Toxicology in Vitro

Our medical research library holds 23 studies published in Toxicology in Vitro (1987–2021). 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. 23 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: Pergamon Press
• Published: 1987 to the present, England
• Language: English
• ISSN: 0887-2333 (print), 1879-3177 (electronic)
• Its record in the NLM Catalog

2020s

• Osteopontin mRNA expression by rat mesothelial cells exposed to multi-walled carbon nanotubes as a potential biomarker of chronic neoplastic transformation in vitro. S. Sridharan, A. Taylor-Just, J.C. Bonner. 2021;73:105126. PubMed · Publisher · Free full text

  Abstract

  Mesothelioma is a cancer of the lung pleura primarily associated with inhalation of asbestos fibers. Multi-walled carbon nanotubes (MWCNTs) are engineered nanomaterials that pose a potential risk for mesothelioma due to properties that are similar to asbestos. Inhaled MWCNTs migrate to the pleura in rodents and some types cause mesothelioma. Like asbestos, there is a diversity of MWCNT types. We investigated the neoplastic potential of tangled (tMWCNT) versus rigid (rMWCNT) after chronic exposure using serial passages of rat mesothelial cells in vitro. Normal rat mesothelial (NRM2) cells were exposed to tMWCNTs or rMWCNTs for 45 weeks over 85 passages to determine if exposure resulted in transformation to a neoplastic phenotype. Rat mesothelioma (ME1) cells were used as a positive control. Osteopontin (OPN) mRNA was assayed as a biomarker of transformation by real time quantitative polymerase chain reaction (qPCR) and transformation was determined by a cell invasion assay. Exposure to rMWCNTs, but not tMWCNTs, resulted in transformation of NRM2 cells into an invasive phenotype that was similar to ME1 cells. Moreover, exposure of NRM2 cells to rMWCNTs increased OPN mRNA that correlated with cellular transformation. These data suggest that OPN is a potential biomarker that should be further investigated to screen the carcinogenicity of MWCNTs in vitro.

  Copyright © 2021 Elsevier Ltd. All rights reserved.

2010s

• Multi-walled carbon nanotubes induce stronger migration of inflammatory cells in vitro than asbestos or granular particles but a similar pattern of inflammatory mediators. G.A. Westphal, N. Rosenkranz, A. Brik, et al. 2019;58:215-223. PubMed · Publisher

  Abstract

  Biopersistent pro-inflammatory fibers are suspected human carcinogens. Cytotoxicity and transcription of pro- and anti-inflammatory mediators of different fibers were investigated in functional relationship to chemotaxis in vitro as a model for fiber-induced inflammation of the lung. We challenged NR8383 rat macrophages with multi-walled carbon nanotubes (MWCNT) and various asbestos fibers. The resulting cell supernatants were than studied using the Particle-induced Cell Migration Assay (PICMA) and cytotoxicity was determined using the LDH test. Expression of inflammatory mediators was analyzed with qPCR and verified by ELISA. Chrysotile A and the rigid, needle-shaped NM-401 caused the strongest cytotoxic effects and the largest number of migrated cells. In contrast, the MWCNT NM-400, NM-402, and NM403 were apparently non-cytotoxic but induced pronounced cell migration showing a very steep dose response. However, the strength of cell migration and cytotoxicity of the asbestos fibers were correlated. The expression profile of inflammatory mediators was comparable, although cytotoxicity of the MWCNT NM-401 and NM-403 differed strongly. Induction of the corresponding proteins was confirmed for CCL2, CCL3, CXCL1, CXCL3, IL1RA (IL1RN), CSF1, GDF15 and TNFa. Chrysotile A and NM-401 induced much stronger chemotaxis than the non-fibrous particles reported in our previous study. Cytotoxic and chemotactic effects correspond to the induction of inflammatory mediators.

  Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.

