Toxicology Letters

Our medical research library holds 52 studies published in Toxicology Letters (1981–2021). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 52 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: Elsevier
• Published: 1977 to the present, Netherlands
• Language: English
• ISSN: 0378-4274 (print), 1879-3169 (electronic)
• Its record in the NLM Catalog

2020s

• Chemo-physical properties of asbestos bodies in human lung tissues studied at the nano-scale by non-invasive, label free x-ray imaging and spectroscopic techniques. F. Bardelli, F. Brun, S. De Panfilis, et al. 2021;348:18-27. PubMed · Publisher

  Abstract

  In the lungs, asbestos develops an Fe-rich coating (Asbestos Body, AB) that becomes the actual interface between the foreign fibers and the host organism. Conventional approaches to study ABs require an invasive sample preparation that can alter them. In this work, a novel combination of x-ray tomography and spectroscopy allowed studying unaltered lung tissue samples with chrysotile and crocidolite asbestos. The thickness and mass density maps of the ABs obtained by x-ray tomography were used to derive a truly quantitative elemental analysis from scanning x-ray fluorescence spectroscopy data. The average mass density of the ABs is compatible with that of highly loaded ferritin, or hemosiderin. The composition of all ABs analyzed was similar, with only minor differences in the relative elemental fractions. Silicon concentration decreased in the core-to-rim direction, indicating a possible partial dissolution of the inner fiber. The Fe content in the ABs was higher than that possibly contained in chrysotile and crocidolite. This finding opens two opposite scenarios, the first with Fe coming from the fiber bulk and concentrating on the surface as long as the fiber dissolves, the second where the Fe that takes part to the formation of the AB originates from the host organism Fe-pool.

  Copyright © 2021 Elsevier B.V. All rights reserved.

• Functional effects of differentially expressed microRNAs in A549 cells exposed to MWCNT-7 or crocidolite. C. Ventura, L. Vieira, C. Silva, et al. 2020;328:7-18. PubMed · Publisher

  Abstract

  Multi-walled carbon nanotubes (MWCNT) are engineered nanomaterials widely used in industrial and biomedical applications. Yet, MWCNT inhalation may induce pulmonary adverse effects, and the MWCNT-7 (Mitsui-7) has been classified as possibly carcinogenic to humans. However, its molecular mechanisms of action are poorly understood and there are no biomarkers of exposure for occupational monitoring. Several pulmonary diseases, including lung cancer, have been associated with alterations in microRNA expression that are used as biomarkers of disease progression, and differentially-expressed microRNAs (DE miRNAs) can also allow understanding the molecular effects induced by a toxicant. In this study, we identify DE miRNAs in A549 alveolar epithelial cells following 24 h exposure to MWCNT-7 or crocidolite, as well as their enriched cellular functional pathways. These indicate that both materials change cell survival, differentiation and proliferative properties under the influence of AMPK, FoxO, TGF-β and Hippo pathways, and their metabolic activity and cell-to-cell communication. In addition, MWCNT-7 affects the actin cytoskeleton, ubiquitin mediated proteolysis, and ECM-receptor interactions; crocidolite the PI3K-Akt and mTOR pathways, endocytosis, and central carbon metabolism. Since deregulation of these pathways may be related to carcinogenesis, an interaction network of DE miRNAs and corresponding target cancer-related genes was constructed, highlighting the carcinogenic potential of Mitsui-7.

  Copyright © 2020 Elsevier B.V. All rights reserved.

• Long-term instillation to four natural representative chrysotile of China induce the inactivation of P53 and P16 and the activation of C-JUN and C-FOS in the lung tissues of Wistar rats. Y. Luo, J. Deng, Y. Cui, et al. 2020;333:140-149. PubMed · Publisher

  Abstract

  Chrysotile is the only type of asbestos still widely exploited, and all kinds of asbestos including chrysotile was classified as a group I carcinogen by the IARC. There is a wealth of evidence that chrysotile can cause a range of cancers, including cancer of the lung, larynx, ovary, and mesothelioma. As the second largest chrysotile producer, China is at great risk of occupational exposure. Moreover, our previous experiment and some other studies have shown that the toxicity of mineral fibre from various mining areas may be different. To explore the oncogenic potential of chrysotile from different mining areas of China, Wistar rats were administered 0.5 mL chrysotile asbestos suspension of 2.0 mg/mL (from Akesai, Gansu; Mangnai, Qinghai; XinKang, Sichuan; and Shannan, Shaanxi) dissolved in saline by intratracheal instillation once-monthly and were sacrificed at 1 mo, 6 mo, and 12 mo. Our results found that chrysotile caused lung inflammation and lung tissue damage. Moreover, prolonged exposure of chrysotile can induce inactivation of the tumor suppressor gene P53 and P16 and activation of the protooncogene C-JUN and C-FOS both in the messenger RNA and protein level. In addition, chrysotile from Shannan and XinKang has a stronger effect which may link to cancer than that from Akesai and Mangnai.

  Copyright © 2020 Elsevier B.V. All rights reserved.

2010s

• 3-(2-deoxy-β-d-erythro-pentafuranosyl)pyrimido[1,2-α]purin-10(3H)-one deoxyguanosine adducts of workers exposed to asbestos fibers. S. Bonassi, F. Cellai, A. Munnia, et al. 2017;270:1-7. PubMed · Publisher · Free full text

  Abstract

  Asbestos is the commercial name for a group of silicate minerals naturally occurring in the environment and widely used in the industry. Asbestos exposure has been associated with pulmonary fibrosis, mesothelioma, and malignancies, which may appear after a period of latency of 20-40 years. Mechanisms involved in the carcinogenic effects of asbestos are still not fully elucidated, although the oxidative stress theory suggests that phagocytic cells produce large amounts of reactive oxygen species, due to their inability to digest asbestos fiber. We have conducted a mechanistic study to evaluate the association between 3-(2-deoxy-β-d-erythro-pentafuranosyl)pyrimido[1,2-α]purin-10(3H)-one deoxyguanosine (M1dG) adducts, a biomarker of oxidative stress and lipid peroxidation, and asbestos exposure in the peripheral blood of 327 subjects living in Tuscany and Liguria, Italy, stratified by occupational exposure to asbestos. Adduct frequency was significantly greater into exposed subjects with respect to the controls. M1dG per 108 normal nucleotides were 4.0±0.5 (SE) in 156 asbestos workers, employed in mechanic, naval, petrochemical, building industries, and in pottery and ceramic plants, versus a value of 2.3±0.1 (SE) in 171 controls (p<0.001). After stratification for occupational history, the effects persisted in 54 current asbestos workers, mainly employed in building renovation industry (2.9±0.3 (SE)), and in 102 former asbestos workers (4.5±0.7 (SE)), with p-values of 0.033, and <0.001, respectively. A significant effect of smoking on heavy smokers was found (p=0.005). Our study gives additional support to the oxidative stress theory, where M1dG may reflect an additional potential mechanism of asbestos-induced toxicity.

  Copyright © 2017 Elsevier B.V. All rights reserved.

• Geometry of carbon nanotubes and mechanisms of phagocytosis and toxic effects. V.M. Harik. 2017;273:69-85. Review PubMed · Publisher

  Abstract

  A review of in vivo and in vitro toxicological studies of the potential toxic effects of carbon nanotubes is presented along with the analysis of experimental data and a hypothesis about the nanotube-asbestos similarity. Developments of the structure-activity paradigm have been reviewed along with the size effects and the classification of carbon nanotubes into eleven distinct classes (e.g., the high aspect ratio nanotubes, thick multi-wall nanotubes and short nanotubes). Scaling analysis of similarities between different classes of carbon nanotubes and asbestos fibers in the context of their potential toxicity and the efficiency of phagocytosis has been reviewed. The potential toxic effects of carbon nanotubes have been characterized by their normalized length, their aspect ratio and other parameters related to their inhalability, engulfment by macrophages and the effectiveness of phagocytosis. Geometric scaling parameters and the classification of carbon nanotubes are used to develop an updated parametric map for the extrapolation of the potential toxic effects resulting from the inhalation of long and short carbon nanotubes. An updated parametric map has been applied to the evaluation of the efficiency of phagocytosis involving distinct classes of carbon nanotubes. A critical value of an important nondimensional parameter characterizing the efficiency of phagocytosis for different nanotubes is presented along with its macrophage-based normalization. The present evaluation of the potential toxicological effects of the high aspect ratio carbon nanotubes is found to be in the agreement with other available studies and earlier scaling analyses.

