Toxicology

Our medical research library holds 22 studies published in Toxicology (1981–2025). 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. 22 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: Elsevier
• Published: 1973 to the present, Ireland
• Language: English
• ISSN: 0300-483X (print), 1879-3185 (electronic)
• Its record in the NLM Catalog

2020s

• Toxicity of size separated chrysotile fibres: The relevance of the macrophage-endothelial axis crosstalk. S. Mirata, V. Almonti, M. Passalacqua, et al. 2025;511:154032. PubMed · Publisher

  Abstract

  Asbestos minerals have been widely exploited due to their physical-chemical properties, and chrysotile asbestos has accounted for about 95% of all asbestos commercially employed worldwide. The exposure to chrysotile, classified like other five amphibole asbestos species as carcinogenic to humans, represents a serious occupational and environmental hazard. Nevertheless, this mineral is still largely employed in about 65% of the countries worldwide, which still allow its "safe use". The complex mechanisms through which the mineral fibres induce toxicity are not yet completely understood. In this regard, the morphometric parameters of asbestos fibres (e.g., length, width, aspect ratio) are known for their fundamental role in determining the degree of pathogenicity. In this context, the potential toxicity of short chrysotile fibres remains widely debated due to the contradictory results from countless studies. Thus, the present study investigated the different toxicity mechanisms of two representative batches of short (length ≤5 µm) and long (length >5 µm) chrysotile fibres obtained by cryogenic milling. The fibre doses were based upon equal mass and size, since due to chrysotile ability to form bundles, it was not possible to calculate the number of fibers applied per cell. The cytotoxic, genotoxic, and pro-inflammatory potential of the two size-separated chrysotile fractions was investigated on human THP-1-derived macrophages and HECV endothelial cells, both separately and in a co-culture setup, mimicking the alveolar pro-inflammatory microenvironment, in time course experiments up to 1 week. Both chrysotile fractions displayed cytotoxic, genotoxic, and pro-inflammatory effects, with results comparable to the well-known damaging effects of crocidolite asbestos, or higher, as in the case of the longer chrysotile fraction. Furthermore, in presence of HECV, fibre-treated macrophages showed prolonged inflammation, indicating an interesting crosstalk between these cells able to sustain a low-grade chronic inflammation in the lung. In conclusion, these results help to shed light on some important open questions on the mechanisms of toxicity of chrysotile asbestos fibres.

  Copyright © 2024 Elsevier B.V. All rights reserved.

• Acute cytotoxicity of mineral fibres observed by time-lapse video microscopy. D. Di Giuseppe, S. Scarfì, A. Alessandrini, et al. 2022;466:153081. PubMed · Publisher

  Abstract

  Inhalation of mineral fibres is associated with the onset of an inflammatory activity in the lungs and the pleura responsible for the development of fatal malignancies. It is known that cell damage is a necessary step for triggering the inflammatory response. However, the mechanisms by which mineral fibres exert cytotoxic activity are not fully understood. In this work, the kinetics of the early cytotoxicity mechanisms of three mineral fibres (i.e., chrysotile, crocidolite and fibrous erionite) classified as carcinogenic by the International Agency for Research on Cancer, was determined for the first time in a comparative manner using time-lapse video microscopy coupled with in vitro assays. All tests were performed using the THP-1 cell line, differentiated into M0 macrophages (M0-THP-1) and exposed for short times (8 h) to 25 μg/mL aliquots of chrysotile, crocidolite and fibrous erionite. The toxic action of fibrous erionite on M0-THP-1 cells is manifested since the early steps (2 h) of the experiment while the cytotoxicity of crocidolite and chrysotile gradually increases during the time span of the experiment. Chrysotile and crocidolite prompt cell death mainly via apoptosis, while erionite exposure is also probably associated to a necrotic-like effect. The potential mechanisms underlying these different toxicity behaviours are discussed in the light of the different morphological, and chemical-physical properties of the three fibres.

