Malignant Mesothelioma and Its Non-Asbestos Causes
Malignant Mesothelioma and Its Non-Asbestos Causes
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).
There is a complex relationship between malignant mesothelioma and its etiologic agents. The proportion of cases attributable to asbestos varies according to sex, anatomic location, fiber type, occupation, and industry.1–4 Whilst most pleural mesotheliomas in males are causally related to prior occupational amphibole asbestos exposure, the relationship between asbestos and mesothelioma is subject to considerable sex- and
site-specific variation. For workers heavily exposed to commercial forms of amphibole asbestos, between 2% and 18% have developed pleural mesothelioma. Following occupational chrysotile exposure the incidence of pleural mesothelioma ranges from 0% to 0.47% (the latter recorded in chrysotile miners/millers).5
Historically, peritoneal mesotheliomas were associated with heavy commercial amphibole asbestos exposures.6 Such exposures are now uncommon and currently the epidemiologic evidence correlating time trends, incidence in both sexes, and asbestos exposure suggests that a much smaller fraction of tumors in men are related to asbestos, and very few tumors in women.7 Recently, one mineralogic study8 identified almost 50% (20 of 42) of peritoneal mesotheliomas arising in persons with fiber counts within background control values, indicating a likely alternative cause in these tumors.
Owing to the rarity of malignant pericardial and testicular mesotheliomas, analytic epidemiologic studies do not exist but an ecologic study of Surveillance, Epidemiology, and End Results (SEER) data did not support the role for asbestos in these sites.9,10 Anecdotal case studies of pericardial, gonadal, and localized mesotheliomas report an inconstant relationship with asbestos and alone do not allow for any definite causal association with asbestos to be made.11–13
It is clear that not all mesotheliomas are related to asbestos exposure. In this article we review the current literature on non-asbestos–induced mesothelioma.
MINERAL FIBERS OTHER THAN ASBESTOS
Erionite
Erionite is a fibrous form of zeolite that has physical characteristics resembling the amphiboles amosite or crocidolite.14 Erionite is a potassium aluminum silicate with variable amounts of calcium and sodium, found mostly in volcanic regions associated with rhyolitic tuffs. Deposits have been described in the Cappadocian region of Turkey, but some of the highest concentrations of this fiber can be found in the Intermountain West of the United States from Oregon into Mexico and the Sierra Madre Occidental region.15–17 High amounts of airborne erionite were found in North Dakota after hundreds of miles of roads were surfaced with erionite-containing gravel.18 More recently, erionite has also been identified in North Eastern Italy.19
Baris and colleagues20 and Artvinli and Baris21 first reported an outbreak of mesothelioma in 2 small villages in the Anatolian region of Turkey. Some of the villagers also had chronic fibrosing pleurisy. Ferruginous bodies with erionite cores were isolated from the lungs of some of these villagers.22 The cause of the outbreak was believed to be exposure to erionite fibers used in the whitewash on the exterior of houses in the villages,
although some asbestos was also identified in the region.23 Subsequent studies demonstrated other malignancies among the villagers as well, including lung cancers.24 With greater than 50% of mesotheliomas in Turkish villagers being caused by erionite, a genetic predisposition to fiber-induced carcinogenesis was proposed by some researchers, although the same was challenged by others.25,26
In consideration of the high concentration of erionite fibers in North America as noted above, perhaps it is not surprising that a high incidence of lung cancer and malignant mesothelioma has been identified in 1 rural area with erionite contamination.27 Kliment et al28 reported a case of a 47-year-old Mexican emigrant to the United States who was diagnosed with malignant pleural mesothelioma and pleural plaques. He had lived the first 20 to 25 years of his life in Central Mexico, and fiber burden analysis demonstrated considerable
quantities of high-aspect ratio erionite fibers in the patient's lung tissue. Oczypok et al29 reported an additional case of a 53-year-old Mexican emigrant to the United States who was diagnosed with malignant pleural mesothelioma. He moved to the United States as a young adult, and analysis of his lung tissue samples revealed elevated quantities of high-aspect ratio erionite fibers. Similar fibers were identified in rhyolitic tuff material and soil on the family farm where the patient grew up.
Experimental animal studies have confirmed the high carcinogenic potential of erionite, including the production of malignant mesotheliomas.30–32 Early changes including pleural fibrosis, mesothelial hyperplasia, and mesothelial dysplasia have also been reported.33,34 Although the exact mechanisms of carcinogenesis are unknown, it is of interest that like asbestos, erionite primes and activates the NLRP3 inflammasome,
which in turn triggers an autocrine feedback loop in mesothelial cells. This feedback loop is modulated by the interleukin-1 receptor.35 Based on the foregoing, more cases of erionite-induced mesothelioma are likely to be identified in regions of the world where this fiber is prevalent and exposures to humans occur.
