Mesothelioma Induction Research Articles

Difference in carcinogenicities of two different vapor grown carbon fibers with different physicochemical characteristics induced by intratracheal instillation in rats

BackgroundCarbon fibers are high aspect ratio structures with diameters on the submicron scale. Vapor grown carbon fibers are contained within multi-walled carbon tubes, with VGCF™-H commonly applied as a conductive additive in lithium-ion batteries. However, several multi-walled carbon fibers, including MWNT-7, have been reported to induce lung carcinogenicity in rats. This study investigated the carcinogenic potential of VGCF™-H fibers in F344 rats of both sexes with the vapor grown carbon fibers VGCF™-H and MWNT-7 over 2 years. The carbon fibers were administered to rats by intratracheal instillation at doses of 0, 0.016, 0.08, and 0.4 mg/kg (total doses of 0, 0.128, 0.64, and 3.2 mg/kg) once per week for eight weeks and the rats were observed for up to 2 years after the first instillation.ResultsHistopathological examination showed the induction of malignant mesothelioma on the pleural cavity with dose-dependent increases observed at 0, 0.128, 0.64, and 3.2 mg/kg in rats of both sexes that were exposed to MWNT-7. On the other hand, only two cases of pleural malignant mesothelioma were observed in the VGCF™-H groups; both rats that received 3.2 mg/kg in male. The animals in the MWNT-7 groups either died or became moribund earlier than those in the VGCF™-H groups, which is thought related to the development of malignant mesothelioma. The survival rates were higher in the VGCF™-H group, and more carbon fibers were observed in the pleural lavage fluid (PLF) of the MWNT-7 groups. These results suggest that malignant mesothelioma is related to the transfer of carbon fibers into the pleural cavity.ConclusionsThe intratracheal instillation of MWNT-7 clearly led to carcinogenicity in both male and female rats at all doses. The equivocal evidence for carcinogenic potential that was observed in male rats exposed to VGCF™-H was not seen in the females. The differences in the carcinogenicities of the two types of carbon fibers are thought due to differences in the number of carbon fibers reaching the pleural cavity. The results indicate that the carcinogenic activity of VGCF™-H is lower than that of MWNT-7.

Further Studies of Bolivian Crocidolite –Part IV: Fibre Width, Fibre Drift and their relation to Mesothelioma Induction: Preliminary Findings


 Background
 The hypothesis that fibre width is a major determinant of mesothelioma induction has been examined by comparative studies of two crocidolites from different sources. Fine fibres fromCapesouthAfricaand the thicker fibre found and used similarly inBolivia.
 
 It is well established that ‘thin’ fibre crocidolite fromCapeSouth Africais extremely mesotheliomagenic. Bolivian crocidolite has a much wider width distribution and relatively little mesothelioma inducing potential.
 
 Methods
 We analysed the mesothelioma demography inBoliviawhere local crocidolite has been used for decades This was compared with the mesothelioma demography in theItalianCityof Casale Monteferrato whereCapecrocidolite was processed for many decades in the Eternit Asbestos Cement plant producing numerous cases of mesothelioma.
 We also conducted a limited downwind study from the fiberizing part of the historical operating plant where products containing Bolivian crocidolite were made for sale and use inCochabamba.
 
 Results
 The demographic study confirmed the absence of a significant mesothelioma excess inBolivia.
 Despite the extremely high fibre concentrations measured in the plant, no significant fibre levels were detected 100 meters away.
 
 Conclusion 
 These preliminary findings undermine claims such as those made at Casale that crocidolite fibre can drift up to 15 km and remain airborne in quantities sufficient to contribute significantly to mesothelioma induction.
 
 We propose the difference in thickness and the attendant reduction in the percentage ofStantonfibres provides an explanation for the difference in mesothelioma patterns found in each city.

Comments on: Further studies of Bolivian crocidolite-Part IV: Fibre width, fibre drift and their relation to mesothelioma induction: Preliminary findings, by Ilgren EB, van Orden DR, Lee RJ, Kamiya YM, Hoskins JA


 Comments on: Further studies of Bolivian crocidolite-Part IV: Fibre width, fibre drift and their relation to mesothelioma induction: Preliminary findings, by Ilgren EB, van Orden DR, Lee RJ, Kamiya YM, Hoskins JA.