  Copyright © 2017 Elsevier B.V. All rights reserved.

• New insights into the toxicity of mineral fibres: A combined in situ synchrotron μ-XRD and HR-TEM study of chrysotile, crocidolite, and erionite fibres found in the tissues of Sprague-Dawley rats. A.F. Gualtieri, N. Bursi Gandolfi, S. Pollastri, et al. 2017;274:20-30. PubMed · Publisher

  Abstract

  Along the line of the recent research topic aimed at understanding the in vivo activity of mineral fibres and their mechanisms of toxicity, this work describes the morpho-chemical characteristics of the mineral fibres found in the tissues of Sprague-Dawley rats subjected to intraperitoneal/intrapleural injection of UICC chrysotile, UICC crocidolite and erionite-Na from Nevada (USA). The fibres are studied with in situ synchrotron powder diffraction and high resolution transmission electron microscopy to improve our understanding of the mechanisms of toxicity of these mineral fibres. In contact with the tissues of the rats, chrysotile fibres are prone to dissolve, with leaching of Mg and production of a silica rich relict. On the other hand, crocidolite and erionite-Na fibres are stable even for very long contact times within the tissues of the rats, showing just a thin dissolution amorphous halo. These findings support the model of a lower biopersistence of chrysotile with respect to crocidolite and erionite-Na but the formation of a silica-rich fibrous residue after the pseudo-amorphization of chrysotile may justify a higher cytotoxic potential and intense inflammatory activity of chrysotile in the short term in contact with the lung tissues.

  Copyright © 2017 Elsevier B.V. All rights reserved.

• Synchrotron X-ray microscopy reveals early calcium and iron interaction with crocidolite fibers in the lung of exposed mice. L. Pascolo, G. Zabucchi, A. Gianoncelli, et al. 2016;241:111-20. PubMed · Publisher

  Abstract

  Human exposure to asbestos can cause a wide variety of lung diseases that are still a current major health concern, even if asbestos has been banned in many countries. It has been shown in many studies that asbestos fibers, ingested by alveolar macrophages, disrupt lung iron homeostasis by sequestering iron. Calcium can also be deposited on the fibers. The pathways along which iron and above all calcium interact with fibers are still unknown. Our aim was that of investigating if the iron accumulation induced by the inhaled asbestos fibers also involves calcium ions accumulation. Lung sections of asbestos-exposed mice were analyzed using an extremely sensitive procedure available at the synchrotron facilities, that provides morphological and chemical information based on X-ray fluorescence microspectroscopy (μ-XRF). In this study we show that (1) where conventional histochemical procedures revealed only weak deposits of iron and calcium, μ-XRF analysis is able to detect significant deposits of both iron and calcium on the inhaled asbestos fibers; (2) the extent of the deposition of these ions is proportionally directly related and (3) iron and calcium deposition on inhaled asbestos fibers is concomitant with the appearance of inflammatory and hyperplastic reactions.

  Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

• Epithelial-mesenchymal transition involved in pulmonary fibrosis induced by multi-walled carbon nanotubes via TGF-beta/Smad signaling pathway. T. Chen, H. Nie, X. Gao, et al. 2014;226(2):150-62. PubMed · Publisher

  Abstract

  Multi-walled carbon nanotubes (MWCNT) are a typical nanomaterial with a wide spectrum of commercial applications. Inhalation exposure to MWCNT has been linked with lung fibrosis and mesothelioma-like lesions commonly seen with asbestos. In this study, we examined the pulmonary fibrosis response to different length of MWCNT including short MWCNT (S-MWCNT, length=350-700nm) and long MWCNT (L-MWCNT, length=5-15μm) and investigated whether the epithelial-mesenchymal transition (EMT) occurred during MWCNT-induced pulmonary fibrosis. C57Bl/6J male mice were intratracheally instilled with S-MWCNT or L-WCNT by a single dose of 60μg per mouse, and the progress of pulmonary fibrosis was evaluated at 7, 28 and 56 days post-exposure. The in vivo data showed that only L-MWCNT increased collagen deposition and pulmonary fibrosis significantly, and approximately 20% of pro-surfactant protein-C positive epithelial cells transdifferentiated to fibroblasts at 56 days, suggesting the occurrence of EMT. In order to understand the mechanism, we used human pulmonary epithelial cell line A549 to investigate the role of TGF-β/p-Smad2 signaling pathway in EMT. Our results showed that L-MWCNT downregulated E-cadherin and upregulated α-smooth muscle actin (α-SMA) protein expression in A549 cells. Taken together, both in vivo and in vitro study demonstrated that respiratory exposure to MWCNT induced length dependent pulmonary fibrosis and epithelial-derived fibroblasts via TGF-β/Smad pathway.

  Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

• Mesothelial cell and anti-nuclear autoantibodies associated with pleural abnormalities in an asbestos exposed population of Libby MT. L.S. Marchand, S. St-Hilaire, E.A. Putnam, et al. 2012;208(2):168-73. PubMed · Publisher · Free full text

  Abstract

  Despite data linking amphibole asbestos exposure with production of autoantibodies, the role of autoantibodies in subsequent disease is unknown. Residents of Libby, Montana have experienced significant exposure to amphibole asbestos due to the mining of asbestos-contaminated vermiculite near the community over several decades. This population predominantly exhibits pleural disease, and an autoimmune-like disorder that has yet to be well defined. This study sought to determine whether autoantibodies from asbestos-exposed subjects were associated with pleural lesions. Serum samples of subjects from Libby were evaluated for anti-nuclear antibodies (ANA) and mesothelial cell autoantibodies (MCAA) using cell based ELISA. The presence of radiographic abnormalities detected during the time frame of serum collection was determined from screening records. In accord with previous studies, 61.3% (76/124) of the Libby samples were ANA positive, a frequency much higher than expected for a healthy population. The odds of having pleural or interstitial abnormalities in Libby was nearly 3.55 times greater for individuals that tested positive for ANA compared with individuals negative for ANA (p=0.004). MCAA were also detected at a strikingly high frequency (18.5%; 23/124) in samples from Libby. Individuals with MCAA had 4.9 times the risk of having pleural abnormalities compared to MCAA-negative subjects (p=0.044). In conclusion, ANA and MCAA were elevated in a study population that was known to have chronic exposure to asbestos, and these autoantibodies were associated with pleural abnormalities, the predominant finding in the asbestos-exposed population of Libby. Additional research is needed to determine the role these autoantibodies may play in pulmonary disease.

  Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

• A comparison of acute and long-term effects of industrial multiwalled carbon nanotubes on human lung and immune cells in vitro. T. Thurnherr, C. Brandenberger, K. Fischer, et al. 2011;200(3):176-86. PubMed · Publisher

  Abstract

  The close resemblance of carbon nanotubes to asbestos fibers regarding their high aspect ratio, biopersistence and reactivity increases public concerns on the widespread use of these materials. The purpose of this study was not only to address the acute adverse effects of industrially produced multiwalled carbon nanotubes (MWCNTs) on human lung and immune cells in vitro but also to further understand if their accumulation and biopersistence leads to long-term consequences or induces adaptive changes in these cells. In contrast to asbestos fibers, pristine MWCNTs did not induce overt cell death in A549 lung epithelial cells and Jurkat T lymphocytes after acute exposure to high doses of this material (up to 30 μg/ml). Nevertheless, very high levels of reactive oxygen species (ROS) and decreased metabolic activity were observed which might affect long-term viability of these cells. However, the continuous presence of low amounts of MWCNTs (0.5 μg/ml) for 6 months did not have major adverse long-term effects although large amounts of nanotubes accumulated at least in A549 cells. Moreover, MWCNTs did not appear to induce adaptive mechanisms against particle stress in long-term treated A549 cells. Our study demonstrates that despite the high potential for ROS formation, pristine MWCNTs can accumulate and persist within cells without having major long-term consequences or inducing adaptive mechanisms.

