The presence of erionite in North American geologies and the estimated mesothelioma potency by region.

OBJECTIVE: Erionite is a naturally occurring fibrous mineral found in soils in some geographical regions. Known for its potency for causing mesothelioma in the Cappadocia region of Turkey, the erionite fiber has attracted interest in the United States due to its presence in a band of rock that extends from Mexico to Montana. There are few toxicology studies of erionite, but all show it to have unusually high chronic toxicity. Despite its high potency compared to asbestos fibers, erionite has no occupational or environmental exposure limits. This paper takes what has been learned about the chemical and physical characteristics of the various forms of asbestos (chrysotile, amosite, anthophyllite, and crocidolite) and predicts the potency of North American erionite fibers. MATERIALS AND METHODS: Based on the fiber potency model in Korchevskiy et al. (2019) and the available published information on erionite, the estimated mesothelioma potency factors (the proportion of mesothelioma mortality per unit cumulative exposure (f/cc-year)) for erionites in the western United States were determined. RESULTS AND DISCUSSION: The model predicted potency factors ranged from 0.19 to 11.25 (average ∼3.5), depending on the region. For reference, crocidolite (the most potent commercial form of asbestos) is assigned a potency factor ∼0.5. CONCLUSION: The model predicted mesothelioma potency of Turkish erionite (4.53) falls in this same range of potencies as erionite found in North America. Although it can vary by region, a reasonable ratio of average mesothelioma potency based on this model is 3,000:500:100:1 comparing North American erionite, crocidolite, amosite, and chrysotile (from most potent to least potent).

Low Exposures to Amphibole or Serpentine Asbestos in Germline Bap1-mutant Mice Induce Mesothelioma Characterized by an Immunosuppressive Tumor Microenvironment.

Asbestos and BAP1 germline mutations are risk factors for malignant mesothelioma (MM). While it is well accepted that amphibole asbestos is carcinogenic, the role of serpentine (chrysotile) asbestos in MM has been debated. To address this controversy, we assessed whether minimal exposure to chrysotile could significantly increase the incidence and rate of MM onset in germline Bap1-mutant mice. With either crocidolite or chrysotile, and at each dose tested, MMs occurred at a significantly higher rate and earlier onset time in Bap1-mutant mice than in wild-type littermates. To explore the role of gene-environment interactions in MMs from Bap1-mutant mice, we investigated proinflammatory and protumorigenic factors and the tumor immune microenvironment (TIME). IHC and immunofluorescence staining showed an increased number of macrophages in granulomatous lesions and MMs. The relative number of CD163-positive (CD163+) M2 macrophages in chrysotile-induced MMs was consistently greater than in crocidolite-induced MMs, suggesting that chrysotile induces a more profound immunosuppressive response that creates favorable conditions for evading immune surveillance. MMs from Bap1-mutant mice showed upregulation of CD39/CD73-adenosine and C-C motif chemokine ligand 2 (Ccl2)/C-C motif chemokine receptor 2 (Ccr2) pathways, which together with upregulation of IL6 and IL10, promoted an immunosuppressive TIME, partly by attracting M2 macrophages. Interrogation of published human MM RNA sequencing (RNA-seq) data implicated these same immunosuppressive pathways and connections with CD163+ M2 macrophages. These findings indicate that increased M2 macrophages, along with upregulated CD39/CD73-adenosine and Ccl2/Ccr2 pathways, contribute to an immunosuppressive TIME in chrysotile-induced MMs of Bap1-mutant mice, suggesting that immunotherapeutic strategies targeting protumorigenic immune pathways could be beneficial in human BAP1 mutation carriers who develop MM. SIGNIFICANCE: We show that germline Bap1-mutant mice have enhanced susceptibility to MM upon minimal exposure to chrysotile asbestos, not only amphibole fibers. Chrysotile induced a more profound immune tumor response than crocidolite in Bap1-mutant mice by upregulating CD39/CD73-adenosine and Ccl2/Ccr2 pathways and recruiting more M2 macrophages, which together contributed to an immunosuppressive tumor microenvironment. Interrogation of human MM RNA-seq data revealed interconnected immunosuppressive pathways consistent with our mouse findings.

Association Study of Pleural Mesothelioma and Oncogenic Simian Virus 40 in the Crocidolite-Contaminated Area of Dayao County, Yunnan Province, Southwest China.