• N-acetylcysteine prevents cytotoxic effects induced by man-made mineral fibers in a human bronchial epithelial cell line. M. Zhang, H. Xia, M. Yu, et al. 2018;53:200-207. PubMed · Publisher

  Abstract

  Man-made mineral fibres (MMMFs) such as glass wool (GW), rock wool (RW) and refractory ceramic fibres (RCFs) are widely used as substitutes of asbestos. The present study aimed to investigate the cytotoxic effects on human bronchial epithelial cells (BEAS-2B) exposed to GW1, RW1 and RCF2, considering their properties similar to that of asbestos. We assessed cell viability; cell morphological changes; apoptotic rate; DNA damage; reactive oxygen species (ROS) generation; activities of caspase-3, caspase-8 and caspase-9; and expression levels of FasL, phosphorylated p38, and total p38 MAPK proteins. N-acetyl-l-cysteine (NAC) was used as an ROS scavenger. We observed that MMMFs, especially RCF2, evidently changed cellular morphology, promoted DNA damage, and induced apoptosis. In addition, the cytotoxicities of MMMFs were dependent on ROS generation, and NAC could decrease their toxicity. Furthermore, our results showed that apoptosis induced by MMMFs was mediated by the mitochondrial apoptotic pathway and Fas death receptor pathway. Moreover, the p38 MAPK signalling pathway was also involved in the cytotoxicities of MMMFs. NAC exerts a protective effect against apoptosis and DNA damage induced by GW1, RW1 and RCF2. This study provides important implications for understanding the potential toxic effects of GW1, RW1 and RCF2 exposure; it also indicates that NAC may prevent respiratory diseases induced by exposure to MMMFs.

  Copyright © 2018. Published by Elsevier Ltd.

• Reduced cell viability and apoptosis induction in human thyroid carcinoma and mesothelioma cells exposed to cidofovir. S. Catalani, F. Palma, S. Battistelli, et al. 2017;41:49-55. PubMed · Publisher

  Abstract

  Besides its well-recognized antiviral activity, Cidofovir (CDV) has been shown to exert anticancer properties both within in vitro and in vivo models. The aim of this study was to evaluate the effects of CDV on still unexplored cultured cancer cells from human mesothelioma as well as breast, colon, liver, lung, prostate, and thyroid carcinomas. Overall, a dose- and time-dependent inhibition of cell viability was observed after CDV exposure. To clarify the mechanisms underlying CDV action, apoptotic cell death was investigated in two infected cell lines [Ist-Mes1 and Ist-Mes2 mesothelioma cells (SV40+)] and in two uninfected cell lines (NCI-H2425 mesothelioma cells and FTC-133 thyroid cancer cells), which resulted the most sensitive to CDV treatment. Reduced expression of procaspase-3 and increased expression of PARP p85 fragment were observed in both infected and uninfected mesothelioma cells, indicating apoptosis induction by CDV in a virus-independent manner. Similarly, the increase of the pro-apoptotic proteins p53, cytochrome c and caspase-3, the decrease of the survival protein Bcl-x, and the increment of Bax/Bcl-2 ratio revealed the occurrence of apoptosis in CDV-treated FTC-133. The presence of nuclear DNA fragmentation confirmed apoptotic cell death by CDV. Overall, our findings warrant further investigations to explore the therapeutic potential of CDV for human mesothelioma and follicular thyroid carcinoma.

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

• Cytotoxicity, oxidative stress and genotoxicity induced by glass fibers on human alveolar epithelial cell line A549. V. Rapisarda, C. Loreto, C. Ledda, et al. 2015;29(3):551-7. PubMed · Publisher

  Abstract

  Man-made vitreous fibers have been widely used as insulation material as asbestos substitutes; however their morphology and composition raises concerns. In 1988 the International Agency for Research on Cancer classified fiberglass, rock wool, slag wool, and ceramic fibers as Group 2B, i.e. possibly carcinogenic to humans. In 2002 it reassigned fiberglass, rock and slag wool, and continuous glass filaments to Group 3, not classifiable as carcinogenic to humans. The aim of this study was to verify the cytotoxic and genotoxic effects and oxidative stress production induced by in vitro exposure of human alveolar epithelial cells A549 to glass fibers with a predominant diameter <3 μm (97%) and length >5 μm (93%). A549 cells were incubated with 5, 50, or 100 μg/ml (2.1, 21, and 42 μg/cm(2), respectively) of glass fibers for 72 h. Cytotoxicity and DNA damage were tested by the MTT and the Comet assay, respectively. Oxidative stress was determined by measuring inducible nitric oxide synthase (iNOS) expression by Western blotting, production of nitric oxide (NO) with Griess reagent, and concentration of reactive oxygen species by fluorescent quantitative analysis with 2',7'-dichlorofluorescein-diacetate (DCFH-DA). The results showed that glass fiber exposure significantly reduced cell viability and increased DNA damage and oxidative stress production in a concentration-dependent manner, demonstrating that glass fibers exert cytotoxic and genotoxic effects related to increased oxidative stress on the human alveolar cell line A549.