  © 2010 Elsevier Ireland Ltd. All rights reserved.

• Exposure to chrysotile asbestos causes carbonylation of glucose 6-phosphate dehydrogenase through a reaction with lipid peroxidation products in human lung epithelial cells. Y. Ogasawara, K. Ishii. 2010;195(1):1-8. PubMed · Publisher

  Abstract

  Exposure to asbestos is known to lead to a reduction in glucose 6-phosphate dehydrogenase (G6PDH) activity and to cause oxidative damage to cells. In the present study, we exposed the human lung carcinoma cell line A549 to chrysotile. We observed an increase in the production of thiobarbituric acid-reactive substances (TBARS, the breakdown products of lipid peroxide) along with a significant decrease in G6PDH activity. Alternatively, when chrysotile was added directly to the cell extract obtained by removing the cell membrane, no loss of G6PDH activity was observed. To elucidate the mechanism of G6PDH inactivation due to exposure to chrysotile, we focused on the TBARS responsible for protein modification via carbonylation. When malondialdehyde or 4-hydroxy-2-nonenal was added to a membrane-free A549 cell extract, G6PDH activity was reduced markedly. However, when t-butylhydroperoxide was added to the extract, there was no significant decrease in G6PDH activity. Western blot analysis and immunoprecipitation of the carbonylated proteins in the A549 cell lysate that was prepared after exposure to chrysotile demonstrated that G6PDH had been carbonylated. Our findings indicate that the decrease in G6PDH activity that occurs after exposure of the cultured cells to chrysotile results from the carbonylation of G6PDH by TBARS.

  Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

2000s

• The degree and kind of agglomeration affect carbon nanotube cytotoxicity. P. Wick, P. Manser, L.K. Limbach, et al. 2007;168(2):121-31. PubMed · Publisher

  Abstract

  The urgent need for toxicological studies on carbon nanotubes (CNTs) has arisen from the rapidly emerging applications of CNTs well beyond material science and engineering. In order to provide a basis for comparison to existing epidemiological data, we have investigated CNTs at various degrees of agglomeration using an in vitro cytotoxicity study with human MSTO-211H cells. Non-cytotoxic polyoxyethylene sorbitan monooleate was found to well-disperse CNT. In the present study, the cytotoxic effects of well-dispersed CNT were compared with that of conventionally purified rope-like agglomerated CNTs and asbestos as a reference. While suspended CNT-bundles were less cytotoxic than asbestos, rope-like agglomerates induced more pronounced cytotoxic effects than asbestos fibres at the same concentrations. The study underlines the need for thorough materials characterization prior to toxicological studies and corroborates the role of agglomeration in the cytotoxic effect of nanomaterials.

• Evaluation of cellular toxicity of TAFMAG, a natural substitute for asbestos from China. H.J. Kim, H.Y. Nam, Y. Hiroshi, et al. 2005;155(1):65-71. PubMed · Publisher

  Abstract

  Asbestos is a very important material for industrial use. However, the need for a substitute for asbestos fiber is currently on the rise due to its high disease causing potential. This study evaluated the potential bio-hazardous effects of TAFMAG, a natural fibrous silicate produced in China, in comparison with chrysotile, a typical toxic asbestos. The physicochemical properties of TAFMAG were very similar to those of chrysotile when it was examined by a scanning electron microscope (SEM) and X-ray diffraction (XRD) analyses. Both of TAFMAG and chrysotile showed high content of magnetite and Fenton activity when compared with wollastonite, a non-asbestos fiber with a known low toxicity. When their cellular toxicity was assessed, TAFMAG showed no or less comparable to that of chrysotile in the hemolysis and lipid peroxidation of erythrocytes, and also on a MTT assay in RLE-6TN, a rat alveolar epithelial cell line. Pre-treatment of fibers with desferrioxamine, an iron chelator, showed that iron content of TAFMAG and chrysotile might be important in their cellular toxicity. These results suggest that TAFMAG is potentially toxic when inhaled into the lung and appropriate laws and regulations should be established for its use.

• Reduction of chrysotile asbestos-induced genotoxicity in human peripheral blood lymphocytes by garlic extract. K. Bhattacharya, S. Yadava, T. Papp, et al. 2004;153(3):327-32. PubMed · Publisher

  Abstract

  Asbestos fibers are well known environmental carcinogen, however, the underlying mechanisms of their action have still not clearly been identified. Asbestos is capable of depleting glutathione and generating reactive oxygen species (ROS), which are important mediators of damage in biological system. Asbestos-induced mutagenecity, may be mediated by the generation. It is known that a number of scavengers and antioxidants attenuate asbestos-induced ROS release. Furthermore, it is known that garlic, contains numerous sulfur compounds and glutathione precursors which act as antioxidants and also demonstrate anticarcinogenic properties. The aim of this study was to investigate whether garlic extract has any influence on asbestos-mediated genotoxicity. As an assay system, we applied the micronucleus assay, sister chromatid exchanges, and chromosomal aberrations with human peripheral blood lymphocytes, which has already been used to analyze the genotoxicity of asbestos fibers. Our results indicate that garlic extract, when administered to the lymphocytes cell culture simultaneously with chrysotile reduced the rates of micronucleus formation, sister chromatid exchanges, and chromosomal aberrations significantly. We conclude that garlic extract may be an efficient, physiologically tolerable quencher of asbestos-mediated genotoxicity.

• Diallylsulfide attenuates asbestos-induced genotoxicity. M. Lohani, S. Yadav, D. Schiffmann, et al. 2003;143(1):45-50. PubMed · Publisher

  Abstract

  It is well known that asbestos fibers induced genotoxicity is mediated by reactive oxygen species (ROS) and insufficient endogenous antioxidant protection. Asbestos exposure can result in ROS generation in two different ways: (a) by catalyzation of Fe(2+), which is present in asbestos fibers, and (b) via oxidative bursts during phagocytosis of the fibers. On the other hand, it has been discussed that the physical presence of the fibres may mechanically influence the normal segregation of chromosomes during mitosis resulting in the induction of micronuclei in late ana/telophase, and aneuploidy. Glutathione and the glutathione redox system protect cells from the oxidative damage after exposure to xenobiotics. Glutathione depletion occurs during oxidative stress conditions and it is observed that supplementation of a precursor of glutathione and other sulphur containing compounds results in reduced toxicity. In the present study, diallyl sulfide (DAS), a lipid soluble allyl sulphur compound present in fresh extracts of garlic was evaluated for its protective effects. The micronucleus (MN) assay was performed in human mesothelial cells (HMC) exposed to 1 microg/cm(2) of crocidolite and chrysotile. Simultaneously, the cells were treated with 5 and 10 microM DAS, incubated for 48 and 66 h. Asbestos fibers induced significant genetic damage in HMC. The assay revealed a significant reduction in MN induction after treatment of cells with 5 microM but not with 10 microM DAS in mesothelial cells. The study revealed that at appropriate concentrations DAS protects mesothlelial cells against asbestos induced genotoxicity.

• Expression of Clara cell secretory protein in the lungs of rats exposed to silicon carbide whisker in vivo. Y. Morimoto, L. Ding, T. Oyabu, et al. 2003;145(3):273-9. PubMed · Publisher

  Abstract

  Intratracheal instillation studies have shown that exposure to silicon carbide whiskers (SiCW), an asbestos substitute, produces pulmonary fibrotic changes, suggesting that SiCW might have fibrogenic potential. It has been theorized that Clara cell secretory protein (CCSP) plays a critical role in regulating the acute inflammatory response in the lung. The present study was conducted to investigate the time course of the expression of CCSP in lungs exposed to SiCW in vivo. Male Wistar rats were administered 2 mg or 10 mg of SiCW suspended in saline by a single intratracheal instillation and were sacrificed at 3 days, 1 week, 1 month, 3 months and 6 months of recovery time. The expression of CCSP was observed by reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot and immunostaining. Exposure to 10 mg of SiCW decreased in levels of CCSP mRNA at 3 days, 1 week, 1 month and 6 months following intratracheal instillation. The protein level of CCSP in SiCW-exposed rats was decreased at 1 day, 3 days and 1 month after a single instillation of 2 and 10 mg. These findings suggest that CCSP are involved not only in the acute injury but also in the chronic injury of the lung exposed to SiCW.

