesothelioma, the cause of which is associated with exposure to an environmental carcinogenic substance, erionite, which is present in large deposits in the ground, in the stones, and white stucco that the villagers used to build their homes, and in the air in the form of dust. However, an examination of patients' disease trends, experiences, and local explanations has led to new investigations of possible familial risk cofactors. This paper selectively focuses on different aspects of cancer risk and its manifested metaphors, aesthetics, and perceptions. The different categories of cancer risk freely interact, derive an important part of their meaning from the context of the doctor-cancer patient relationship, and are created and navigated by the cancer narrative.

Fragile castles: the paradox of research politics, scientific progress, and the mutation of medical knowledge.

This paper is based on fieldwork done from 1996-1999 in different locations among village communities from Central Anatolia afflicted with the deadly malignancy of mesothelioma. Medical research has long established the relationship between mesothelioma and the environment; yet in earlier work correlations deduced through my genealogies provide evidence of a possible genetic cofactor causing these cancer deaths. This paper illustrates how medical research becomes an arena for local and global political interests and how the disruption of the doctor-cancer patient relationship impedes medical research. Methods include illness and clinical narratives, kinship charts and pedigrees, and observation of involved doctors and patients in multiple sites and geographical locations. Under focus are the anthropologist's involvement in global biomedical research and her interconnectedness with its political events.

Malignant pleural mesothelioma in Turkey, 2000-2002.

Both asbestos and erionite related malignant pleural mesothelioma (MPM) is a serious health problem in Turkey. Erionite has a higher potency in the lung than asbestos and familial clustering of malignant mesothelioma suggests a genetic predisposition to this cancer among affected individuals. Neither Simian virus 40 (SV40) nor human herpes virus 8 (HHV-8) are co-factors in the pathenogenesis of environmentally induced mesothelioma. A survival advantage has been demonstrated in patients with asbestos-induced mesothelioma compared with erionite-induced mesothelioma. This together with the proliferation index (PI) can be used as an independent prognostic factor for patients with malignant pleural mesothelioma. It is envisaged that the application of these prognostic approaches together with the new TNM staging system will allow investigations to be more precisely carried out and evaluated.