RE: Comments on: Further studies of Bolivian crocidolite-Part IV: Fibre width, fibre drift and their relation to mesothelioma induction: Preliminary findings, by Ilgren EB, van Order DR, Lee RJ, Kamiya YM, Hoskins JA ebph 2015; 12 (2) e11167

RE: Comments on: Further studies of Bolivian crocidolite-Part IV: Fibre width, fibre drift and their relation to mesothelioma induction: Preliminary findings, by Ilgren EB, van Order DR, Lee RJ, Kamiya YM, Hoskins JA Epidemiology Biostatistics and Public Health 2015; 12 (2), e11167

Public health risks from asbestos cement roofing.

There is no identified risk‐free threshold exposure to asbestos. Based on epidemiology and toxicology, asbestos fiber dimensions have been implicated in causing asbestos‐related diseases. Phase‐contrast microscopy provides only a limited index of exposure to fiber dimensions implicated in mesothelioma induction. Installed asbestos‐containing materials (ACMs) create an ongoing risk of intense exposure during natural disasters and remodeling, along with low‐level exposure arising from the continual emission of airborne asbestos into the environment arising from weathering of installed ACM. Epidemiological studies have demonstrated a risk of disease associated with proximity to asbestos cement roofing (ACR), while ongoing environmental emissions of asbestos from installed ACR have also been demonstrated. Owing to the limitations of the available data, a precautionary approach is warranted; asbestos‐free roofing materials should be used in new construction and existing ACR should be removed at the earliest opportunity.

Anthophyllite Asbestos: The Role of Fiber Width in Mesothelioma Induction. Part 4: Mechanistic Considerations regarding the Failure to Observe Anthophyllite Asbestos Mesotheliomas in Humans

Anthophyllite is an amphibole mineral formed through a prograde metamorphism of magnesium-rich ultramafic talcose rocks through increasing pressure and temperature and dehydration. The talc and anthophyllite are in phase equilibrium. Anthophyllite asbestos is therefore not a ‘contaminant’ of talc but a product derived from it. Fibrous talc, or so-called transitional fibers, are anthophyllite fibers undergoing retrograde degeneration. In its fibrous asbestiform state, anthophyllite differs in several fundamental ways from other commercially exploited forms of amphibole asbestos of which there are two broad families: monoclinic and orthorhombic. The more common forms of commercial amphibole asbestos such as crocidolite and amosite are monoclinic. The anthophyllites are orthorhombic. The differences between the two crystal systems are reflected at the level of the basic amphibole-structure in a greater overall fiber width dimensional profile and a significant reduction in microstructural strength. Strength reduction most probably arises at the cellular level and is particularly pronounced within the thinner population of fibers. Here microstructural differences, due in significant part to stacking defects in the basic amphibole structure, can account for these observations. The lack of an observed attendant mesothelioma risk following exposure to anthophyllite and transitional fibers in humans is a consequencel of these microstructural features that appear to differentiate them from the equidimensional monoclinic forms of amphibole asbestos such as South African crocidolite and amosite.

Anthophyllite Asbestos: The Role of Fiber Width in Mesothelioma Induction. Part 3: Studies of American and Japanese Anthophyllite Asbestos – Additional Supportive Evidence

The largest anthopyllite deposits in the world are found in Finland and it is from here that most of the commercial anthophyllite derives. However, other large deposits exist in both North America and Japan. Commercial production has existed in both these countries although not on a scale which matches the Finnish mines. Small deposits are known from several other countries but, apart from minor exploitation in India no significant mining has taken place. The North American deposits are primarily in the Eastern US states, mostly Maryland, Georgia and North Carolina although there was also extensive exploration in Alabama. In Japan, the major mining site was at Matsubase on the southermost island of Kyushu. Although these mines and attendant commercial concerns operated for decades and under conditions of high dust exposure no mesothelioma clusters are known from the mining areas.