Background: In Dayao County, Chuxiong Yi Autonomous Prefecture, Yunnan Province, Southwest China, 5% of the surface is scattered with blue asbestos, which has a high incidence of pleural mesothelioma (PMe). Simian virus 40 (SV40) is a small circular double-stranded DNA polyomavirus that can cause malignant transformation of normal cells of various human and animal tissue types and promote tumor growth. In this study, we investigate whether oncogenic SV40 is associated with the occurrence of PMe in the crocidolite-contaminated area of Dayao County, Yunnan Province, Southwest China. Methods: Tumor tissues from 51 patients with PMe (40 of whom had a history of asbestos exposure) and pleural tissues from 12 non-PMe patients (including diseases such as pulmonary maculopathy and pulmonary tuberculosis) were collected. Three pairs of low-contamination risk primers (SVINT, SVfor2, and SVTA1) were used to detect the gene fragment of SV40 large T antigen (T-Ag) by polymerase chain reaction (PCR). The presence of SV40 T-Ag in PMe tumor tissues and PMe cell lines was detected by Western blotting and immunohistochemical staining with SV40-related antibodies (PAb 101 and PAb 416). Results: PCR, Western blotting, and immunohistochemical staining results showed that the Met5A cell line was positive for SV40 and contained the SV40 T-Ag gene and protein. In contrast, the various PMe cell lines NCI-H28, NCI-H2052, and NCI-H2452 were negative for SV40. PCR was negative for all three sets of low-contamination risk primers in 12 non-PMe tissues and 51 PMe tissues. SV40 T-Ag was not detected in 12 non-PMe tissues or 51 PMe tissues by immunohistochemical staining. Conclusion: Our data suggest that the occurrence of PMe in the crocidolite-contaminated area of Yunnan Province may not be related to SV40 infection and that crocidolite exposure may be the main cause of PMe. The Clinical Trial Registration number: 2020-YXLL20.

Toxicity and inflammatory potential of mineral fibres: The contribute of released soluble metals versus cell contact direct effects.

Asbestos fibres have been considered an environmental hazard for decades. However, little is known about the attempts of circulating immune cells to counteract their toxicity. We addressed the early effects of fibre-released soluble factors (i.e. heavy metals) in naïve immune cells, circulating immediately below the alveolar/endothelial cell layer. By comparison, the direct fibre effects on endotheliocytes were also studied since these cells are known to sustain inflammatory processes. The three mineral fibres analysed showed that mainly chrysotile (CHR) and erionite (ERI) were able to release toxic metals in extracellular media respect to crocidolite (CRO), during the first 24 h. Nevertheless, all three fibres were able to induce oxidative stress and genotoxic damage in indirectly challenged naïve THP-1 monocytes (separated by a membrane). Conversely, only CHR-released metal ions induced apoptosis, NF-κB activation, cytokines and CD163 gene overexpression, indicating a differentiation towards the M0 macrophage phenotype. On the other hand, all three mineral fibres in direct contact with HECV endothelial cells showed cytotoxic, genotoxic and apoptotic effects, cytokines and ICAM-I overexpression, indicating the ability of these cells to promote an inflammatory environment in the lung independently from the type of inhaled fibre. Our study highlights the different cellular responses to mineral fibres resulting from both the nature of the cells and their function, but also from the chemical-physical characteristics of the fibres. In conclusion, CHR represented the main pro-inflammatory trigger, able to recruit and activate circulating naïve monocytes, through its released metals, already in the first 24 h after inhalation.

Iron nuclearity in mineral fibres: Unravelling the catalytic activity for predictive modelling of toxicity.