Fluoro-edenite
Fluoro-edenite is a non-asbestos mineral fiber with similar morphology and composition to the actinolite-tremolite series. It was originally characterized in 1997 from rock deposits taken near the city of Biancavilla (Catania, Eastern Sicily, Italy). The mineral ore was extracted from quarries in Monte Calvario, southeast of
Biancavilla and subsequently commercially used as a building material for road paving, and residential and commercial plaster and mortar construction. A 10-fold increase in pleural neoplasms was reported in exposed subjects in a mortality study.36 Pleural plaques have also been identified in Biancavilla construction workers exposed to fluoro-edenite.37
Animal experimental studies show mesothelioma induction following fluoro-edenite implantation in rat peritoneal cavities.38 In vitro studies show that fluoro-edenite is an inducer of DNA damage and reactive oxygen species production, with overall decreased cell viability.39 The International Agency for Research on Cancer has subsequently classified fibrous fluoro-edenite as carcinogenic to humans (group 1).40
Balangeroite
This gageite-like mineral is a fibrous iron-rich magnesium silicate with a complex structure often intergrown with chrysotile deposits. It comprises around 0.2% to 0.5% contamination of the chrysotile from the San Vittore mine in Balangero, Italy. The fibrous mineral has similarities in morphology but lower biodurability than commercial amphiboles.41–43 The role of this fibrous amphibolic mineral in the induction of mesothelioma in Balangero,
Italy, is controversial with some authors attributing mesotheliomas to it and others questioning its precise role.44–46 The controversy is complicated by the fact that the Balangero mine occasionally milled imported commercial amphibole from South Africa; this conclusion is supported by the fact that some Balangero chrysotile miners have identifiable commercial amphiboles (crocidolite, amosite) as well as noncommercial amphibole tremolite in lung tissue on mineral analysis.47,48
Carbon Nanotubes
Carbon nanotubes have a number of wide applications in industry. They are formed from varying high-aspect ratio graphene cylinders, which can assume a fibrous habit. There has been concern that their close physical similarities to asbestos may pose a health risk.49 It is recognized that both in vitro and in vivo studies do not necessarily transfer any significance to human populations. Nonetheless, there exist in vitro studies that show carbon nanotube
cytotoxicity, and in vivo studies have shown the development of mesothelioma in both genetically modified cancer-sensitized mice and Fischer 344 rats exposed to carbon nanotubes via peritoneal and intrascrotal inoculation, respectively.50,51 Pleural inflammation has been correlated with fiber length.52,53 Presently it is not practicable to evaluate at an epidemiologic level whether there exists any association between carbon nanotube exposure and human disease.
Other Minerals
A variety of man-made vitreous fibers have been studied to evaluate their potential to induce mesothelioma in humans. These include rock wool, slag wool, glass fiber, and glass filament. Systematic reviews of synthetic vitreous fibers have concluded that the combined evidence based on epidemiologic and toxicologic data provides little support of any increased risk of mesothelioma following exposure.54,55 Such man-made fibers have low biopersistence in tissue systems. In contrast, in vivo high-dose chronic inhalational experiments to more biopersistent refractory ceramic fibers have been associated with the induction of mesothelioma in Syrian golden hamsters.56
Anecdotal case reports linking mesothelioma to metals beryllium and nickel,57,58 and crystalline silica in sugar cane,59 have never been supported by analytic epidemiologic studies. At present, the weight of evidence does not support that these minerals are causes of malignant mesothelioma in humans.
RADIATION
Radiation is a recognized pancarcinogen. The evidence linking radiation with malignant mesothelioma in humans has come from 3 sources: first, case reports, case series, and retrospective cohort studies of patients previously receiving therapeutic irradiation for tumors; second, from reported mesothelioma cases following radioactive thorium dioxide contrast medium “Thorotrast” and; third, from studies of atomic energy/nuclear industry workers exposed to prolonged lower levels of irradiation.
Pleural, peritoneal, and pericardial mesotheliomas have all been reported after radiotherapy to treat childhood and adolescent tumors, most notably with Hodgkin and non-Hodgkin lymphoma, germ cell neoplasms, Wilms tumor of the kidney, and breast cancer.60–66 The latent period has been reported to be between 5 to more than 50 years with radiation-induced mesotheliomas showing an equal male to female ratio.67,68
A variety of tumors including pleural and peritoneal mesothelioma, hepatocellular carcinoma, hemangioendothelioma, and cholangiocarcinoma have been reported after intravenous Thorotrast administration.69–71 The radioactive 232ThO2 is insoluble and following injection, deposits in organs and is associated with slow decay and prolonged alpha-ray emission.
Mesotheliomas have also been reported in an occupational setting in radiation technologists exposed to external gamma-ray emission and internal radionuclides.72 The risk of mesothelioma was also elevated among British Atomic Energy workers employed between 1946 and 1990 and at the Idaho National Engineering and Environmental Laboratory where nuclear processing and demolition occurred, emphasizing the significance of external scatter radiation at lower doses.73,74
Animal experiments with 239plutonium dioxide have shown epithelial tumors, sarcomas, and mesotheliomas in around 30% of rats after intraperitoneal injection.75 Inhalation and intrapleural injection studies showed much lower rates of mesothelioma formation (0.2% and 3.7%, respectively).76 Aerosolized 144cerium dioxide was found to induce mesothelioma in 0.7% of 566 rats.77
A recent review of SEER data found that post external beam radiation mesothelioma risk increased with longer latency and showed a stronger association with peritoneal mesothelioma.78 A recent genetic profiling study of radiation-induced mesotheliomas showed some copy number gains outnumbering deletions, whereas deletions of 6q, 14q, 17p, and 22q were more frequently seen in those asbestos-associated mesotheliomas tested, signifying potential different molecular mechanisms of induction.79
Overall there is consistency of evidence that shows radiation is a risk factor for malignant mesothelioma in directly irradiated tissues and to a lesser extent in tissue remote from the target area.