Anthophyllite Asbestos: The Role of Fiber Width in Mesothelioma Induction Part 2: Further Epidemiological Studies of Occupational, Domestic and Environmental Exposure to Finnish Anthophyllite Asbestos

Although people in all sectors of the Finnish anthophyllite industry, including their families, have been heavily exposed to anthophyllite there is no evidence for even a single proven case of attributable mesothelioma. A few cases have been claimed but the evidence either, that they were mesotheliomas or that amphibole exposure was solely to anthophyllite is, in every case examined, insufficient. Even among the population who lived in Karelia in Central Finland who were exposed domestically or enviromentally to anthophyllite released during agricultural and various domestic activities and during transport from the mines, Finnish epidemiology found no risk of mesothelioma. There is also an absence of mesotheliomas reported in the earlier Finnish literature. This anomaly compared to the effects of exposure to other amphiboles is strong support for the role of fiber width in mesothelioma production. Anthophyllite, though, is not without clinical effect. As screening techniques improved it was discovered that of every person over the age of 65 years, one third living in Karelia had bilateral pleural plaques. The area was henceforth called the Endemic Pleural Plaque (EPP) zone. Radiographic analysis of the residents living in the district of Kuusjarvi led to suggestions that the cases resulted from asbestos blown from the Paakila facility via fiber drift as far away as 30 km. Later studies showed that ‘fiber drift’ was very unlikely to be a factor in the radiological findings thus observed.

Anthophyllite Asbestos: The Role of Fiber Width in Mesothelioma Induction Part 1: Epidemiological Studies of Finnish Anthophyllite Asbestos

Anthophyllite asbestos only occurs in a few parts of the world in sufficient quantities to be mined. The largest deposits of anthophyllite asbestos occur in Finland where it was mined for more than 75 years and very extensively used and distributed, anciently, for more than six millennia. Anthophyllite is one of the five minerals known collectively as amphibole asbestos. Studies of the effect of these five mineral fibre types when inhaled have shown that fibre width is an important determinant of mesothelioma induction. Only the “thinner” fibres or those with fiber diameter dimensional profiles predominantly less than 0.25 – 0.30 µm, are clearly mesotheliogenic. The “thicker” ones or those whose predominant widths are greater than these diameters do not appear to show an observable attendant risk of mesothelioma. Observations based on studies of at least, two “thick” forms of amphibole asbestos support these hypotheses. The one is Bolivian crocidolite; the other Finnish anthophyllite. The Finnish anthophyllite industry presents an important opportunity to study the robustness of the theory that fibre width is key to mesothelioma genesis as vast numbers of people in all sectors of the Finnish industry and their families have historically incurred massive fiber exposures sufficient to cause a gross excess of asbestosis. Nonetheless, in spite of these long term, high dose exposures clear evidence for a mesothelioma risk due to anthophyllite asbestos is still lacking.

Re: Comments on the causation of malignant mesothelioma: Rebutting the false concept that recent exposures to asbestos do not contribute to causation of mesothelioma.

BACKGROUND European asbestos manufacturers and their expert witnesses have advanced the claim that recent exposures to asbestos are not of significance in the causation of malignant mesothelioma. They argue that in cases of prolonged exposure to asbestos only the earliest exposures contribute to mesothelioma induction. METHODS The Collegium Ramazzini examined this claim and compared it with the findings of the Epidemiology and Public Health Working Group of the Second Italian Consensus Conference on Pleural Mesothelioma. This independent Working Group noted that earlier exposures are more effective in inducing mesothelioma, but that subsequent exposures also contribute and cannot be excluded. They found convincing evidence to support the conclusion that mesothelioma incidence is proportional to cumulative asbestos exposure. CONCLUSION The Collegium Ramazzini concludes that risk of malignant mesothelioma is proportional to cumulative exposure to asbestos in which all exposures - early as well as late - contribute to the totality of risk. The Collegium Ramazzini rejects as false and scientifically unfounded the notion that only the earliest exposures to asbestos contribute to mesothelioma induction.