Chronic inflammation induced in vivo by mineral fibres, such as asbestos, is sustained by the cyclic formation of cytotoxic/genotoxic oxidant species that are catalysed by iron. High catalytic activity is observed when iron atoms are isolated in the crystal lattice (nuclearity=1), whereas the catalytic activity is expected to be reduced or null when iron forms clusters of higher nuclearity. This study presents a novel approach for systematically measuring iron nuclearity across a large range of iron-containing standards and mineral fibres of social and economic importance, and for quantitatively assessing the relation between nuclearity and toxicity. The multivariate curve resolution (MCR) empirical approach and density functional theory (DFT) calculations were applied to the analysis of UV-Vis spectra to obtain information on the nature of iron and nuclearity. This approach led to the determination of the nuclearity of selected mineral fibres which was subsequently used to calculate a toxicity-related index. High nuclearity-related toxicity was estimated for chrysotile samples, fibrous glaucophane, asbestos tremolite, and fibrous wollastonite. Intermediate values of toxicity, corresponding to a mean nuclearity of 2, were assigned to actinolite asbestos, amosite, and crocidolite. Finally, a low nuclearity-related toxicity parameter, corresponding to an iron-cluster with a lower catalytic power to produce oxidants, was assigned to asbestos anthophyllite.

An updated evaluation of reported no-observed adverse effect levels for chrysotile, amosite, and crocidolite asbestos for lung cancer and mesothelioma.

This analysis updates two previous analyses that evaluated the exposure-response relationships for lung cancer and mesothelioma in chrysotile-exposed cohorts. We reviewed recently published studies, as well as updated information from previous studies. Based on the 16 studies considered for chrysotile (<10% amphibole), we identified the "no-observed adverse effect level" (NOAEL) for lung cancer and/or mesothelioma; it should be noted that smoking or previous or concurrent occupational exposure to amphiboles (if it existed) was not controlled for. NOAEL values ranged from 2.3-<11.5 f/cc-years to 1600-3200 f/cc-years for lung cancer and from 100-<400 f/cc-years to 800-1599 f/cc-years for mesothelioma. The range of best-estimate NOAELs was estimated to be 97-175 f/cc-years for lung cancer and 250-379 f/cc-years for mesothelioma. None of the six cohorts of cement or friction product manufacturing workers exhibited an increased risk at any exposure level, while all but one of the six studies of textile workers reported an increased risk at one or more exposure levels. This is likely because friction and cement workers were exposed to much shorter chrysotile fibers. Only eight cases of peritoneal mesothelioma were reported in all studies on predominantly chrysotile-exposed cohorts combined. This analysis also proposed best-estimate amosite and crocidolite NOAELs for mesothelioma derived by the application of relative potency estimates to the best-estimate chrysotile NOAELs for mesothelioma and validated by epidemiology studies with exposure-response information. The best-estimate amosite and crocidolite NOAELs for mesothelioma were 2-5 f/cc-years and 0.6-1 f/cc-years, respectively. The rate of peritoneal mesothelioma in amosite- and crocidolite-exposed cohorts was between approximately 70- to 100-fold and several-hundred-fold higher than in chrysotile-exposed cohorts, respectively. These findings will help characterize potential worker and consumer health risks associated with historical and current chrysotile, amosite, and crocidolite exposures.

Resposta comparativa pleural in vivo e do mesotélio in vitro à exposição por diferentes fibras de asbesto / Comparison of in vivo pleural response and in vitro mesothelial response to different asbestos fibers

Os produtos derivados de asbesto são amplamente utilizados pelo setor industrial, sendo descritas diversas doenças relacionadas à sua exposição, entre elas, o tumor primário da pleura, ou mesotelioma. O mecanismo fisiopatológico da lesão pelas fibras de asbesto no espaço pleural ainda não está totalmente estabelecido. Entre os fatores possivelmente implicados estão os efeitos provocados por uma resposta inflamatória com migração celular e liberação de mediadores moleculares levando à necrose, apoptose e alterações na proliferação e fibrogênese. No entanto, existem dificuldades no estudo da resposta in vivo ao asbesto, principalmente em virtude da população multicelular da cavidade pleural. Neste sentido, tem sido preconizado na literatura o estudo envolvendo animais geneticamente modificados ou selecionados, a fim de melhor compreender o papel das diversas populações envolvidas neste processo. Neste trabalho, tivemos como objetivo estudar comparativamente a resposta inflamatória aguda no líquido pleural e em células mesoteliais em cultura expostas a diferentes fibras de asbesto. Para tanto, animais controle e geneticamente selecionados para alta (AIR max) e baixa (AIR min) resposta inflamatória, e células mesoteliais em cultura foram expostas às fibras de asbesto crocidolita ou crisotila. Após 4, 24 ou 48 horas foram avaliadas a produção das citocinas IL-1b, IL-6 e MIP-2. Adicionalmente, no modelo in vivo foi avaliado o perfil celular do líquido pleural e a expressão do Ra PDGF em RESUMO fragmentos de pleura, e no modelo in vitro a resposta celular de apoptose e necrose. Como resultados, as fibras de asbesto crocidolita e crisotila produziram, em animais AIR max, uma elevação significativa no líquido pleural de leucócitos, neutrófilos e da IL-1b em comparação aos controles e aos animais AIR min. Entretanto, não houve diferença no número de macrófagos, IL-6 e MIP-2. As células mesoteliais em cultura expostas tanto às fibras crocidolita quanto crisotila...