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

• In vitro toxicity of fibrous glaucophane. A.F. Gualtieri, A. Zoboli, M. Filaferro, et al. 2021;454:152743. PubMed · Publisher

  Abstract

  The health hazard represented by the exposure to asbestos may also concern other minerals with asbestos-like crystal habit. One of these potentially hazardous minerals is fibrous glaucophane. Fibrous glaucophane is a major component of blueschist rocks of California (USA) currently mined for construction purposes. Dust generated by the excavation activities might potentially expose workers and the general public. The aim of this study was to determine whether fibrous glaucophane induces in vitro toxicity effects on lung cells by assessing the biological responses of cultured human pleural mesothelial cells (Met-5A) and THP-1 derived macrophages exposed for 24 h and 48 h to glaucophane fibres. Crocidolite asbestos was tested for comparison. The experimental configuration of the in vitro tests included a cell culture without fibres (i.e., control), cell cultures treated with 50 μg/mL (i.e., 15.6 μg/cm2) of crocidolite fibres and 25-50-100 μg/mL (i.e., 7.8-15.6-31.2 μg/cm2) of glaucophane fibres. Results showed that fibrous glaucophane may induce a decrease in cell viability and an increase in extra-cellular lactate dehydrogenase release in the tested cell cultures in a concentration dependent mode. Moreover, it was found that fibrous glaucophane has a potency to cause oxidative stress. The biological reactivity of fibrous glaucophane confirms that it is a toxic agent and, although it apparently induces lower toxic effects compared to crocidolite, exposure to this fibre may be responsible for the development of lung diseases in exposed unprotected workers and population.

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

• Increased production of matrix metalloproteinase-7 (MMP-7) by asbestos exposure enhances tissue migration of human regulatory T-like cells. S. Lee, S. Yamamoto, B. Srinivas, et al. 2021;452:152717. PubMed · Publisher

  Abstract

  The effects of asbestos on immunocompetent cells have been investigated. In particular, attention was paid to regulatory T cell function, which was observed using the HTLV-1 immortalized human polyclonal T cell line MT-2. Exposure to asbestos (approximately more than 25 μg/mL for 1-3 day) induced apoptosis, and we observed an increase in regulatory T cell function and acceleration of the cell cycle with continuous exposure to low concentrations of asbestos (5-10 μg/mL for more than eight months). Furthermore, cDNA microarray analysis in this study revealed that expression of matrix metalloproteinase-7 (MMP-7) was markedly higher in exposed sublines compared to original MT-2 cells. It was determined that MMP-7 had no effect on Treg function, as determined by examination of sublines and by addition of recombinant MMP-7 and neutralizing antibodies or inhibitors of MMP-7. However, when examining melting of the extracellular matrix (an MMP-7-mediated event) or the extent to which the MT-2 parent strain or long-term exposed subline cells pass through a fibronectin-coated filter, more filter passes were observed for the subline. These results suggest that the effect of asbestos fibers on Treg cells results in excessive migration of the tumor microenvironment through hypersecretion of MMP-7 together with an increase in suppressive function and enhancement of cell cycle progression. Therefore, one possible way to prevent the development of asbestos-induced cancer is to reduce the function (including MMP-7 production) or amount of Treg cells by physiologically active substances or food ingredients. Alternatively, it may be possible to invoke immune checkpoint treatments when carcinogenesis occurs.

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

2010s

• Enhancement of regulatory T cell-like suppressive function in MT-2 by long-term and low-dose exposure to asbestos. C. Ying, M. Maeda, Y. Nishimura, et al. 2015;338:86-94. PubMed · Publisher

  Abstract

  Asbestos exposure causes lung fibrosis and various malignant tumors such as lung cancer and malignant mesothelioma. The effects of asbestos on immune cells have not been thoroughly investigated, although our previous reports showed that asbestos exposure reduced anti-tumor immunity. The effects of continuous exposure of regulatory T cells (Treg) to asbestos were examined using the HTLV-1 immortalized human T cell line MT-2, which possesses a suppressive function and expresses the Treg marker protein, Foxp3. Sublines were generated by the continuous exposure to low doses of asbestos fibers for more than one year. The sublines exposed to asbestos showed enhanced suppressive Treg function via cell-cell contact, and increased production of soluble factors such as IL-10 and transforming growth factor (TGF)-β1. These results also indicated that asbestos exposure induced the reduction of anti-tumor immunity, and efforts to develop substances to reverse this reduction may be helpful in preventing the occurrence of asbestos-induced tumors.

  Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

• Mixtures research at NIEHS: an evolving program. C.V. Rider, D.J. Carlin, M.J. Devito, et al. 2013;313(2-3):94-102. PubMed · Publisher · Free full text

  Abstract

  The National Institute of Environmental Health Sciences (NIEHS) has a rich history in evaluating the toxicity of mixtures. The types of mixtures assessed by the Division of the National Toxicology Program (DNTP) and the extramural community (through the Division of Extramural Research and Training, DERT) have included a broad range of chemicals and toxicants, with each study having a unique set of questions and design considerations. Some examples of the types of mixtures studied include: groundwater contaminants, pesticides/fertilizers, dioxin-like chemicals (assessing the toxic equivalency approach), drug combinations, air pollution, metals, polycyclic aromatic hydrocarbons, technical mixtures (e.g., pentachlorophenol, flame retardants), and mixed entities (e.g., herbals, asbestos). These endeavors have provided excellent data on the toxicity of specific mixtures and have been informative to the human health risk assessment process in general (e.g., providing data on low dose exposures to environmental chemicals). However, the mixtures research effort at NIEHS, to date, has been driven by test article nominations to the DNTP or by investigator-initiated research through DERT. Recently, the NIEHS has embarked upon an effort to coordinate mixtures research across both intramural and extramural divisions in order to maximize mixtures research results. A path forward for NIEHS mixtures research will be based on feedback from a Request for Information (RFI) designed to gather up-to-date views on the knowledge gaps and roadblocks to evaluating mixtures and performing cumulative risk assessment, and a workshop organized to bring together mixtures experts from risk assessment, exposure science, biology, epidemiology, and statistics. The future of mixtures research at NIEHS will include projects from nominations to DNTP, studies by extramural investigators, and collaborations across government agencies that address high-priority questions in the field of mixtures research.

  Published by Elsevier Ireland Ltd.

• Angiogenic effect induced by mineral fibres. D. Carbonari, A. Campopiano, D. Ramires, et al. 2011;288(1-3):34-42. PubMed · Publisher

  Abstract

  Due to the toxic effect of asbestos, other materials with similar chemical-physical characteristics have been introduced to substitute it. We evaluate the angiogenic effect of certain asbestos substitute fibres such as glass fibres (GFs), ceramic fibres (CFs) and wollastonite fibres (WFs) and then compare angiogenic responses to those induced by crocidolite asbestos fibres (AFs). An in vitro model using human endothelial cells in small islands within a culture matrix of fibroblasts (Angio-Kit) was used to evaluate vessel formation. The release of IL-6, sIL-R6, IL-8, VEGF-A and their soluble receptors, sVEGFR-1, sVEGFR-2, was determined in the conditioning medium of Angio-Kit system after fibre treatment. ROS formation and cell viability were evaluated in cultured endothelial cells (HUVEC). To evaluate the involvement of intracellular mechanisms, EGFR signalling, ROS formation and nuclear factor-κB (NFκB) pathway were then inhibited by incubating HUVEC cells with AG1478, NAC and PDTC respectively, and the cytokine and growth factor release was analyzed in the culture medium after 7 days of fibre incubation. Among the mineral fibres tested, WFs markedly induced blood vessel formation which was associated with release of IL-6 and IL-8, VEGF-A and their soluble receptors. ROS production was observed in HUVEC after WFs treatment which was associated with cell cytotoxicity. The EGFR-induced ERK phosphorylation and ROS-mediated NFκB activation were involved in the cytokine and angiogenic factor release. However, only the EGFR activation was able to induce angiogenesis. The WFs are potential angiogenic agents that can induce regenerative cytokine and angiogenic factor production resulting in the formation of new blood vessels.

  Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

• Carbon nanotubes induce inflammation but decrease the production of reactive oxygen species in lung. D. Crouzier, S. Follot, E. Gentilhomme, et al. 2010;272(1-3):39-45. PubMed · Publisher

  Abstract

  With the rapid spread of carbon nanotubes (CNTs) applications, the respiratory toxicity of these compounds has attracted the attention of many scientists. Several studies have reported that after lung administration, CNTs could induce granuloma, fibrosis, or inflammation. By comparison with the mechanisms involved with other toxic particles such as asbestos, this effect could be attributed to an increase of oxidative stress. The aim of the present work was to test this hypothesis in vivo. Mice were intranasally instilled with 1.5mg/kg of double walled carbon nanotubes (DWCNTs). Six, 24, or 48h after administration, inflammation and localisation of DWCNTs in lungs were microscopically observed. Local oxidative perturbations were investigated using ESR spin trapping experiments, and systemic inflammation was assessed by measuring the plasma concentration of cytokines TNF-alpha, IL-1alpha, IL-1beta, IL-6, IGF-1, Leptin, G-CSF, and VEGF. Examination of lungs and the elevation of proinflammatory cytokines in the plasma (Leptin and IL-6 at 6h) confirmed the induction of an inflammatory reaction. This inflammatory reaction was accompanied by a decrease in the local oxidative stress. This effect could be attributed to the scavenger capability of pure CNTs.

  Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

2000s

• Autoantibodies from mice exposed to Libby amphibole asbestos bind SSA/Ro52-enriched apoptotic blebs of murine macrophages. D.J. Blake, S.A. Wetzel, J.C. Pfau. 2008;246(2-3):172-9. PubMed · Publisher · Free full text

  Abstract

  Asbestos exposure is associated with increased autoimmune responses in humans. For example, in Libby, MT where significant asbestos exposure has occurred due to an asbestos-contaminated vermiculite mine near the community, residents have developed increased autoimmune responses compared to an unexposed population. However, the exact mechanism by which Libby amphibole asbestos generates autoimmune responses is unclear. A murine model of amphibole asbestos-induced autoimmunity was recently established, and one of the targets of the autoantibodies (AAs) was the SSA/Ro52 autoantigen. The purpose of this study was to determine whether the SSA/Ro52 autoantigen is exposed at the surface of cells as a result of asbestos exposure as a possible mechanism leading to antigenicity. Our results indicate that Libby asbestos induces apoptosis in murine macrophages as determined by phosphatidylserine exposure, cleavage of poly(ADP-ribose) polymerase and morphological changes such as nuclear condensation. Moreover, asbestos-induced apoptosis results in the formation of apoptotic cell surface blebs enriched in SSA/Ro52 as determined by confocal microscopy. Most importantly, apoptotic cell surface blebs are recognized by AAs from mice exposed to amphibole asbestos suggesting that these cell surface structures may be antigenic when presented in a pro-inflammatory context. This study supports the hypothesis that the induction of apoptosis plays a key role in environmentally induced autoimmunity through cell surface exposure of a known autoantigen.

• Mechanisms of silica-induced IL-8 release from A549 cells: initial kinase-activation does not require EGFR activation or particle uptake. J. Øvrevik, M. Refsnes, E. Namork, et al. 2006;227(1-2):105-16. PubMed · Publisher

  Abstract

  Understanding how mineral particles trigger cellular responses is crucial in order to elucidate what characteristics determine their harmful effects. It is not clear whether cellular effects are triggered through the cell membrane or require particle uptake. However, studies with asbestos suggest that activation of the epidermal growth factor receptor (EGFR) may be important. We have previously reported that crystalline silica-induced interleukin (IL)-8 release from human lung epithelial cells (A549) was regulated through Src family kinases (SFKs) and the mitogen-activated protein kinases (MAPKs) p38 and extracellular signal-regulated kinase (ERK)-1 and -2. The present study shows that SFK and p38 phosphorylation increased almost immediately upon crystalline silica exposure, whereas ERK1/2 phosphorylation increased after 10 min of exposure. The p38 inhibitor SB202190 increased the silica-induced ERK1/2 phosphorylation suggesting that p38 activity may attenuate activation of ERK1/2. Scanning electron microscopy showed that some silica particles were phagocytosed between 1 and 4h of exposure, but that the majority remained bound by microvilli on the cell surface. The EGFR inhibitor AG1478 attenuated both silica-induced IL-8 release and phosphorylation of SFKs and ERK1/2. However, AG1478 also inhibited the respective background levels, and the EGFR was not phosphorylated at the onset of silica exposure. The results suggest that crystalline silica triggers p38 and SFK-ERK1/2 signaling through interactions with membrane components as both pathways were rapidly activated prior to particle internalization. However, the silica-induced up-regulation of IL-8 release through the SFK-ERK1/2 pathway does not appear to be initiated through activation of the EGFR, although basal EGFR activity may affect the magnitude of the responses.