Comments on the Causation of Malignant Mesothelioma: Rebutting the False Concept That Recent Exposures to Asbestos Do Not Contribute to Causation of Mesothelioma

BackgroundEuropean asbestos manufacturers and their expert witnesses have advanced the claim that recent exposures to asbestos are not of significance in the causation of malignant mesothelioma. They argue that in cases of prolonged exposure to asbestos only the earliest exposures contribute to mesothelioma induction. MethodsThe Collegium Ramazzini examined this claim and compared it with the findings of the Epidemiology and Public Health Working Group of the Second Italian Consensus Conference on Pleural Mesothelioma. This independent Working Group noted that earlier exposures are more effective in inducing mesothelioma, but that subsequent exposures also contribute and cannot be excluded. They found convincing evidence to support the conclusion that mesothelioma incidence is proportional to cumulative asbestos exposure. ConclusionThe Collegium Ramazzini concludes that risk of malignant mesothelioma is proportional to cumulative exposure to asbestos in which all exposures - early as well as late - contribute to the totality of risk. The Collegium Ramazzini rejects as false and scientifically unfounded the notion that only the earliest exposures to asbestos contribute to mesothelioma induction.

Comments on the causation of malignant mesothelioma: Rebutting the false concept that recent exposures to asbestos do not contribute to causation of mesothelioma.

BACKGROUND European asbestos manufacturers and their expert witnesses have advanced the claim that recent exposures to asbestos are not of significance in the causation of malignant mesothelioma. They argue that in cases of prolonged exposure to asbestos only the earliest exposures contribute to mesothelioma induction. METHODS The Collegium Ramazzini examined this claim and compared it with the findings of the Epidemiology and Public Health Working Group of the Second Italian Consensus Conference on Pleural Mesothelioma. This independent Working Group noted that earlier exposures are more effective in inducing mesothelioma, but that subsequent exposures also contribute and cannot be excluded. They found convincing evidence to support the conclusion that mesothelioma incidence is proportional to cumulative asbestos exposure. CONCLUSION The Collegium Ramazzini concludes that risk of malignant mesothelioma is proportional to cumulative exposure to asbestos in which all exposures - early as well as late - contribute to the totality of risk. The Collegium Ramazzini rejects as false and scientifically unfounded the notion that only the earliest exposures to asbestos contribute to mesothelioma induction.

Reactive oxygen species a double-edged sword for mesothelioma

It is well known that oxidative stress can lead to chronic inflammation which, in turn, could mediate most chronic diseases including cancer. Oxidants have been implicated in the activity of crocidolite and amosite, the most powerful types of asbestos associated to the occurrence of mesothelioma. Currently rates of mesothelioma are rising and estimates indicate that the incidence of mesothelioma will peak within the next 10-15 years in the western world, while in Japan the peak is predicted not to occur until 40 years from now. Although the use of asbestos has been banned in many countries around the world, production of and the potentially hazardous exposure to asbestos is still present with locally high incidences of mesothelioma. Today a new man-made material, carbon nanotubes, has arisen as a concern; carbon nanotubes may display 'asbestos-like' pathogenicity with mesothelioma induction potential. Carbon nanotubes resulted in the greatest reactive oxygen species generation. How oxidative stress activates inflammatory pathways leading to the transformation of a normal cell to a tumor cell, to tumor cell survival, proliferation, invasion, angiogenesis, chemoresistance, and radioresistance, is the aim of this review.