• Inhalation toxicity of mineral particles: critical appraisal of endpoints and study design. H. Muhle, I. Mangelsdorf. 2003;140-141:223-8. Review PubMed · Publisher

  Abstract

  Many of the mineral particles that are of concern in regard to lung toxicity are poorly soluble particles (PSPs). They include biopersistent mineral fibers and dusts containing crystalline silica. The preparation of well-defined test particles of respirable size range and their characterization are an essential step that may require more time and effort than the toxicity study itself. For toxicity studies with mineral particles, an investigation of the toxicokinetics is recommended. Such an investigation will yield information that will help to interpret the results if dust overload conditions occur. For mineral particles such as crystalline silica and mineral fibers, an important endpoint is their potential carcinogenicity. The following parameters are important for the design of chronic toxicity studies, and for the prediction of severe chronic effects: lung retention of inhaled materials for assessing the accumulation of particles, persistent inflammation in lungs, persistent proliferation of epithelial lung cells, progressive fibrogenicity, and genotoxicity in the lung cells. These endpoints should indicate whether the materials investigated are of concern in the health effects on exposed humans, and in the effects of the mineral particles for which chronic studies may be required. In addition, this paper focuses on the effects of PSPs combined with fibers, and on the strategies for investigating the potential carcinogenicity of quartz-containing dusts.

• Lung diseases due to environmental exposures to erionite and asbestos in Turkey. S. Emri, A. Demir, M. Dogan, et al. 2002;127(1-3):251-7. PubMed · Publisher

  Abstract

  Asbestos deposits have been used locally by the rural inhabitants of Central and Southeastern Anatolia for domestic purposes for many years. Mineralogical analysis revealed that tremolite is the most prominent asbestos type found in the region. There is in addition another mineral fiber found particularly in three villages located in the Cappadocian region of Central Anatolia (zeolite villages). This is a non-asbestos mineral, which has been identified as the fibrous zeolite, erionite. This fiber is present in the volcanic tuffs, which are used as building stone. Hence, exposure to erionite fibers is always possible in the houses, annexes, and streets of the villages. It has been demonstrated that both asbestos and erionite cause a variety of benign and malignant chest diseases. Among the diseases, calcified pleural plaques (CPP) are the most frequently seen and may be used as an indicator of mineral fiber exposure. Asbestos and erionite exposure are the main causes of malignant mesotheliomas in Turkey. In zeolite villages malignant mesothelioma is responsible for more than 50% of the total deaths. A recent study showed that simian virus 40 is not a cofactor in the pathogenesis of environmental malignant mesothelioma in Turkey. An additional recent genetic-epidemiological study showed that there are some families, which are genetically predisposed to mesothelioma.

• Pi*S and Pi*Z alpha 1 antitrypsin polymorphism and the risk for asbestosis in occupational exposure to asbestos. M.J. Lafuente, X. Casterad, N. Laso, et al. 2002;136(1):9-17. PubMed · Publisher

  Abstract

  Alpha 1 antitrypsin is a highly polymorphic anti-elastase enzyme, especially active in the protection of alveoli and liver. Here we studied the distribution of two deficient alleles Pi*Z and Pi* S, in 194 asbestos workers, of whom 100 were asbestosis cases, and 94 were controls without disease (exposed controls, EC). A second group of controls without asbestos exposure (non-exposed controls, NEC; n=122) was also included. Multivariate analysis adjusted by age and smoking habit showed ninefold risk for asbestosis in Pi*Z heterozygous individuals and 5.9-fold risk for Pi*S homozygous although differences were only significant in the first case (cases vs. EC: OR 8.9; p=0.04). Considering both genotypes (Pi*Z heterozygous, Pi*S homozygous) we obtained an OR of 8 (p=0.01). Our results suggest that the alpha 1 antitrypsin polymorphisms, especially Pi*Z, could help to predict asbestosis risk and confirm the high prevalence of the Pi*S allele in Spain.

• Smoking enhances asbestos-induced genotoxicity, relative involvement of chromosome 1: a study using multicolor FISH with tandem labeling. M. Lohani, E. Dopp, H.H. Becker, et al. 2002;136(1):55-63. PubMed · Publisher

  Abstract

  Several experimental and epidermological studies have indicated augmentation of asbestos induced diseases by cigarette smoke by the mechanisms, which are still unknown. To determine whether smoking affects genetic system of the cells and further modifies asbestos induced genotoxicity, whole blood from non-smokers and smokers was exposed to asbestos fibres separately in vitro and micronucleus test was performed. The number of micronuclei was found to be significantly higher (P<0 05) in cases of smoker's lymphocytes, asbestos exposed non-smokers lymphocytes as well as asbestos exposed smokers lymphocytes, as compared with unexposed non-smokers lymphocytes. Further we investigated involvement of chromosome 1 in the damaging process using multicolor FISH technique. FISH is fast and reliable method, distinguishing both structural and numerical alterations. The centric/pericentric regions of chromosome 1 (cen-q12) were labeled, as the pericentric heterochromatin region 1 (q12) is quite large, highly repetitive and prone to breakage. Multicolor FISH assay suggested that the genetic damage by asbestos fibres mainly involve chromosome 1 but in case of cigarette smoking the damage is not strictly connected to chromosome 1 only, but also involves damage to other chromosomes. Further the study suggested that smoking makes genetic system of the cells more vulnerable to the deleterious effects of asbestos.

• Chemoprevention of cancer: lessons to be learned from beta-carotene trials. H. Vainio. 2000;112-113:513-7. Review PubMed · Publisher

  Abstract

  Observational studies indicate a lower incidence of chronic diseases, including various cancers and cardiovascular disease, related to higher intakes of carotenoid containing foods (fruits and vegetables). Beta-carotene, one of the large number of naturally occurring carotenoids, thus appears to actively participate in health. However, recent intervention trials indicate that beta-carotene supplements are not efficacious in the prevention of cardiovascular disease and major cancers occurring in well-nourished populations. In fact, supplemental beta-carotene appears to increase, rather than to reduce, lung cancer incidence and deaths from cardiovascular disease in current smokers and in asbestos exposed workers. In order to resolve these paradoxes, we need to better understand the underlying biology, identify interactions, develop mechanistic hypotheses and test them in clinical trials in humans. Until that time, we should confine any premature enthusiasm for chemopreventive supplementation.

• Kerosene soot genotoxicity: enhanced effect upon co-exposure with chrysotile asbestos in Syrian hamster embryo fibroblasts. M. Lohani, E. Dopp, D.G. Weiss, et al. 2000;114(1-3):111-6. PubMed · Publisher

  Abstract

  Epidemiological and experimental studies have suggested an enhancement of asbestos-induced bronchogenic carcinoma by cigarette smoke. Further, our recent experimental and epidemiological studies have indicated that besides smoking, several other compounds including kerosene soot may accelerate disease processes in asbestos-exposed animals as well as in the humans. Incomplete combustion of kerosene oil generates large volumes of soot, which contains various polycyclic aromatic hydrocarbons and aliphatic compounds. As reported earlier, exposure to kerosene soot is known to cause biochemical and pathological changes in the pulmonary tissue, which may cause cardiopulmonary disorders. In this study we investigated genotoxic effects caused by kerosene soot and chrysotile asbestos as well as co-exposure of kerosene soot and chrysotile using Syrian hamster embryo fibroblasts (SHE). The micronucleus assay revealed a significant increase of induced micronuclei (MN), (P</=0.05) in SHE cells after treatment with kerosene soot (0.5-1.0 microg/cm(2)) for 66 h (36 MN/1000 cells). Combined treatment with chrysotile and soot induced up to 110 MN/1000 cells (chrysotile alone: 80 MN/1000 cells; concentrations: 1 microg/cm(2), exposure times: 66 h). Kinetochore staining revealed mainly clastogenic effects in all cases (soot: 21.3% CRMN(+); chrysotile: 27%; soot+chrysotile: 27.6%; control: 20.8%). This is the first study showing that kerosene soot is not only genotoxic but it can also elevate the genotoxic potential of chrysotile asbestos. This information may be of importance for workers occupationally exposed to asbestos and domestically exposed to kerosene soot.