  Copyright © 2014 Elsevier Ltd. All rights reserved.

• Multi-walled carbon nanotube induced frustrated phagocytosis, cytotoxicity and pro-inflammatory conditions in macrophages are length dependent and greater than that of asbestos. M.S. Boyles, L. Young, D.M. Brown, et al. 2015;29(7):1513-28. PubMed · Publisher

  Abstract

  The potential toxicity of carbon nanotubes (CNTs) has been compared to pathogenic fibres such as asbestos. It is important to test this hypothesis to ascertain safe methods for CNT production, handling and disposal. In this study aspects reported to contribute to CNT toxicity were assessed: length, aspect ratio, iron content and crystallinity; with responses compared to industrially produced MWCNTs and toxicologically relevant materials such as asbestos. The impacts of these particles on a range of macrophage models in vitro were assessed due to the key role of macrophages in particle clearance and particle/fibre-induced disease. Industrially produced and long MWCNTs were cytotoxic to cells, and were potent in inducing pro-inflammatory and pro-fibrotic immune responses. Short CNTs did not induce any cytotoxicity. Frustrated phagocytosis was most evident in response to long CNTs, as was respiratory burst and reduction in phagocytic ability. Short CNTs, metal content and crystallinity had less or no influence on these endpoints, suggesting that many responses were fibre-length dependent. This study demonstrates that CNTs are potentially pathogenic, as they were routinely found to induce detrimental responses in macrophages greater than those induced by asbestos at the same mass-based dose.

  Copyright © 2015 Elsevier Ltd. All rights reserved.

• In vitro screening of synergistic ascorbate-drug combinations for the treatment of malignant mesothelioma. S. Martinotti, E. Ranzato, B. Burlando. 2011;25(8):1568-74. PubMed · Publisher

  Abstract

  Malignant mesothelioma (MMe) is a lethal tumor arising from the mesothelium of serous cavities as a result of exposure to asbestos. Current clinical standards consist of combined treatments, but an effective therapy has not been established yet and there is an urgent need for new curative approaches. Ascorbate is a nutrient that is also known as a remedy in the treatment of cancer. In the present study, we have tested the cytotoxicity of ascorbate to MMe cells in combination with drugs used in MMe therapy, such as cisplatin, etoposide, gemcitabine, imatinib, paclitaxel, and raltitrexed, as well as with promising antitumor compounds like taurolidine, α-tocopherol succinate, and epigallocatechin-3-gallate (EGCG). Dose-response curves obtained for each compound by applying the neutral red uptake (NRU) assay to MMe cells growing in vitro, allowed to obtain IC50 values for each compound used singularly. Thereafter, NRU data obtained from each ascorbate/drug combination were analyzed through Tallarida's isobolograms at the IC50 level (Tallarida, 2000), revealing synergistic interactions for ascorbate/gemcitabine and ascorbate/EGCG. These results were further confirmed through comparisons between theoretical additivity IC50 and observed IC50 from fixed-ratio dose-response curves, and over a broad range of IC levels, by using Chou and Talalay's combination index (Chou and Talalay, 1984). Synergistic interactions were also shown by examining apoptosis and necrosis rates, using the caspase 3 and lactic dehydrogenase assays, respectively. Hence, data indicate that ascorbate/gemcitabine and ascorbate/EGCG affect synergistically the viability of MMe cells and suggest their possible use in the clinical treatment of this problematic cancer.

  Copyright © 2011 Elsevier Ltd. All rights reserved.