• Immunological monitoring in workers occupationally exposed to asbestos. S. Ilavská, E. Jahnová, J. Tulinská, et al. 2005;206(2):299-308. PubMed · Publisher

  Abstract

  Occupational exposure to asbestos is strongly associated with pulmonary diseases, cancer and immunotoxic effects. Both systemic and local immunity may play an important role in the pathogenesis of these events. Immune cells appear to be influenced by asbestos exposure, either through direct effects or as a result of the host's protective response to exposure. In this study several immune system parameters were assessed in workers (n = 61) with at least 5 years' exposure to asbestos at an industrial plant. Workers exposed to asbestos fibres had significantly increased levels of immunoglobulin E and concentrations of interleukin-6 and -8 in comparison with two sets of controls (in-plant and town control groups). The levels of soluble adhesion molecule ICAM-1 were higher in the exposed group compared to the town control group. Significantly increased levels of IgA were found in asbestos-exposed group in comparison to the town control. Evaluation of the expression of adhesion molecules on lymphocytes, monocytes and granulocytes by flow cytometry showed significant increases in the class of selectins CD62L on monocytes and granulocytes. Moreover, significantly increased expression of markers CD69 and CD66b on eosinophils was found among workers exposed to asbestos. In conclusion, exposure to asbestos fibres was found to have several effects on immune system. Alterations of these immune parameters may indicate hypersensitivity (increased levels of IgE, increased expression of activation markers CD66b and CD69 on eosinophils) and an elevated inflammatory status (increased levels of interleukins--IL-6, IL-8) in exposed workers.

• Cytotoxic and oxidative effects induced by man-made vitreous fibers (MMVFs) in a human mesothelial cell line. D. Cavallo, A. Campopiano, G. Cardinali, et al. 2004;201(1-3):219-29. PubMed · Publisher

  Abstract

  The introduction of man-made vitreous fibers (MMVFs) as a substitute for asbestos in industrial and residential applications raises concerns about their potential health hazards. The aim of our study was to assess cytotoxic and oxidative effects induced on a human mesothelial cell line (MeT-5A) by exposure to glass wool (GW), rock wool (RW) and refractory ceramic fibers (RCF) in comparison with crocidolite asbestos (CR). MeT-5A cells were exposed for 24 h to 2, 5 and 10 microg/cm2 of MMVF and crocidolite fibers and analysed by scanning electron microscope (SEM) for cell surface alterations. Cells were exposed for 2 h to 1, 2, 5 and 10 microg/cm2 of the same fibers and analysed by enzyme Fpg-modified comet test for direct and oxidative DNA damage. SEM revealed loss of microvilli in cells exposed to RCF and numerous blebs in cells exposed to higher doses of RW. Comet test showed significant direct DNA damage in cells exposed to RCF even at the lowest dose. Comet test with Fpg, that permits the detection of oxided DNA bases, showed significant oxidative DNA damage in cells exposed to higher doses of RW. The presence of DNA damage and alterations of cell surface induced by low doses of RCF and the presence of oxidative DNA damage and blebs on cell surface in cells exposed to higher dose of RW suggest possible cytotoxic, oxidative and genotoxic effects for these MMVFs.

• Effects of crocidolite asbestos on human bronchoepithelial-dependent fibroblast stimulation in coculture: the role of IL-6 and GM-CSF. D.S. Lang, H. Schocker, S. Hockertz. 2001;159(1-2):81-98. PubMed · Publisher

  Abstract

  Cocultures of human pulmonary epithelial cells (BEAS-2B) and lung fibroblasts (WISTAR-38), representing two cell types of central regulatory potential in (chronic) lung disease, were used as an in vitro model to study the role of interleukin 6 (IL-6) and of granulocyte macrophage-colony stimulating factor (GM-CSF) in early fibrogenesis. For this purpose, epithelial cells were pre-exposed to UICC crocidolite asbestos fibers or titanium dioxide (TiO2) particles for 96 h and subsequently cocultured with fibroblasts for additional 72 h. Gene expression of IL-6 or GM-CSF in both cell types as well as of alpha1 procollagens types I and III in fibroblasts was determined by RT-PCR. Synthesis of IL-6, GM-CSF or collagen I was quantified using IL-6 bioassay or ELISA tests, respectively. Both mediators were directly induced in bronchoepithelial cells by crocidolite but not by TiO2. Likewise, steady-state mRNA levels of procollagens as well as collagen synthesis were upregulated in cocultured fibroblasts. As a result of coculture, cytokine concentrations were synergistically enhanced and further increased by crocidolite in a dose-dependent manner. Suppression of cytokine induction by corresponding neutralizing antibodies consistently abrogated collagen enhancement. Direct stimulation of fibroblast monocultures with recombinant human IL-6 or GM-CSF significantly increased collagen synthesis and transcription in a dose-dependent manner. Thus, our results demonstrate that crocidolite selectively stimulated production of IL-6 and GM-CSF in bronchoepithelial cells. In epithelial-fibroblast interactions, these mediators appear to play a key role in regulating fibroblast activity, indicating a close correlation between these cytokines and the fibrogenic potential of particulates.