• N-acetyl L-cysteine attenuates oxidant-mediated toxicity induced by chrysotile fibers. F. Afaq, P. Abidi, Q. Rahman. 2000;117(1-2):53-60. PubMed · Publisher

  Abstract

  Chrysotile, an important commercial variety of asbestos, is known to cause oxidative stress by enhancing production of hydrogen peroxide (H(2)O(2)) and thiobarbituric acid reactive substances (TBARS), depleting glutathione (GSH) and altering levels of GSH redox system enzymes. N-acetyl L-cysteine (NAC), a compound that increases GSH levels, protects cells against chrysotile toxicity. In the present study, rats were exposed intratracheally to a single dose (5 mg/rat) of chrysotile. This was followed by a daily dose of NAC 50 mg/kg. b. wt., i.p. At 1, 4, 8 and 16 days post chrysotile exposure lung lavage fluid was collected to determine H(2)O(2) generation, TBARS production, GSH level and its redox system enzymes activities. A significant decrease in H(2)O(2) and TBARS, an increase in GSH content and its redox system enzymes was observed in chrysotile+NAC animals in comparison to chrysotile-exposed animals. In this preliminary study it appears that NAC may be protecting cells against oxidative damage. This protection may be due to its ability to maintain intracellular GSH/oxidative scavenging capability.

• Production of reactive oxygen species by phagocytic cells after exposure to glass wool and stone wool fibres - effect of fibre preincubation in aqueous solution. T. Zoller, W.J. Zeller. 2000;114(1-3):1-9. PubMed · Publisher

  Abstract

  The potential of four man-made vitreous fibres (MMVFs) (glass wool Code A, stone wool Code G, HT-N and MMVF 21) and of two natural mineral fibres (crocidolite, erionite) to induce production of reactive oxygen species (ROS) by differentiated HL-60 cells (HL-60-M cells) was investigated by determination of luminol-enhanced chemiluminescence (CL). Quartz served as positive control. The same system was used to uncover possible influences of fibre preincubation in aqueous solutions on the ROS-generating potential. Following preincubation in unbuffered saline over about 4 weeks, Code A and G fibres showed decreased ROS-generating potential as compared to freshly suspended fibres. On the other hand, MMVF 21 and HT-N fibres as well as crocidolite and erionite showed no decreased CL after incubation in aqueous solutions. The observed decrease of the ROS-generating potential of Code A and G fibres after preincubation may be an expression of fibre surface alterations (leaching, initiation of dissolution) that influences the response of exposed phagocytic cells. After incubation of both fibres in buffered solutions at different pH values (5.0, 7.4) a reduced ROS-generating potential was still discernible as compared to freshly suspended fibres.

• TNFalpha and MIP-2: role in particle-induced inflammation and regulation by oxidative stress. K.E. Driscoll. 2000;112-113:177-83. Review PubMed · Publisher

  Abstract

  The cytokine tumor necrosis factor alpha (TNFalpha) plays a critical role in particle-induced inflammation in the lung. TNFalpha production by macrophage can be stimulated by a variety of noxious particles and initiate a cascade of responses involving adhesion molecule expression and production of chemotactic cytokines which ultimately result in the infiltration of inflammatory cells to site of infection or tissue injury in the respiratory tract. Regarding chemotactic cytokines, TNFalpha is a potent agonist of chemokine expression in both immune and non-immune cells (e.g. epithelial cells, fibroblasts). The chemokine macrophage inflammatory protein-2 (MIP-2) plays a major role in mediating the neutrophilic inflammatory response of the rodent lung to particles such as quartz, crocidolite asbestos, as well as high doses of other relative innocuous dusts such as titanium dioxide. The documented sources of MIP-2 in the rodent lung after particle exposure include macrophages as well as epithelial cells. Recent studies indicate that expression of the MIP-2 gene in rat lung epithelial cells is dependent on the transcription factor NFkappaB and is regulated, in part, by oxidative stress induced by particle exposure.

1990s

• Absence of synergistic effects on micronucleus formation after exposure to electromagnetic fields and asbestos fibers in vitro. M. Simkó, E. Dopp, R. Kriehuber. 1999;108(1):47-53. PubMed · Publisher

  Abstract

  Exposure of human amniotic fluid (AFC) cells to horizontally applied magnetic fields (hMF) of 50 Hz and 1 mT generated in a Helmholtz-coil system leads to a significant increase in micronucleus frequency (MN), without affecting cell proliferation. To investigate whether hMF-exposure has an additive or synergistic effect on the genotoxic capacity of asbestos fibers, MN induction was investigated in hMF pre-exposed cells, treated before or after with asbestos (1 microg/cm2). Neither synergistic nor additive effects on MN induction were observed. The results indicate, that under our experimental conditions, exposure to hMF and treatment with asbestos fibers possess genotoxic capability, but no interactive effects, in AFC cells.

• Chrysotile-mediated imbalance in the glutathione redox system in the development of pulmonary injury. P. Abidi, F. Afaq, J.M. Arif, et al. 1999;106(1):31-9. PubMed · Publisher

  Abstract

  A significant depletion in the content of glutathione (GSH) and alteration in GSH redox system enzymes were observed in the lung of chrysotile-exposed animals (5 mg) during different developmental stages of asbestosis. In the alveolar macrophages (AM) of exposed animals, the depletion in GSH started from day 1 and reached a maximum at day 16, whereas in lung tissue the maximum depletion was observed when fibrosis has matured. It appears that cellular GSH depletion triggers oxidative stress in the system as observed from increased thiobarbituric acid reactive substance (TBARS) production and alteration in the activities of glutathione peroxidase (GPx), glutathione reductase (GR), glucose 6-phosphate dehydrogenase (G6PD) and glutathione S-transferase (GST), the enzymes regulating oxidative tone. The depletion in GSH was also observed in red blood cells (RBC) of the exposed animals reaching a maximum when fibrosis matured. Thus the observed depletion in GSH, ascorbic acid and alteration in GSH redox system enzymes may be involved in fibrosis and carcinogenesis induced by chrysotile.

• Frequency of sister chromatid exchange in chrysotile-exposed workers. S.H. Lee, M. Shin, K.J. Lee, et al. 1999;108(2-3):315-9. PubMed · Publisher

  Abstract

  Chrysotile, which is an industrial carcinogen, has been shown to induce a dose-dependent increase in the frequency of sister chromatid exchange (SCE) in vitro. Authors designed this study to examine the increase of SCEs frequency in the workers occupationally exposed to chrysotile. Heparinized whole blood samples from 45 chrysotile-exposed and 45 control volunteers were cultured for 72 h. The significant difference of SCE frequency was found between chrysotile-exposed workers and control group. The highest SCEs frequency was found in chrysotile-exposed smokers, and the lowest in control non-smokers. The effect of chrysotile exposure on SCEs was marginally significant after controlling the effects of age and smoking by multiple regression analysis.