• Biological effects and comparative cytotoxicity of thermal transformed asbestos-containing materials in a human alveolar epithelial cell line. F. Giantomassi, A.F. Gualtieri, L. Santarelli, et al. 2010;24(6):1521-31. PubMed · Publisher

  Abstract

  Asbestos fibres can be transformed into potentially non-hazardous silicates by high-temperature treatment via complete solid-state transformation. A549 cells were exposed to standard concentrations of raw cement asbestos (RCA), chrysotile and cement asbestos subjected to an industrial process at 1200 degrees C (Cry_1200 and KRY.AS, respectively), raw commercial grey cement (GC). Cell growth rate and viability (MTT test) were detected in vitro. RCA and KRY.AS subjected to comprehensive microstructural study by electron microscopy were further in vitro assayed to compare their cytotoxic potential by morphostructural studies, proliferation index (Ki-67 antigen), apoptosis induction (AO/EB staining) assays and detection of intracellular reactive oxygen species (ROS) with the fluorescent DCFA dye. More severe cytotoxic damage was induced by RCA than by KRY.AS after each incubation period. Exposure to KRY.AS and GC resulted in comparable cell growth rates and cytotoxic effects. Cells incubated with RCA showed greater apoptotic induction and ROS production and a lower cell proliferation index than those exposed to KRY.AS. Chrysotile asbestos and RCA subjected to heat treatment underwent complete microstructure transformation. The final product of heat treatment of cement asbestos, KRY.AS, was considerably more inert and had lower cytotoxic potential than the original asbestos material in all in vitro tests.

  Copyright 2010 Elsevier Ltd. All rights reserved.

2000s

• Multinucleation and pro-inflammatory cytokine release promoted by fibrous fluoro-edenite in lung epithelial A549 cells. S. Travaglione, B.M. Bruni, L. Falzano, et al. 2006;20(6):841-50. PubMed · Publisher

  Abstract

  An unusual cluster of malignant mesothelioma was evidenced in Biancavilla, a Sicily village where no inhabitant had been significantly and professionally exposed to asbestos. Mineralogical and environmental studies led to the identification of a new prismatic amphibole, named fluoro-edenite. We previously reported, by using the human lung epithelial A549 cells, that prismatic fluoro-edenite was unable to induce changes that could be somehow related to cellular transformation, and this was in accordance with studies carried out in vivo. More recently, a fibrous amphibole with a composition very similar to that of prismatic fluoro-edenite, was identified in Biancavilla. This fibrous fluoro-edenite was shown to induce mesothelioma in rats. In keeping with this effect in vivo, in the present work we observed multinucleation and spreading, common features of transformed cells, as well as pro-inflammatory cytokine release in A549 cells. Such cell changes occurred without interfering with the passage of the resulting multinucleated cells through the cell cycle and without condemning cells to death. Hence, in lung epithelial cells, fibrous fluoro-edenite behaved similarly to the unrelated asbestos type crocidolite, whose connection with severe inflammation and cancer of the lung is renowned.

• Effects of the new-identified amphibole fluoro-edenite in lung epithelial cells. S. Travaglione, B. Bruni, L. Falzano, et al. 2003;17(5-6):547-52. PubMed · Publisher

  Abstract

  An epidemiological survey on mortality for malignant pleural neoplasm in Italy evidenced a number of patients in Biancavilla, a village located in a volcanic area of eastern Sicily, none of which had been significantly exposed to asbestos during their professional lives. Environmental studies suggested the involvement of the material derived from stone quarries in the disease onset. A detailed crystal-chemical analysis of amphiboles contained in this material allowed the discovery and the identification of a new fiber that was named fluoro-edenite. In order to define the mode of action of fluoro-edenite at a subcellular level, we have conducted a study by using A549 cells, a tumor-cell line from a human lung carcinoma with properties of alveolar epithelial cells. The results obtained showed a remarkable tropism of A549 cells toward fluoro-edenite fibers. In fact, these epithelial cells contacted the fibers via the extension of membrane ruffles and filopodia that allowed the capture and most probably the internalization of material into the cytoplasm. Moreover, fluoro-edenite interfered with epithelial cell physiology, by reducing the proliferation rate without perturbing the cell cycle and increasing the release of the proinflammatory cytokine IL-6, one of the main mediators of asbestos-induced pathophysiological response.