ラットによる５種の多層カ－ボンナノチュ－ブの腹腔内中皮腫誘発性に関する検討

ラットによる５種の多層カ－ボンナノチュ－ブの腹腔内中皮腫誘発性に関する検討

Dose‐dependent mesothelioma induction by intraperitoneal administration of multi‐wall carbon nanotubes in p53 heterozygous mice. Histology of a small nodule of moderately to poorly differentiated epithelioid mesothelioma

Dose‐dependent mesothelioma induction by intraperitoneal administration of multi‐wall carbon nanotubes in p53 heterozygous mice. Histology of a small nodule of moderately to poorly differentiated epithelioid mesothelioma

腹腔内投与によるラット中皮腫の誘発性に対して多層カ－ボンナノチュ－ブ(MWCNT)の性状が及ぼす影響

腹腔内投与によるラット中皮腫の誘発性に対して多層カ－ボンナノチュ－ブ(MWCNT)の性状が及ぼす影響

Molecular Mechanism for the Induction of Mesothelioma by Asbestos

Mesothelioma is an incurable form of cancer located in the pleural lining around the lungs. It is associated almost exclusive with the inhalation of mineral fibers called asbestos. Despite the well-known association between asbestos and mesothelioma, little is know about the mechanism of induction. The binding of asbestos to epidermal growth factor receptor (EGFR), a transmembrane signal protein, has been proposed as a trigger switch for downstream signaling of kinases and expression of genes associated with cancer. Here we used atomic force microscopy (AFM) to investigate the binding of the extracellular domain of EGFR to two minerals, crocidolite versus riebeckite in buffer solution. Crocidolite [Na2(Fe,Mg)5Si8O22(OH)2] is the asbestiform mineral most commonly associated with human mesothelioma. Riebeckite is chemically equivalent to crocidolite but has a non-asbestiform, fragmental habit, and it is not associated with cancer. AFM measurements revealed an attractive force between EGFR and each mineral. The rupture force of the mineral-EGFR bond increased with increasing loading rates. The correlation between rupture force and loading rate was stronger for crocidolite-EGFR than riebeckite-EGFR. The Bell model was used to estimate the bond lifetime for both mineral-protein pairs. The lifetime for the EGFR bond was roughly three times shorter for crocidolite than riebeckite. The fast but repeatable binding of EGFR with crocidolite fibers, which persist in the lungs for a period longer than a human's lifespan, may continually trigger the activation switch leading to chronic expression of genes involved in asbestos-related cancers.

ラットにおける多層カ－ボンナノチュ－ブ（MWCNT）による中皮腫の誘発の用量相関性と血清ERC/mesothelinレベルの増加

ラットにおける多層カ－ボンナノチュ－ブ（MWCNT）による中皮腫の誘発の用量相関性と血清ERC/mesothelinレベルの増加

Induction of mesothelioma by a single intrascrotal administration of multi-wall carbon nanotube in intact male Fischer 344 rats

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.

Epigenetic Profiles Distinguish Pleural Mesothelioma from Normal Pleura and Predict Lung Asbestos Burden and Clinical Outcome

Mechanisms of action of nonmutagenic carcinogens such as asbestos remain poorly characterized. As pleural mesothelioma is known to have limited numbers of genetic mutations, we aimed to characterize the relationships among gene-locus-specific methylation alterations, disease status, asbestos burden, and survival in this rapidly fatal asbestos-associated tumor. Methylation of 1505 CpG loci associated with 803 cancer-related genes were studied in 158 pleural mesotheliomas and 18 normal pleura. After false-discovery rate correction, 969 CpG loci were independently associated with disease status (Q < 0.05). Classifying samples based on CpG methylation profile with a mixture model approach, methylation classes discriminated tumor from normal pleura (permutation P < 0.0001). In a random forests classification, the overall misclassification error rate was 3.4%, with <1% (n = 1) of tumors misclassified as normal (P < 0.0001). Among tumors, methylation class membership was significantly associated with lung tissue asbestos body burden (P < 0.03), and significantly predicted survival (likelihood ratio P < 0.01). Consistent with prior work, asbestos burden was associated with an increased risk of death (hazard ratio, 1.4; 95% confidence interval, 1.1-1.8). Our results have shown that methylation profiles powerfully differentiate diseased pleura from nontumor pleura and that asbestos burden and methylation profiles are independent predictors of mesothelioma patient survival. We have added to the growing body of evidence that cellular epigenetic dysregulation is a critical mode of action for asbestos in the induction of pleural mesothelioma. Importantly, these findings hold great promise for using epigenetic profiling in the diagnosis and prognosis of human cancers.