• Activation of alveolar macrophages and peripheral red blood cells in rats exposed to fibers/particles. F. Afaq, P. Abidi, R. Matin, et al. 1998;99(3):175-82. PubMed · Publisher

  Abstract

  The cytotoxic and oxidative responses of crocidolite and chrysotile asbestos fibers and ultrafine titanium dioxide (UF-TiO2) particles were measured in alveolar macrophages (AM) and peripheral red blood cells (RBC) of rat after 30 days with a single intratracheal exposure (5 mg). The following responses were observed one month after fiber/particle instillation: (1) AM population increased; (2) lactate dehydrogenase and acid phosphatase activities in cell free lung lavage fluid increased; (3) substances that react with hydrogen peroxide or thiobarbituric acid were elevated in both AM and peripheral RBC; (4) glutathione peroxidase, glutathione reductase, and catalase were altered in both AM and peripheral RBC; (5) glutathione and ascorbic acid decreased in both AM and peripheral RBC. A significant difference from negative controls was noted in all responses of the two fiber-exposed groups, and in most responses of the UF-TiO2-exposed group. The level of responses to the three test substances suggested a decreasing order of toxicity, with crocidolite > chrysotile > UF-TiO2.

• Analysis of chromosomal alterations induced by asbestos and ceramic fibers. E. Dopp, D. Schiffmann. 1998;96-97:155-62. PubMed · Publisher

  Abstract

  Asbestos and other mineral fibers have long been known as carcinogenic agents. However, the primary mechanisms of fiber-induced carcinogenesis still remain unclear. We have investigated mitotic disturbances caused by amosite, crocidolite, and chrysotile in Syrian hamster embryo (SHE) fibroblasts. We also analyzed micronucleus formation as a result of mitotic disturbances, and carried out a characterization of the induced micronucleus population by kinetochore staining. In addition, the spindle fiber morphology was examined. Supravital UV-microscopy was used to analyze changes in chromatin structure, impaired chromatid separation and blocked cytokinesis. All three fiber types induced micronuclei in SHE cells with a high frequency (up to 200 MN/2000 cells; dose range: 0.1-5.0 microg/cm2) in a dose-dependent manner with a maximum between 48 and 66 h. Kinetochore staining revealed that 48% of fiber-induced micronuclei reacted positively. Furthermore, spindle deformation was observed in cells with disturbed meta- and anaphases while the spindle fiber morphology appeared unchanged. Our results show that asbestos fibers may cause both loss as well as breakage of chromosomes in the absence of direct interaction with spindle fibers. In addition, we analyzed the induction of micronuclei, hyperdiploidy and chromosome breakage in human amniotic fluid cells (AFC) in vitro by amosite, chrysotile and crocidolite asbestos and ceramic fibers. The response of human (AFC) and rodent (SHE) cells to fiber treatment was compared using the micronucleus assay. AFC were much less susceptible than SHE cells to the induction of micronuclei by mineral fibers. The application of fluorescence in situ hybridization (FISH) with tandem DNA probes yielded more detailed informations about specific structural chromosome aberrations in the 1(cen-q12) and 9(cen-q12) regions and about abnormal numbers of chromosomes in interphase AFC. Using this FISH approach we found a statistically significant increase of chromosomal breakage in the pericentric heterochromatin regions of chromosomes 1 and 9 in AFC after exposure to asbestos and ceramic fibers. The number of hyperdiploid cells was also significantly increased. These results show that asbestos as well as ceramic fibers are inducers of structural and numerical chromosomal alterations.

• Asbestos induces inflammatory cytokines in the lung through redox sensitive transcription factors. M.I. Luster, P.P. Simeonova. 1998;102-103:271-5. PubMed · Publisher

  Abstract

  Studies are summarized demonstrating that the inflammatory cytokines, interleukin IL-6 and IL-8, play a direct role in asbestos lung diseases and are produced by lung epithelial cells in direct response to the fibers. This response is controlled by changes in the cellular oxidative/state induced by iron present in the fiber through Fenton-type chemistry. As a result of this oxidative stress, the redox sensitive transcription factors, NF-kappaB and NF-IL-6, which help regulate cytokine gene expression, are activated.

• Low dose effects of fibrous and non-fibrous mineral dusts on the proliferation of mammalian cells in vitro. A.B. Fischer, J.L. Kaw, K. Diemer, et al. 1998;96-97:97-103. PubMed · Publisher

  Abstract

  This report presents preliminary results of studies on the growth stimulating properties of mineral dusts. The studies were carried out with Syrian hamster diploid embryonic fibroblasts and Chinese hamster fibroblasts, line B14F28. Toxicity testing was done by the determination of the plating efficiency as a measure of growth and viability. The following dusts were used: the modified UICC asbestos fibres amosite, (AFF) crocidolite (KFF), chrysotile (KFF): in addition glass fibre (GFF), corundum and quartz DQ12. Concentrations > 2 microg/cm2 of AFF, CFF, KFF and GFF depressed the plating efficiency of B14F28 cells in a dose-dependent manner, but all of the fibres and corundum increased colony sizes at concentrations of 0.16-0.33 microg/cm2, in the case of corundum, AFF, KFF, and CFF also at up to 0.66 or 1.32 microg/cm2. DQ12 did not enhance colony growth. The stimulation of proliferation could be demonstrated both in terms of colony size (diameter) and cell numbers. The factor(s) responsible for proliferation stimulation reside in the supernatant, since the medium of dust-treated cell cultures was able to stimulate colony growth after removal of the dusts by filtration. The results indicate the induction of growth factors (cytokines) by low concentrations of the mineral dusts. Experiments concerning the effect of dusts on embryonic golden hamster fibroblasts yielded similar results. The plating efficiency was inhibited by concentrations of GFF and CFF > 0.25 microg cm2 and by AFF, KFF, GFF and corundum at concentrations > 5 microg/cm2, but colony counts were significantly increased by AFF, KFF and corundum at concentrations of 0.25-3 microg/cm2. This biological reaction which was observed in different cell types appears to be especially relevant in the context of environmental exposure where low dust concentrations prevail.

• Cultured airway epithelium responses to mineral particles: role of the oxidative stress. C. Guilianelli, A. Baeza-Squiban, E. Lapart, et al. 1996;88(1-3):39-44. PubMed · Publisher

  Abstract

  We tested the hypothesis according to which mineral particles containing iron would be able to produce cytotoxic-ROS. We approached this problem in vitro using primary cultures of rabbit tracheal epithelial cells. The oxidizing power of three mineral particles, i.e. nemalite, chrysotile and hematite, has been evaluated for their capacity to induce lipid peroxidation, and to activate intra-cellular anti-oxidant enzymes. The results show that nemalite and chrysotile which contain Fe2+ have a strong oxidizing power, inducing an oxidative stress on airway epithelial cells, whereas hematite, the Fe3+ containing particles, is without effect.

• Free radical activity associated with the surface of particles: a unifying factor in determining biological activity?. K. Donaldson, P.H. Beswick, P.S. Gilmour. 1996;88(1-3):293-8. PubMed · Publisher

  Abstract

  Using a sensitive phi X174 RF plasmid DNA assay, free radical activity was detected at the surface of normal and ultrafine titanium dioxide (TiO2), environmental particles (PM-10), asbestos and a range of man-made fibres. There were differences in the amount of free radical activity that was detected, with ultrafine TiO2 being much more active than normal-sized TiO2; PM-10 also had substantial free radical activity. Amphibole asbestos samples were highly active, whilst man-made fibres were much less active than asbestos. For all of the particles, the DNA damage could be ameliorated by mannitol, showing that hydroxyl radicals were involved. The ability of particles to generate free radicals at or near their surface, and thereby impose oxidant stress in key target cells, could be central to determining their pathogenicity.