• Release of TNFalpha in response to SiC fibres: differential effects in rodent and human primary macrophages, and in macrophage-like cell lines. C.E. Fisher, A.G. Rossi, J. Shaw, et al. 2000;14(1):25-31. PubMed · Publisher

  Abstract

  Asbestos has been implicated in the pathogenesis of several lung diseases, but its mechanism of action is not fully understood. However, asbestos-induced oxidative stress and production of inflammatory cytokines may play a significant role. TNFalpha is an inflammatory cytokine which has a central role in inflammation and fibrosis due to its ability to stimulate fibroblasts and collagen deposition. In this study, a panel of fibres designated either pathogenic or non-pathogenic in recent animal studies, were utilized. The amount of TNFalpha released after a 16-hour exposure to the panel of fibres was compared in four different cell types; two primary macrophage cell types and two cell lines. TNFalpha release by cells exposed to the panel did not equate to pathogenicity, although the most pathogenic fibre caused three out of the four cell types tested, to produce the greatest amount of TNFalpha. Primary rat cells and primary human cells behaved in a similar manner as regards to TNFalpha production; the cell lines behaved quite differently to their primary counterparts with regards to TNFalpha production in this study.

1990s

• Biological effects of contaminated silicon carbide particles from a workstation in a plant producing abrasives. M. Governa, M. Valentino, M. Amati, et al. 1997;11(3):201-7. PubMed · Publisher

  Abstract

  A sample of silicon carbide dust taken in the field from a plant producing abrasives was studied in vitro. The SiC particles (part unmilled and part milled) were able to disturb the structure of erythrocyte membranes and to lead to blood red-cell lysis; they also either interfered with complement and activated the alternate pathway, or interacted with biological media and polymorphonuclear leucocyte membranes, thus eliciting reactive oxygen species production. These in vitro properties were detected both in original large particles and unmilled particles, over 40% of which were of respirable size. The ability of these SiC particles to produce complement activation in vitro lends support to the previous hypothesis, that the radiographic opacities found in two workers employed in the same area of the plant from which the dust tested was taken are due to a reaction by pulmonary interstitial structures to SiC particle inhalation. It is speculated that SiC particles could act like asbestos, the ability of which to activate complement through the alternate pathway is considered to be one of the mechanisms by which the initial asbestotic lesions and subsequent fibrotic inflammatory infiltrates are generated in the lung.

• Formation of hydroxyl radicals and toxicity of tungsten oxide fibres. P. Leanderson, W. Sahle. 1995;9(2):175-83. PubMed · Publisher

  Abstract

  Occupational exposure to hard metal dust may cause interstitial pulmonary fibrosis and asthma. The cause of asthma is well established, whereas the cause of lung fibrosis is still under debate. Recently, slightly reduced airborne tunsten oxide fibres, the role of which in hard metal pneumoconiosis has never been accounted for, were detected in an air sample from a hard metal production plant. In this study, the capacity to generate hydroxyl radicals, toxicity to cultured human lung cells and haemolytic activity of tungsten oxide fibres were compared with crocidolite asbestos fibres. The results show (a) that tungsten oxide fibres can generate hydroxyl radicals, and (b) that tunsten oxide fibres were more cytotoxic to human lung cells than was crocidolite, but (c) that the haemolytic activity of tungsten oxide fibres was lower than for crocidolite.

• A simple fluorescence method for the study of the internalization of particles in cultured cells: Application to asbestos and glass fibres. S.O. Mikalsen, K.R. Modalsli. 1994;8(2):243-50. PubMed · Publisher

  Abstract

  A model for the study of internalization of particles in mammalian cells was applied to asbestos and glass fibres. Briefly, a fluorescent fluid-phase endocytic marker, Lucifer Yellow CH (LY), was allowed to be incorporated into the lysosomal compartment of Syrian hamster embryo cells. Mineral fibres that were internalized by the cells subsequently became 'fluorescent', presumably when the fibre-containing endosome fused with the LY-containing lysosomes. This method was compared with differential interference contrast (DIC) optics. Approximately three times as many of the cell-associated fibres were determined to be internalized by the fluorescence method compared with DIC optics. Both fine and coarse glass fibres were internalized as effectively as asbestos fibres. The relative frequency of internalized (i.e. fluorescent) fibres increased until 4 hr after exposure compared with the total number of cell-associated fibres. The frequency of internalized fibres compared with the number of cell-associated fibres was constant over the range of fibre levels studied. A surface modification (octadecyldimethylchlorosilane-derivatization) of amosite fibres that decreased the carcinogenicity of the fibres, decreased slightly the number of internalized fibres relative to the number of cell-associated fibres, but this was not statistically significant. Cytoskeleton-interfering agents significantly decreased the relative number of internalized fibres.

