Archives of Toxicology

Our medical research library holds 22 studies published in Archives of Toxicology (1988–2026). 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. 21 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it. For 1 study PubMed has no abstract for, we give the abstract printed in the article or, where there is none, a summary we wrote from it, each labeled as such.

About the journal

• Publisher: Springer-Verlag
• Published: 1974 to the present, Germany
• Language: English
• ISSN: 0340-5761 (print), 1432-0738 (electronic)
• Continues: Archiv Für Toxikologie
• Its record in the NLM Catalog

2020s

• Defining early carcinogenic markers for the prediction of the hazard potential of mineral fibres in an in vitro human 3D bronchial model. V. Almonti, S. Mirata, M. Passalacqua, et al. 2026;100(10):4777-4797. PubMed · Publisher · Free full text

  Abstract

  This study aimed to identify early carcinogenic markers to predict the hazard potential of mineral fibres using a human 3D bronchial model. Traditional 2D cell models inadequately mimic lung complexity, prompting the use of more physiologically relevant 3D systems. We investigated the effects of crocidolite (CRO) and two size fractions of chrysotile (≤ and > 5 μm length: CHR S and CHR L) to elucidate early toxicological mechanisms and relate them to the IARC key characteristics (KCs) of carcinogens. Initial analyses (MTT, TEER, and histology) at 24-48 h showed a transient acute toxicity and tissue resilience, indicating limited predictive value at this time point. However, after 12 d of exposure, fibre-treated tissues exhibited persistent alterations corresponding to established IARC KCs, suggesting the early onset of cell transformation pathways. Key findings included: sustained inflammatory signalling, characterized by prolonged overexpression of IL-1β, IL-6, and IL-8; ii) persistent genotoxicity, marked by the prolonged nuclear positivity of γH2AX, indicating DNA double-strand breaks without significant cell death; and iii) induction of fibrotic and epithelial-to-mesenchymal transition (EMT) signals, including the increased expression of key markers such as TGF-β, VEGF, ZEB-2, N-Cadherin, Vimentin, and Mesothelin. These alterations correspond to IARC KCs 2, 6, and 8. They were observed within a short time frame of tissue treatment and could serve as reliable, early predictive endpoints for in vitro toxicological tests. We propose that integrating these specific KC-based biosignatures in 3D lung models with physicochemical fibre characterization may provide a robust framework for predictive assessment of inhalable fibre carcinogenicity.

  © 2026. The Author(s).

• NLRP3 inflammasome activation by particles and fibers: implications for human hazard assessment. M. Busch, G. Bredeck, H. Bouwmeester, et al. 2026;100(10):4299-4318. Review PubMed · Publisher · Free full text

  Abstract

  The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome has been shown to be involved in the manifestation of adverse effects following exposure to occupational, dietary and environmental particulate matter. In this review, we summarize knowledge on NLRP3 inflammasome activation by particles and fibers in vitro and in vivo, outline dominant activation mechanisms and discuss the link to human diseases. While the association between NLRP3 activation and development of diseases is well established for occupational exposure to mineral dusts like asbestos and quartz, the health effects of low-level exposure to environmental particulate pollutants, such as micro- and nanoplastics, desert dust or novel nanocomposites remain to be unraveled. Based on the combined literature of well-studied and emerging particles, we emphasize the relevance of testing for NLRP3 activation in the hazard assessment of novel particulate materials.

  © 2026. The Author(s).

• TEAD inhibitor induced switch in energy metabolism drives human podocyte injury in vitro. A. Zielinski, J. Hauptstein, B. Baier, et al. 2026;100(11):5181-5194. PubMed · Publisher · Free full text

  Abstract

  Early detection and understanding of the potential adverse effects of a drug candidate is of utmost importance to reduce the attrition rate during drug development while delivering safe medications to patients. The kidney is one of the most frequently challenged organs involved in drug-induced toxicity, including general glomerulopathy and podocyte- specific cytotoxicity with ensuing overt proteinuria. Whilst TEAD inhibitors address the need for treatment of mesotheliomas and other tumours unaffected by approved drugs, animal testing and clinical trials provide evidence of renal toxicity induced by this novel class of drugs. Here we present an in vitro test system consisting of immortalized human podocytes PODO/TERT256 to characterize the potential adverse effects of TEAD inhibitors. We demonstrate that TEAD inhibitors K-975, IK-930 and VT-107 affect the podocyte monolayer in a wide dose range (33.3-100 µM), disrupt the cellular vesicle system, and subsequently induce cell death, especially after exposure to pan-TEAD inhibitors (VT-107 and K-975). Of note, low micromolar concentrations of TEAD inhibitors lowered mitochondrial oxidative phosphorylation directly after exposure which was confirmed by reduced basal ATP levels after 3 d of exposure. In summary, the in vitro human podocyte model presented can characterize glomerular filtration functionality decline subsequent to TEAD inhibitor exposure and thus represents a promising model for early detection and prediction of potential drug related glomerulopathy in humans.

  © 2026. The Author(s).