1990s

• Short-term crocidolite inhalation studies in mice: validation of an inhalation chamber. B. Rihn, E. Kauffer, P. Martin, et al. 1996;109(2-3):147-56. PubMed · Publisher

  Abstract

  A nose-only inhalation chamber is described: this chamber being computer automated has been particularly designed for mice on which it was validated using a crocidolite aerosol at a nominal concentration of 13.6 mg/m3, 6 h/day during 5 days. A month later the mice showed typical inflammatory bronchoalveolar liquids with many polynucleated or activated macrophages and asbestos bodies. The burden of crocidolite fibers ranged from 345,000 to 1,300,000 fibers per mg of dried lung. This study demonstrates that during the month that followed a short-term mice exposure to crocidolite fibers, the inflammatory response was still persistent. These toxicological endpoints validate the nose-only inhalation chamber to be useful for common or transgenic mice.

• The role of G-proteins in the activation of human leukocytes by particulate stimuli to produce reactive oxygen metabolites. M. Ruotsalainen, K.M. Savolainen. 1995;99(1-2):67-76. PubMed · Publisher

  Abstract

  Effects of pertussis toxin (PTX), cholera toxin (CTX) and an anhydrolyzable GTP analogue, GTP gamma S, on the levels of free intracellular calcium ([Ca2+]i) and the production of reactive oxygen metabolites (ROM) in human polymorphonuclear leukocytes (PMNL) were studied during cell activation. Cells were stimulated by particulate stimuli, quartz or chrysotile, and soluble stimuli, formyl-methionyl-leucyl-phenylalanine (fMLP) or phorbol myristate acetate (PMA). Pretreatment of PMNL with PTX decreased fMLP-induced elevations of [Ca2+]i but not those induced by quartz or chrysotile. CTX, in turn, decreased both quartz- and fMLP-induced elevations of [Ca2+]i. Likewise, PTX inhibited only fMLP-induced production of ROM, whereas CTX inhibited also those induced by quartz, chrysotile or fMLP. PTX or CTX did not, however, have an impact on PMA-induced production of ROM. GTP gamma S alone did not elevate [Ca2+]i or amplify fMLP-, quartz- or chrysotile-induced [Ca2+]i elevation. However, GTP gamma S alone increased the production of ROM and amplified ROM production induced by fMLP and quartz. The present results suggest that a CTX-sensitive G-protein may be involved in quartz-induced PMNL activation whereas an fMLP-induced neutrophil activation may be regulated by G-proteins sensitive to both PTX and CTX. The involvement of G-protein in chrysotile-induced leukocyte activation is not likely. There may be, however, a relationship between G-protein-mediated cell signalling and quartz-induced production of reactive oxygen metabolites in these cells.

• Changes in free intracellular calcium and production of reactive oxygen metabolites in human leukocytes by soluble and particulate stimuli. M. Tuomala, M.R. Hirvonen, K.M. Savolainen. 1993;80(1):71-82. PubMed · Publisher

  Abstract

  Changes in free intracellular calcium concentration ([Ca2+]i) and in the production of reactive oxygen metabolites (ROM) were studied in human polymorphonuclear leukocytes (PMNL) exposed to graded concentrations of formyl-methionyl-leucyl-phenylalanine (fMLP), a chemotactic peptide, phorbol myristate acetate (PMA), a stimulator of protein kinase C (PKC), quartz, or chrysotile. fMLP, quartz, and chrysotile induced a concentration-dependent elevation in [Ca2+]i. PMA did not affect [Ca2+]i. fMLP caused a rapid and transient increase in [Ca2+]i, whereas that caused by quartz or chrysotile was slow and sustained. fMLP, PMA and quartz all caused a concentration-dependent ROM production in PMNL. Chrysotile also caused a concentration-dependent increase in ROM production, but the slope of the curve was more gentle, with the maximum response being only 25% of that caused by the other stimuli. fMLP caused a rapid and transient peak in ROM production at 5 min, PMA a peak at 15 min, whereas quartz and chrysotile induced a biphasic ROM production with peaks at 5 and 20 min, and at 18 and 28 min, respectively. These results suggest that [Ca2+]i may have an important role in the production of ROM by PMNL after an exposure to fMLP, quartz, or chrysotile, and that the involvement of PKC in ROM production is possible.