• In vitro response of rat pleural mesothelial cells to talc samples in genotoxicity assays (sister chromatid exchanges and DNA repair). S. Endo-Capron, A. Renier, X. Janson, et al. 1993;7(1):7-14. PubMed · Publisher

  Abstract

  The genotoxicity of three samples of talc has been determined using in vitro cell systems previously developed for testing asbestos fibres. The talc samples used consisted of particles of respirable size in order to test the effect of particles likely to be deposited in the lung. Genotoxicity was tested in cultures of rat pleural mesothelial cells (RPMC) using genotoxicity assays for unscheduled DNA synthesis (UDS) and sister chromatid exchanges (SCEs). The effects were compared with those obtained with negative controls (attapulgite and anatase) and positive controls (chrysotile and crocidolite asbestos). In contrast to asbestos, none of the talc samples, nor the negative controls, induced enhancement of UDS or SCEs in treated cultures in comparison with the untreated cultures.

• Cytotoxicity and anaphase aberrations induced by mineral fibres in cultured human mesothelial cells. K. Pelin, K. Husgafvel-Pursiainen, M. Vallas, et al. 1992;6(5):445-50. PubMed · Publisher

  Abstract

  The in vitro cytotoxicity of two amphibole asbestos fibres (amosite and crocidolite), a serpentine asbestos (chrysotile), a non-asbestos fibrous aluminosilicate (erionite) and three different size fractions of both glass wool and rock wool fibres were assessed in an immortalized human mesothelial cell line, MeT-5A. We also investigated the induction of anaphase aberrations by the asbestos and erionite fibres. On a comparison by weight, amosite, crocidolite and chrysotile showed similar toxic effects (2-5 mug/cm(2) of the asbestos fibres caused 50% of cells to die) but erionite was less toxic (10-20 mug/cm(2) was needed for the same effect). When the doses were converted to the number of fibres/cm(2) of culture area, amosite was shown to be about 10 times more cytotoxic than crocidolite and chrysotile. Crocidolite and chrysotile showed similar cytotoxicity, and erionite was again less toxic. Of the man-made mineral fibres (MMMF), thin glass wool was the most cytotoxic (50% cell death for 10-20 mug/cm(2)), followed (in descending order of cytotoxicity) by thin rock wool, coarse glass wool, milled rock wool, milled glass wool and coarse rock wool. In general, the MMMF samples were less toxic than the asbestos and erionite samples. All three asbestos types studied induced anaphase aberrations at high (near toxic) doses. A statistically significant increase in the number of aberrant anaphases was observed in cultures treated with crocidolite or chrysotile at 5 mug/cm(2). The increase was caused by lagging chromatids, chromosomes or chromosome fragments.

• Cytotoxicity of refractory ceramic fibres to Chinese hamster ovary cells in culture. G.A. Hart, M.M. Newman, W.B. Bunn, et al. 1992;6(4):317-26. PubMed · Publisher

  Abstract

  The toxicity/oncogenicity of refractory ceramic fibres have been tested in chronic inhalation studies in rodents. Because these studies are time consuming and expensive, there is a need to develop and validate short-term models to screen fibres for their toxicological potential. In the present study, the toxic effects of four different compositions of refractory ceramic fibres were determined using Chinese hamster ovary cells grown in culture. These refractory ceramic fibres were the same size-selected fibres that had been used in animal inhalation studies, thus facilitating a direct comparison of findings in the two systems. Chinese hamster ovary cells were treated with refractory ceramic fibres 24 hr after seeding into 60-mm culture dishes in Ham's F12 medium with 10% serum. Inhibition of cell proliferation and colony formation were determined after 3-5 days of fibre exposure. Crocidolite and chrysotile asbestos were used as positive controls. Concentration-dependent inhibition of both cell proliferation and colony formation was observed after treatment with refractory ceramic fibres. The LC(50) for the different refractory ceramic fibres ranged from 10 to 30 mug/cm(2). The LC(50)s for crocidolite and chrysotile were 5 mug/cm(2) and 1 mug/cm(2), respectively. To assess the genotoxic potential of these fibres, fibre-exposed Chinese hamster ovary cell cultures were stained with acridine orange and scored for the incidence of micronuclei and other nuclear abnormalities. The incidence of nuclear abnormalities for refractory ceramic fibres at 20 mug/cm(2) ranged from 20 to 40%. Toxic endpoints of the in vitro studies were compared with those of the chronic animal inhalation studies. The latter included induction of lung fibrosis and pleural and airway tumours. A correlation was observed between the in vitro and in vivo toxicological potencies of the respective four refractory ceramic fibres: the fibres that were most toxic in vitro were also the most toxic in the chronic animal inhalation studies. A direct relationship was also observed, both in vitro and in vivo, between average fibre length and the severity of the toxic effect.