• Pulmonary effects in rats inhaling size-separated chrysotile asbestos fibres or p-aramid fibrils: differences in cellular proliferative responses. D.B. Warheit, M.A. Hartsky, S.R. Frame. 1996;88(1-3):287-92. PubMed · Publisher

  Abstract

  This study was designed to compare the pulmonary cellular proliferative effects of inhaled, size-separated preparations of chrysotile asbestos fibres with similar aerosol fibre concentrations of para-aramid fibrils. Following fibre preparation, rats were exposed for 2 weeks to aerosols of p-aramid fibrils or chrysotile asbestos fibres at design fibre concentrations of 750 and 400 f/cc. Two week exposures to p-aramid fibrils produced transient pulmonary inflammatory and cell labeling responses in terminal bronchiolar and subpleural regions. Similar to p-aramid, exposure to chrysotile produced a transient increase in neutrophils. In contrast, however, substantial increases compared to controls in pulmonary cell labeling indices were measured on terminal bronchiolar, parenchymal, subpleural, and mesothelial surfaces immediately after exposure, and some increases persisted for 3 months postexposure. In complementary studies we demonstrated that p-aramid is biodegradable in the lungs of exposed rats; in contrast, the clearance of long chrysotile fibres was slow or insignificant, resulting in a pulmonary retention of long chrysotile asbestos fibres. The dimensional changes of asbestos fibres as well as the pulmonary cell labeling data indicate that chrysotile asbestos fibres may produce greater long-term pulmonary effects when compared to inhaled para-aramid fibrils.

• Mineral fiber-induced leukocyte activation: the role of intra- and extracellular calcium. M. Ruotsalainen, J. Naarala, K.M. Savolainen. 1995;78(3):195-205. PubMed · Publisher

  Abstract

  The role of intra- and extracellular calcium in the activation of human polymorphonuclear leukocytes (PMNL) to produce reactive oxygen metabolites (ROM) were studied by using soluble, formyl-methionyl-leucyl-phenylalanine (fMLP) or phorbol myristate acetate (PMA), or particulate stimuli, quartz or chrysotile. A calcium channel inhibitor, verapamil, attenuated only quartz-induced elevation of free intracellular calcium ([Ca2+]i) and ROM production. Likewise, ethyleneglycol-bis (aminoethyl ether) tetraacetic acid (EGTA) attenuated quartz-, chrysotile- and fMLP-induced elevation of [Ca2+]i and ROM production. It also inhibited PMA-induced ROM production. A calcium ionophore, A23187 amplified ROM production by all of these stimuli. These results suggest that both intra- and extra-cellular calcium are required for the full activation of respiratory burst by soluble and particulate stimuli in human PMNL.

• Radiographic changes and lung function in relation to activity of the glutathione transferases theta and mu among asbestos cement workers. K. Jakobsson, A. Rannug, A.K. Alexandrie, et al. 1995;77(1-3):363-9. PubMed · Publisher

  Abstract

  Experimental data indicate that active oxygen species may be casually involved in the development of asbestos-related disease. Thus, it was hypothesized that individual differences in glutathione transferase activity, which may affect the ability to inactivate molecules formed in relation to oxidative stress, could influence the biological response to asbestos exposure. We could, however, not demonstrate an increased risk for radiographic changes or reduced lung function among asbestos cement workers deficient for glutathione transferase theta (GSTT1), glutathione transferase mu (GSTM1), or having a combined deficiency of enzyme activity.

• Role of iron in the reactivity of mineral fibers. B. Fubini, L. Mollo. 1995;82-83:951-60. Review PubMed · Publisher

  Abstract

  Any foreign body containing iron may be (or become) highly toxic in vivo. If its solubility in water is poor, surface chemistry governs the reactivity at the solid-liquid interface. Iron toxicity thus increases with the extent of exposed surface. Iron of endogenous origin may also be deposited on the particle surface and be activated under particular circumstances. The chemical processes that implicate surface iron as a primary cause of toxicity are: free radical release, mobilization by chelators, iron-catalyzed reactions. Three kinds of solids are compared: (i) well-known toxic materials, for example asbestos; (ii) non-toxic iron oxides; and (iii) model solids with surface exposed iron prepared for investigations on the reactivity of iron in biological media. The iron content of the solid is not directly related to the biological response: only a small fraction of ions, in a well-defined coordination and redox state, appears involved in the toxicity of the mineral dust.

• Biological activity of respirable industrial fibres treated to mimic residence in the lung. K. Donaldson. 1994;72(1-3):299-305. PubMed · Publisher

  Abstract

  The durability of fibres in the lung environment after deposition could be a key factor in determining whether they accumulate to a sufficient tissue dose to cause pathological change. There is a shortage of information on the relative durabilities of respirable industrial fibres of various types. We describe a strategy for assessing the ability of different fibre types to persist in the lung milieu and to retain their biological activity. This is particularly important for the development of mesothelioma, where the long latent time that characterises this disease would be expected to exclude, from culpability, fibres that are not durable. We have combined a pre-treatment step in pH 5.0 or 7.0 with an assay that relies on the ability of fibres to damage the mesothelium. The long-term aim is to assess the impact that treatment in various pH solutions has on (a) fibre size/number, (b) loss of key elements, (c) the ability to damage the mesothelium. Such information should enable us to better predict the potential of fibres to cause mesothelioma.

• Use of asbestos, health risks and induced occupational diseases in the former East Germany. W. Sturm, B. Menze, J. Krause, et al. 1994;72(1-3):317-24. Review PubMed · Publisher

  Abstract

  In the period from 1960 to 1990 about 1.4 million tons of asbestos were imported and mainly processed into asbestos-cement products for the building industry. The production was concentrated in the former countries of Magdeburg and Dresden. In the past asbestos was primarily used as insulation and fire prevention material, etc. in the large-scale chemical industry. The asbestos was imported from the former Soviet Union, smaller amounts came from Canada. In the German Federal State of Saxony-Anhalt, approximately 600 asbestoses, almost 2700 pleural changes caused by asbestos, 843 asbestos-induced mesotheliomas and 787 bronchial and laryngeal carcinomas were recorded in the period from 1960 to 1990. A considerable percentage of the mesotheliomas are solely due to exposure to chrysotile asbestos.

• Glutathione release by pulmonary alveolar macrophages in response to particles in vitro. D.S. Boehme, K.R. Maples, R.F. Henderson. 1992;60(1):53-60. PubMed · Publisher

  Abstract

  We studied whether cultured rat pulmonary alveolar macrophages (PAM) could release glutathione (GSH) in response to latex beads, quartz, and crocidolite asbestos. PAM were exposed for 2 h to 0-100 micrograms of particles per 1 x 10(6) cells. Both quartz and asbestos produced concentration-dependent increases (up to 8-10-fold) in the amount of GSH recovered in the medium and decreases in the cellular GSH levels. In contrast, latex beads did not produce any changes in GSH levels. We also measured lactate dehydrogenase (LDH) levels as an index of toxicity. Only quartz and asbestos were able to produce increases in LDH levels in the medium. The release of GSH occurred at particle concentrations that did not cause release of LDH. Our results indicated that, in vitro, PAM release GSH in response to toxic particles.

• Molecular basis for differences in susceptibility to coal workers' pneumoconiosis. P.J. Borm, R. Schins, Y.M. Janssen, et al. 1992;64-65 Spec No:767-72. PubMed · Publisher

  Abstract

  It is generally accepted that there are differences among workers in susceptibility towards the effects of mineral dusts such as silica, coal dust and asbestos. Basic research continues to find new factors involved in the process of pulmonary fibrosis caused by these minerals. In this paper, two hypotheses implicitly generated by recent findings were tested in two case-control studies among coal miners: generation of tumour necrosis factor (TNF) by blood monocytes of miners with coal workers' pneumoconiosis (CWP) and serum type III procollagen peptide (PIIIP) in CWP. Our data indicate that both parameters can be used as biological markers for early diagnosis of CWP. A follow-up study is described in which the predictive power of increased TNF release and serum PIIIP as risk factor to develop lung fibrosis will be assessed.