Asbestos-derived products are used thoroughly by industry. Several diseases related to asbestos exposition have been described, among them the primary tumor of the pleura mesothelioma. The mechanisms by which asbestos fibers produce injury to the pleural space are not clear. Among the factors possibly implicated are the effects secondary to an inflammatory response characterized by cellular migration and the release of molecular mediators leading to necrosis, apoptosis, cellular proliferation and fibrogenesis. However, it is difficulty to characterize the cellular response in vivo, mainly by virtue of the multi-cellular population present into the pleural cavity. Therefore, studies involving animals genetically modified or genetically selected have been proposed in the literature, in order to better understand the role of the several cellular populations involved in this complex process. In this study, our objective was to determine the inflammatory response of the pleural fluid and compare to the response of cultured mesothelial cells exposed to different asbestos fibers. Controls and mice genetically selected for high (AIR max) or low (AIR min) inflammatory response as well as mice cultured mesothelial cells were treated to crocidolite or chrysotile asbestos fibers. After 4, 24 or 48 hours the production of the cytokines IL-1b, IL-6 and MIP-2 were analyzed. In addition, the in vivo cellular profile of the pleural fluid and the Ra PDGF expression in the pleura fragments was documented. In parallel, the in vitro mesothelial cellular response of apoptosis and necrosis was quantified. Both asbestos fibers produced in AIR max mice a significant elevation in the pleural fluid total leukocytes, neutrophils and IL-1b levels in comparison to the controls and AIR min animals. However, no difference was found in the macrophage number, IL-6 and MIP-2 levels. Cultured mesothelial cells had a high apoptosis, necrosis...

Mesoteliomas malignos de la pleura: diagnóstico, tratamiento y evolución en una serie de 43 pacientes / Malignant pleural mesothelioma: diagnosis, treatment and follow-up in our experience with 43 cases

Antecedentes: Los mesoteliomas malignos de la pleura presentan una extrema gravedad. Actualmente han aumentado las observaciones, demostrando una corta y una mala supervivencia. Objetivo: Estudiar los procedimientos para su diagnóstico, estadificación y tratamiento. Analizar el pronóstico y la supervivencia. Lugar de Aplicación: Hospital Público, Sanatorio Privado. Diseño: Estudio Retrospectivo. Población: De 43 enfermos (lapso 1960-1997) 27 por ciento eran mujeres y 73 por ciento varones, con edades extremas de 10a 89 años. Padeció dolor torácico el 69,9 por cientoLocalización: 62,7 por ciento derecha y 37,3 izquierda. Se intervinieron quirúrgicamente 32 (74,4 por ciento) decorticaciones 24 (75 por ciento), neumonectomías 5 (15,6 por ciento), bilobectomía 1(2,3 por ciento) tóraco-lobectomía 1 (3,1 por ciento) y pleuroneumonectomía 1( 3 por ciento). Métodos: Se analizaron los antecedentes clínicos y epidemiológicos, el diagnóstico, las indicaciones quirúrgicas, el tipo de tratamiento y la superviviencia. Resultados: Sobrevivieron 13 enfermos a los 6 meses (40,6 por ceinto), 14 al año (43,7 por ciento). 1 a los 3 años (3,1 por ciento) y 1 a los 8 años (3,1 por ciento). Mortalidad operatoria intermedia: 1 (3,12 por ciento). Conclusiones: La profilaxis de la asbestosis, el diagnóstico temprano, una correcta estadificación y elección del tratamiento, incluyendo el estudio cooperativo de importantes grupos de trabajo, posiblemente alarguen y mejoren la supervivencia de estos pacientes