• Differential effects of mineral dusts on the in vitro activation of alveolar macrophage eicosanoid and cytokine release. K.E. Driscoll, J.M. Higgins, M.J. Leytart, et al. 1990;4(4-5):284-8. PubMed · Publisher

  Abstract

  We investigated the in vitro effects of the pneumotoxic agents, silica and asbestos, and the relatively innocuous materials, aluminium oxide (Al(2)O(3)) and titanium dioxide (TiO(2)), on alveolar macrophages (AM) using endpoints reflecting the cytotoxic and AM activating properties of the dusts. Rat AM were exposed in vitro (24 hr) to 10-1000 mug/ml of the dusts. AM conditioned media was analysed for lactate dehydrogenase (cytotoxicity), beta-glucuronidase (lysosomal enzyme), leukotriene B4 (LTB4), prostaglandin E(2) (PGE(2)), tumour necrosis factor alpha (TNF) and interleukin-1 (IL-1). AM LTB4 and TNF release were increased by silica and asbestos but not by Al(2)O(3) or TiO(2). IL-1 release was not affected, and changes in PGE(2) release were minimal, after dust exposure. Cytotoxic activity was not consistently associated with LTB4, TNF or beta-glucuronidase release. The ability of silica and asbestos, but not Al(2)O(3) and TiO(2), to activate AM to release the pro-inflammatory mediators, LTB4 and TNF, may be responsible, at least in part, for the greater inflammation and pneumotoxicity associated with silica and asbestos exposure. These findings suggest that assessment of AM mediator secretion in vitro can provide information to understand better the potential of a material to cause respiratory toxicity.

1980s

• Differential cytotoxic, growth-inhibiting and lipid-peroxidative activities of four different asbestos fibres in vitro. M. Wydler, P. Maier, G. Zbinden. 1988;2(4):297-302. PubMed · Publisher

  Abstract

  An attempt was made to characterize the carcinogenic hazard of asbestos fibres by using a set of in vitro screening tests. The fibres tested were the serpentine chrysotile and the three amphiboles anthophyllite, crocidolite and amosite. Their cytotoxic and cytostatic activities in rat primary fibroblast-like cells were assessed along with their effects on enzymic lipid peroxidation by liver homogenates. After 24 hr exposure of fibroblast-like cells to 2.1 μg fibres/cm(2), chrysotile induced the highest cytotoxicity, followed by crocidolite, anthophyllite and amosite. Similarly, after 48 hr exposure, chrysotile had the most growth inhibiting effect, followed by crocidolite, anthophyllite and amosite. Enzymic lipid peroxidation, as measured by pentane or malondialdehyde production, was determined at ambient (21% O(2)) or tissue (4% O(2)) oxygen tension in incubation mixtures containing rat-liver homogenate and asbestos fibres. At 4% O(2), only the two iron-containing fibres, crocidolite and amosite, stimulated lipid peroxidation. The results suggest that the cytotoxic activity is influenced by the surface charge, structure and dimensions of the fibres, and that cell-growth inhibition is associated with surface charge, structure and the Mg(2+) content of the fibres. Effects on enzymic lipid peroxidation appear to be associated with the structure and iron content of the tested fibres. When these results are considered along with epidemiological data, it seems that the carcinogenic potency of asbestos fibres is characterized by an ability to induce high levels of enzymic lipid peroxidation along with moderate cytotoxic and growth inhibiting activities.