• Fullerene and fullerene whisker are not carcinogenic to the lungs and pleura in rat long-term study after 2-week intra-tracheal intrapulmonary administration. A.N. Sheema, A. Naiki-Ito, A. Kakehashi, et al. 2024;98(12):4143-4158. PubMed · Publisher · Free full text

  Abstract

  Fullerene whiskers (FLW)s are thin rod-like structures composed of C60 and C70 fullerene (FL). The shape of FLWs suggests potential toxic effects including carcinogenicity to the lung and pleura, similar to effects elicited by asbestos and multi-walled carbon nanotubes (MWCNT)s. However, no long-term carcinogenic studies of FL or FLW have been conducted. In the present study we investigated the pulmonary and pleural carcinogenicity of FL and FLW. Twelve-week-old male F344 rats were administered 0.25 or 0.5 mg FL, FLW, MWCNT-7, and MWCNT-N by intra-tracheal intra-pulmonary spraying (TIPS). Acute lung lesions and carcinogenicity were analyzed at 1 and 104 weeks after 8 doses/15 days TIPS administration. At week 1, FLW, MWCNT-7, and MWCNT-N significantly increased alveolar macrophage infiltration. Expression of Ccl2 and Ccl3, reactive oxygen species production, and cell proliferation were significantly increased by administration of MWCNT-7 and MWCNT-N but not FL or FLW. At week 104, the incidence of bronchiolo-alveolar adenoma plus adenocarcinoma was significantly increased in the MWCNT-7 and MWCNT-N groups, and the incidence of mesothelioma was significantly increased in the MWCNT-7 group. No significant induction of pulmonary or pleural tumorigenesis was observed in the FL or FLW groups. The number of 8-OHdG-positive cells in the alveolar epithelium was significantly increased in the MWCNT-7 and MWCNT-N groups but not in the FL or FLW groups. FL and FLW did not exert pulmonary or pleural carcinogenicity in our study. In addition, oxidative DNA damage was implicated in MWCNT-induced lung carcinogenesis, suggesting that it may be a useful initial marker of carcinogenicity.

  © 2024. The Author(s).

• Methodological steps forward in toxicological in vitro screening of mineral wools in primary rat alveolar macrophages and normal rat mesothelial NRM2 cells. C. Ziemann, F. Schulz, C. Koch, et al. 2024;98(12):3949-3971. PubMed · Publisher · Free full text

  Abstract

  Man-made vitreous fibers (MMVF) comprise diverse materials for thermal and acoustic insulation, including stone wool. Depending on dimension, durability, and dose, MMVF might induce adverse health effects. Therefore, early predictive in vitro (geno)toxicity screening of new MMVF is highly desired to ensure safety for exposed workers and consumers. Here, we investigated, as a starting point, critical in vitro screening determinants and pitfalls using primary rat alveolar macrophages (AM) and normal rat mesothelial cells (NRM2). A stone wool fiber (RIF56008) served as an exemplary MMVF (fibrous vs. ground to estimate impact of fiber shape) and long amosite (asbestos) as insoluble fiber reference. Materials were comprehensively characterized, and in vivo-relevant in vitro concentrations defined, based on different approaches (low to supposed overload: 0.5, 5 and 50 µg/cm2). After 4-48 h of incubation, certain readouts were analyzed and material uptake was investigated by light and fluorescence-coupled darkfield microscopy. DNA-strand break induction was not morphology-dependent and nearly absent in both cell types. However, NRM2 demonstrated material-, morphology- and concentration-dependent membrane damage, CINC-1 release, reduction in cell count, and induction of binucleated cells (asbestos > RIF56008 > RIF56008 ground). In contrast to NRM2, asbestos was nearly inactive in AM, with CINC-1 release solely induced by RIF56008. In conclusion, to define an MMVF-adapted, predictive in vitro (geno)toxicity screening tool, references, endpoints, and concentrations should be carefully chosen, based on in vivo relevance, and sensitivity and specificity of the chosen cell model. Next, further endpoints should be evaluated, ideally with validation by in vivo data regarding their predictivity.

  © 2024. The Author(s).

2010s

• Pulmonary and pleural toxicity of potassium octatitanate fibers, rutile titanium dioxide nanoparticles, and MWCNT-7 in male Fischer 344 rats. M. Abdelgied, A.M. El-Gazzar, D.B. Alexander, et al. 2019;93(4):909-920. PubMed · Publisher