1980s

• Toxic effect on the rat small intestine of chronic administration of asbestos in drinking water. T.J. Delahunty, D. Hollander. 1987;39(2-3):205-9. PubMed · Publisher

  Abstract

  Sprague-Dawley rats were given a 0.5 g/l Chrysotile asbestos solution in their drinking water (approximately 7 mg/day ingested) for 1.5 years and compared to control rats of the same age. During this time there were no differences in weight or appearance of the asbestos-treated rats in comparison to controls maintained under the same conditions. However, when in vivo intestinal permeability studies were performed using a gavage/urinary collection technique, some significant changes were noted. The recovery of lactulose in the urine of asbestos-treated rats was 0.66 +/- 0.07%, significantly less than that of the controls (1.01 +/- 0.08, P less than 0.005). The recovery of mannitol was similarly decreased (2.2 +/- 0.28 vs. 3.0 +/- 0.17, P less than 0.02), but that of rhamnose was unchanged. Creatinine clearance studies indicated that there was no impairment of kidney function in the asbestos-treated group and polarized light microscopy did not reveal any asbestos fibers in sections of the small bowel. The results suggest that the chronic exposure of rats to asbestos fibers in the drinking water results in a decreased ability of the intestine to absorb some non-metabolizable sugars.

• Interstitial pulmonary fibrosis in an automobile body shop worker. A. Fischbein, A.N. Rohl, Y. Suzuki, et al. 1985;27(1-3):51-7. Case report PubMed · Publisher

  Abstract

  Interstitial pulmonary fibrosis (IPF) is often of uncertain etiology and is therefore named 'idiopathic' pulmonary fibrosis. Some occupational exposures, however, are known to cause interstitial fibrosis, asbestos and silica being well-known examples. We present clinical and pathological findings of a case with IPF and the results of microchemical analysis of inorganic particulate matter in the lung tissue. A very high lung burden of inorganic contaminants was found, including silica and metallic compounds. Emphasis is given to the importance of obtaining detailed occupational histories and conducting microchemical analysis of lung tissue in order to clarify etiological factors in cases with 'idiopathic' pulmonary fibrosis.

• Cytotoxic effects of aramid fibres on rat pulmonary macrophages: comparison with chrysotile asbestos. J. Dunnigan, D. Nadeau, D. Paradis. 1984;20(3):277-82. PubMed · Publisher

  Abstract

  Aramid fibres have been proposed as a substitute for many asbestos uses. Although dimensional characteristics of aramid fibres vary with the type of application, some of the commercial grades proposed contain fibres whose geometry is clearly in a range where biological reactivities have been reported for other natural or man-made fibres. We wish to report that short aramid fibres, when tested on cultures of rat pulmonary alveolar macrophages (PAMs), induce the commonly recognized signs of a cytotoxic effect, that is: leakage of cytoplasmic and lysosomal marker enzymes, concomittant with a decreased ATP cell content.

• Adsorption of nucleic acids on asbestos fibers in vitro. V. Misra, Q. Rahman, P.N. Viswanathan. 1983;15(2-3):187-91. PubMed · Publisher

  Abstract

  Adsorption of DNA and RNA, accompanied by liberation of orthophosphate, occurred on contact with chrysotile asbestos fibers. This indicated that interaction of macromolecules and their components may be a factor, possibly involved in the manifestation of the toxic effect of asbestos fibers.

• Interactions of asbestos fibers with hepatocytes in vitro: an ultrastructural study. J. Fleury, M.G. Côté, M. Marion, et al. 1983;19(1-2):15-22. PubMed · Publisher

  Abstract

  Cultures of rat hepatocytes have been used to study the interaction of chrysotile asbestos fibers with epithelial cells. The hepatocytes were incubated for 20 h with chrysotile asbestos (UICC B and a preparation of short fibers: 90% less than 2 micron) at concentrations of 1 or 10 micrograms/ml. Morphologic studies were then performed by means of transmission electron microscopy. Fibers were incorporated into plasma membrane invaginations, cytoplasmic vacuoles and phagolysosomes. These observations demonstrate that rat hepatocytes can engage in phagocytosis of chrysotile fibers. The results are compared to those previously obtained with mesothelial cells and tracheobronchial epithelium, exposed to asbestos in vitro. The advantages of the hepatocyte model to investigate the effects on cells of the association of asbestos fibers with genotoxic agents in relation to carcinogenesis are discussed.

• Mechanism of haemolysis by chrysotile fibres. M.C. Jaurand, L. Magne, J. Bignon. 1983;15(2-3):205-11. PubMed · Publisher

  Abstract

  Haemolysis by chrysotile fibres may be related to an adsorption of the red blood cell (RBC) membranes on the fibres and not to an interaction between magnesium (Mg) from the fibres and sialic acid from RBC. This was demonstrated using neuraminidase (NANASE)-treated RBC and Mg-depleted chrysotile fibres. The mechanism may be extended to other minerals since a relationship can be obtained between the ability of various minerals to adsorb liposomes of dipalmitoyl phosphatidylcholine (DPPC) and their haemolytic activity.

• Interpretation of the carcinogenicity of amosite asbestos and ferroactinolite on the basis of retained fiber dose and characteristics in vivo. P.M. Cook, L.D. Palekar, D.L. Coffin. 1982;13(3-4):151-8. PubMed · Publisher

  Abstract

  Rats were exposed to amosite asbestos and ferroactinolite fibers by intrapleural inoculation and intratracheal instillation. The ferroactinolite sample was found to be more carcinogenic in both exposures than the amosite sample on the basis of total fiber dose or fiber dose expressed for any size category of hypothetical greatest carcinogenic potency. Quantitative transmission electron microscope analysis of low-temperature ashed whole lung samples collected at different times following intratracheal instillation of fibers demonstrated that concentrations and sizes of fibers retained in rat lungs were greatly influenced by the relative ability of each mineral to undergo longitudinal splitting as a consequence of dissolution in vivo. Ferroactinolite fibers rapidly split to produce many thin fibers so that the number of ferroactinolite fibers retained in the lung 2 years after intratracheal instillation was four times greater than the number of fibers originally instilled. The number of short, thin ferroactinolite fibers retained (10-fold more than amosite) after in vivo splitting best explains the greater lung carcinogenicity of ferroactinolite compared to amosite.

• Pleural plaques in asbestosis: effect of Candida albicans. K.C. Saxena, L. Srivastava, S. Ali, et al. 1982;13(3-4):175-8. PubMed · Publisher

  Abstract

  Effect of chrysotile dust alone or together with Candida albicans administered intratracheally in guinea pigs was studied in the genesis of pleural plaques over a period of 12 months. A significant increase of mucopolysaccharides, phosphorus, calcium and -SH content was detected in pleural fluid of animals treated with chrysotile and Candida albicans together than in those treated with chrysotile or Candida albicans alone. The results suggest that an infection of Candida albicans accentuates the effect of chrysotile by altering the biochemical parameters preceding to the formation of pleural plaques.

• Tumorigenesis by a ferroactinolite mineral. D.L. Coffin, L.D. Palekar, P.M. Cook. 1982;13(3-4):143-9. PubMed · Publisher

  Abstract

  In lifetime exposure of male Fischer-344 rats to ferroactinolite fibers and to UICC amosite asbestos fibers by means of intratracheal and intrapleural treatments, oncogenesis was greater in the lung for the ferroactinolite and in the pleura for the amosite. The lack of correlation between the effects of the two methods of exposure suggests that in this instance intrapleural inoculation was not a good predictor of pulmonary response on the basis of mass dose. Another feature of the ferroactinolite was that pleural tumors resulted from intratracheal instillations. Conversely, lung tumors or tumorlike lesions were also induced by intrapleural inoculations of ferroactinolite. These facts suggest a greater in vivo transport for the ferroactinolite than for the amosite. Since there are far fewer mineral fibers per mass unit in the ferroactinolite the tumor yield per unit of mineral fibers was strikingly greater by both routes of administration for ferroactinolite than for amosite.

• An assessment of the fibrogenic potential of two refractory fibres by intraperitoneal injection in rats. G.H. Pigott, J. Ishmael. 1981;8(3):153-63. PubMed · Publisher

  Abstract

  Two commercially available grades of the refractory fibre SAFFIL were administered to rats by intraperitoneal injection and the tissue reaction was compared. Although the fibres differed considerably in surface properties and porosity the tissue reactions were identical and consisted of a mild chronic inflammatory response with a small amount of collagen present. The reaction was quite distinct from the marked fibrosis induced by chrysotile asbestos. As the reaction to all fibres tested had stabilised after 6 months, a longer observation period is unnecessary.

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