• Lipid peroxidation in rat alveolar macrophages exposed to chrysotile fibres. C. Kandaswami, G. Morin, P. Sirois. 1988;2(2):117-20. PubMed · Publisher

  Abstract

  Lipid peroxidation induced in rat alveolar macrophages incubated with chrysotile asbestos fibres was assessed by measuring the production of malondialdehyde. The rapid onset of lipid peroxidation in macrophages caused by these fibres suggests the process occurs during the attachment of the fibres on the macrophage membranes or during the very early steps of phagocytosis. Metal-ion chelators such as diethylenetriaminepentaacetic acid, 1,10-phenantroline and ethylenediaminetetraacetic acid, as well as iron-complexing agents such as bathophenantrolinesulphonate and desferrioxamine were found to substantially inhibit chrysotile-induced lipid peroxidation. These results suggest a possible role for the iron present in the asbestos structure in catalysing lipid peroxidation in alveolar macrophages. These observations also indicate that asbestos-catalysed lipid peroxidation may be one of the factors involved in asbestos-induced cell damage.

• Effects of fibrous and non-fibrous dusts on Chinese hamster V79 cells: Cytotoxicity or cytostasis?. S.O. Lock, J. Rockley, M. Chamberlain, et al. 1987;1(2):71-6. PubMed · Publisher

  Abstract

  Chinese hamster V79 (CHV79) cells cultured in vitro were used to study the cytopathic effects of seven mineral dusts (four of which were fibrous). Lactate dehydrogenase release and the incorporation of [(3)H]thymidine into DNA were used to study toxic and static interactions, respectively. Crystalline silica dusts had a toxic effect on the cells. In contrast, Canadian chrysotile (chrysotile 'B') was relatively non-toxic but principally had a static effect upon CHV79 cells. Amphibole asbestos dusts demonstrated mainly static properties, albeit less marked than with chrysotile, and some toxic properties. Titanium dioxide was neither toxic nor static in vitro.

  Copyright © 1987. Published by Elsevier Ltd.

• Mechanisms of cytotoxicity of asbestos fibres in rat tracheal epithelial cells in culture. T.W. Hesterberg, D.G. Ririe, J.C. Barrett, et al. 1987;1(2):59-65. PubMed · Publisher

  Abstract

  Little is known about the mechanism(s) of asbestos toxicity, especially in respiratory epithelium. Studies were carried out to elucidate some important aspects of the cytotoxic effects of asbestos, using a tracheal epithelial cell line in culture. Chrysotile and crocidolite asbestos with similar aspect ratios were used. Both induced in 2C5 cells a concentration-dependent inhibition of colony-forming ability, a measure of proliferative capacity. In this respect, chrysotile (LC(50), 0.95 mug/cm(2)) was about six times more toxic than crocidolite (LC(50), 5.8 mug/cm(2)). Both types of asbestos caused only minor changes in membrane permeability, measured by trypan blue exclusion and by [(75)Se]selenomethionine release, even at concentrations of asbestos that caused > 90% inhibition in colony formation. Thus membrane damage was only a minor component of the toxicity produced by the fibres. Chrysotile was phagocytized much more readily than crocidolite and produced an approximately threefold greater increase in binucleated cells and micronuclei than crocidolite, suggesting that phagocytosis was the rate-limiting step in fibre toxicity. Our studies suggest a potentially important pathway of fibre toxicity involving binding, phagocytosis, nuclear damage, disruption of mitosis, inhibition of proliferation and/or cell death. In this process, the fibre aspect ratio is not the only determinant of fibre toxicity, since chrysotile and crocidolite fibres of similar length and diameter exhibit very different degrees of toxicity. It appears that other fibre characteristics, such as fibre surface charge, are of equal importance.

  Copyright © 1987. Published by Elsevier Ltd.

• Role of iron-mediated free-radical generation in asbestos-induced cytotoxicity. R.C. Brown, A. Poole, C.J. Turver, et al. 1987;1(2):67-70. PubMed · Publisher

  Abstract

  While the in vitro toxicity of mineral fibres is largely determined by the number of long thin fibres present, there are a number of contradictory reports in the literature as to whether the production of oxygen free radicals is also involved and whether the addition of antioxidants or radical scavengers can ameliorate or prevent asbestos-induced cytotoxicity. We report here that crocidolite and other types of amphibole asbestos are less toxic to two cell lines in low oxygen concentrations. The treatment of these fibres with the iron chelator Desferral also reduced the toxicity of the amphiboles. The activity of chrysotile asbestos was not affected by oxygen tension and the cytotoxic effects of Desferral and chrysotile were additive.

  Copyright © 1987. Published by Elsevier Ltd.

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