• In vitro assays to predict the pathogenicity of mineral fibers. B.T. Mossman, A.M. Sesko. 1990;60(1-2):53-61. PubMed · Publisher

  Abstract

  A number of mineral dusts are associated with the development of inflammation in lung and pulmonary interstitial fibrosis. In an effort to find alternative approaches to animal testing, cells (rat alveolar macrophages, hamster tracheal epithelial cells, rat lung fibroblasts) of the respiratory tract have been evaluated for cytotoxic and metabolic changes after exposure to fibers (defined as a greater than 3:1 length to diameter ratio) and particles. In all bioassays, fibrous materials provoked greater biological responses in cells in comparison to non-fibrous, chemically similar particulates at identical concentrations. For example, release of superoxide (O2-.) from alveolar macrophages (AMs) was increased (in comparison to that observed in untreated cells) after exposure to the fibers, crocidolite asbestos, erionite, Code 100 fiberglass and sepiolite. Riebeckite, mordenite and glass particles elicited minimal generation of O2-. at similar concentrations of dusts. In hamster tracheal epithelial (HTE) cells, fibers such as chrysotile asbestos, crocidolite asbestos, and Code 100 fiberglass caused increased release of 51Chromium in comparison to the particles antigorite, riebeckite and glass. Another area of exploration is the measurement of collagen and non-collagen protein in a cell line (RL-82) of rat lung fibroblasts as an indication of the fibrogenic potential of minerals. Crocidolite asbestos caused an increase in the ratio of cell-associated collagen to non-collagen protein in these cell types whereas glass beads did not affect biosynthesis of collagen. Results suggest that a battery of in vitro assays can be used to screen the capability of minerals to elicit cell damage and inflammatory changes in the respiratory tract.

1980s

• Lung cell reactions in guinea pigs after inhalation of asbestos (amosite). M. Sjöstrand, R. Rylander, R. Bergström. 1989;57(1):1-14. PubMed · Publisher

  Abstract

  To study the long-term effect of inhaled asbestos, guinea-pigs were exposed to airborne amosite at a concentration of 49 mg/m3, 2 h/day for 3 or 6 weeks and examined up to 2 years after exposure. Macrophages in lung lavage fluid (LLF) were increased at 16, 24 and 93 weeks and lymphocytes at 24 weeks. Examination of lung wall cells (LWC) 2 years after exposure compared to cells obtained by LLF showed higher proportions of LWC lymphocytes and neutrophils. Percoll gradient centrifugation of these cells showed a higher proportion of high density macrophages in LLF from the amosite-exposed animal and an increased number of low density lymphocytes in the LW. Cathepsin D was increased in LLF at 8 and 24 weeks and in alveolar macrophages 24 weeks and 2 years after exposure. Fibroblast cultures exposed to LLF did not show any statistical significant changes in their collagen synthesis. Histology 93 weeks after exposure showed macrophage and mediastinal lymph node accumulation of asbestos, as well as collagen in alveolar walls. Granulomas were found in the vicinity of blood vessels and in connection with the bronchioles. The data suggest that amosite at low doses ultimately causes fibrosis with a reaction pattern different from that seen in silicosis. The inflammation and fibrosis seems to develop only within the interstitium.

• In vitro models of lung toxicity. G.L. Fisher, M.E. Placke. 1987;47(1-2):71-93. PubMed · Publisher

  Abstract

  In vitro assays that emphasize cellular components critical to the host defense system have been developed to evaluate pulmonary toxicity and define deleterious changes in parenchymal cell populations. Assays that employ pulmonary alveolar macrophages (PAM) have demonstrated good correlation between macrophage toxicity and pulmonary fibrogenicity for many inorganic compounds. The PAM assays provide simple and inexpensive screens of potential respiratory tract toxicity. Many investigators screen chemicals for their ability to alter the mucosal epithelial cell conducting airways by performing tracheal organ cultures. The tracheal assays have also provided useful screens for Vitamin A analogues required for epithelial cell differentiation. Most recently, in vitro respiratory tract models have been extended to include whole-lung explants, an approach that allows for development of fibrosis and epithelial cell toxicity after in vitro exposure to inorganic and organic fibrogens. The whole-lung explant system appears to duplicate the in vivo response to a variety of lung toxins, including bleomycin, silica, and crocidolite asbestos. Together, these assays provide a description of potential toxicity to key components of the lung, emphasizing the pulmonary macrophage, conducting airways, and alveolar septae. It is expected that continued research in these models will enhance their predictive abilities and utility in risk assessment.

• Effect of asbestos fibers on aryl hydrocarbon hydroxylase and aminopyrine N-demethylase activities of rat liver microsomes. C. Kandaswami, M. Rahimtula, P.J. O'Brien. 1986;38(1):119-32. PubMed · Publisher

  Abstract

  Chrysotile asbestos fibers impair the activities of rat liver microsomal aryl hydrocarbon hydroxylase (AHH), aminopyrine (AP) N-demethylase and dimethylnitrosamine (DMN) demethylase in vitro. This inhibition is concentration-dependent. Preincubation of 3-methylcholanthrene (3-MC)-pretreated rat liver microsomes with chrysotile depresses the overall metabolism of [G-3H]benzo[a]pyrene (BaP). Various forms of asbestos employed inhibit AHH activity to the same extent. However, other types of asbestos are not as effective as chrysotile in diminishing AP demethylase activity. Chrysotile and crocidolite fibers are not found to significantly change the apparent Km of AHH activity, from 3-MC-pretreated rat liver microsomes, for BaP. Increasing the microsomal protein concentration partially abolishes the inhibition of AHH activity caused by chrysotile fibers. Inhibition of AP demethylase and AHH activities is attenuated by bovine serum albumin (BSA) or ferritin. Depression of AHH activity by crocidolite is significantly reversed by ferritin. Since polymers such as ferritin override enzyme inhibition by chrysotile as well as crocidolite, surface chemical groups of the fibers may be involved in enzyme modification.

• Biochemical studies in infective amosite pneumoconiosis. A.K. Jaiswal. 1981;22(1):59-68. PubMed · Publisher

  Abstract

  The effects of Candida albicans, of amosite dust, and of the 2 agents combined, on some biochemical parameters of the lung in male guinea pigs were determined. Adult guinea pigs were intratracheally injected with 50 mg of amosite dust and 0.3 mg of viable suspension of mycelia of Candida albicans. The other groups received either dust or organism or none. Biochemical measurements done at 30, 60 and 90 days after infection showed that the superimposed state produced more rapid and drastic changes in pulmonary contents of collagen, mucopolysaccharides and phospholipids and activities of lactic dehydrogenase and succinate dehydrogenase. The levels of lactic acid and pyruvic acid were also more profoundly changed after amosite + Candida. These results indicate that Candida albicans which is commonly found in upper respiratory tract could aggrevate the lesions caused by exposure to asbestos.

• In vitro reactivity of alveolar macrophages and red blood cells with asbestos fibres treated with oxalic acid, sulfur dioxide and benzo-3,4-pyrene. M.C. Jaurand, L. Magne, J.L. Boulmier, et al. 1981;21(4):323-42. PubMed · Publisher

  Abstract

  The effects of 3 UICC asbestos fibres (A chrysotile, crocidolite, amosite) were observed in vitro on red blood cells (RBC) and alveolar macrophages (AM). THe reactivity of the fibres after leaching with 0.1 N oxalic acid or adsorption of SO2 or benzo-3,4-pyrene (BP) was studied. The haemolytic activity of crocidolite and amosite was very low. A cytotoxic effect on AM occurred when the fibres were present in high concentration (100 microgram/ml), this was characterized by a release of both cytoplasmic (LDH) and lysosomal (beta-galactosidase) enzymes. The leached fibres were more haemolytic than the unleached ones, and more beta-galactosidase (beta-Gal) than lactic dehydrogenase (LDH) was released from the AM. In contrast to the amphiboles, chrysotile fibres were highly haemolytic and induced a selective release of beta-Gal from AM. Leached fibres were less haemolytic and were cytotoxic for AM (both enzymes were released). Their in vitro reactivity was similar to that observed with quartz. The results showed that SO2 changed the reactivity very little. BP sorption on acid-leached chrysotile decreased the LDH release from AM. The difference in the in vitro reactivity related to the chemical state of asbestos fibres might explain the difference in their in vivo reactivity (latency, degree of fibrosis). This point is discussed.

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