  Abstract

  Potassium octatitanate (K2O·8TiO2, POT) fibers are used as an alternative to asbestos. Their shape and biopersistence suggest that they are possibly carcinogenic. However, inhalation studies have shown that respired POT fibers have little carcinogenic potential. We conducted a short-term study in which we administered POT fibers, and anatase and rutile titanium dioxide nanoparticles (a-nTiO2, r-nTiO2) to rats using intra-tracheal intra-pulmonary spraying (TIPS). We found that similarly to other materials, POT fibers were more toxic than non-fibrous nanoparticles of the same chemical composition, indicating that the titanium dioxide composition of POT fibers does not appear to account for their lack of carcinogenicity. The present report describes the results of the 3-week and 52-week interim killing of our current 2-year study of POT fibers, with MWCNT-7 as a positive control and r-nTiO2 as a non-fibrous titanium dioxide control. Male F344 rats were administered 0.5 ml vehicle, 62.5 µg/ml and 125 µg/ml r-nTiO2 and POT fibers, and 125 µg/ml MWCNT-7 by TIPS every other day for 2 weeks (eight doses: total doses of 0.25 and 0.50 mg/rat). At 1 year, POT and MWCNT-7 fibers induced significant increases in alveolar macrophage number, granulation tissue in the lung, bronchiolo-alveolar cell hyperplasia and thickening of the alveolar wall, and pulmonary 8-OHdG levels. The 0.5 mg POT- and the MWCNT-7-treated groups also had increased visceral and parietal pleura thickness, increased mesothelial cell PCNA labeling indices, and a few areas of visceral mesothelial cell hyperplasia. In contrast, in the r-nTiO2-treated groups, none of the measured parameters were different from the controls.

• Biological response of an in vitro human 3D lung cell model exposed to brake wear debris varies based on brake pad formulation. H. Barosova, S. Chortarea, P. Peikertova, et al. 2018;92(7):2339-2351. PubMed · Publisher · Free full text

  Abstract

  Wear particles from automotive friction brake pads of various sizes, morphology, and chemical composition are significant contributors towards particulate matter. Knowledge concerning the potential adverse effects following inhalation exposure to brake wear debris is limited. Our aim was, therefore, to generate brake wear particles released from commercial low-metallic and non-asbestos organic automotive brake pads used in mid-size passenger cars by a full-scale brake dynamometer with an environmental chamber simulating urban driving and to deduce their potential hazard in vitro. The collected fractions were analysed using scanning electron microscopy via energy-dispersive X-ray spectroscopy (SEM-EDS) and Raman microspectroscopy. The biological impact of the samples was investigated using a human 3D multicellular model consisting of human epithelial cells (A549) and human primary immune cells (macrophages and dendritic cells) mimicking the human epithelial tissue barrier. The viability, morphology, oxidative stress, and (pro-)inflammatory response of the cells were assessed following 24 h exposure to ~ 12, ~ 24, and ~ 48 µg/cm2 of non-airborne samples and to ~ 3.7 µg/cm2 of different brake wear size fractions (2-4, 1-2, and 0.25-1 µm) applying a pseudo-air-liquid interface approach. Brake wear debris with low-metallic formula does not induce any adverse biological effects to the in vitro lung multicellular model. Brake wear particles from non-asbestos organic formulated pads, however, induced increased (pro-)inflammatory mediator release from the same in vitro system. The latter finding can be attributed to the different particle compositions, specifically the presence of anatase.

• DNA methylation profiling of asbestos-treated MeT5A cell line reveals novel pathways implicated in asbestos response. E. Casalone, A. Allione, C. Viberti, et al. 2018;92(5):1785-1795. PubMed · Publisher

  Abstract

  Occupational and environmental asbestos exposure is the main determinant of malignant pleural mesothelioma (MPM), however, the mechanisms by which its fibres contribute to cell toxicity and transformation are not completely clear. Aberrant DNA methylation is a common event in cancer but epigenetic modifications involved specifically in MPM carcinogenesis need to be better clarified. To investigate asbestos-induced DNA methylation and gene expression changes, we treated Met5A mesothelial cells with different concentrations of crocidolite and chrysotile asbestos (0.5 ÷ 5.0 µg/cm2, 72 h incubation). Overall, we observed 243 and 302 differentially methylated CpGs (≥ 10%) between the asbestos dose at 5 µg/cm2 and untreated control, in chrysotile and crocidolite treatment, respectively. To examine the dose-response effect, Spearman's correlation test was performed and significant CpGs located in genes involved in migration/cell adhesion processes were identified in both treatments. Moreover, we found that both crocidolite and chrysotile exposure induced a significant up-regulation of CA9 and SRGN (log2 fold change > 1.5), previously reported as associated with a more aggressive MPM phenotype. However, we found no correlation between methylation and gene expression changes, except for a moderate significant inverse correlation at the promoter region of DKK1 (Spearman rho = - 1, P value = 0.02) after chrysotile exposure. These results describe for the first time the relationship between DNA methylation modifications and asbestos exposure. Our findings provide a basis to further explore and validate asbestos-induced DNA methylation changes, that could influence MPM carcinogenesis and possibly identifying new chemopreventive target.

• Immunological impact of graphene oxide sheets in the abdominal cavity is governed by surface reactivity. A.F. Rodrigues, L. Newman, D.A. Jasim, et al. 2018;92(11):3359-3379. PubMed · Publisher · Free full text

  Abstract

  Graphene oxide (GO) is an oxidised form of graphene that has attracted commercial interest in multiple applications, including inks, printed electronics and spray coatings, which all raise health concerns due to potential creation of inhalable aerosols. Although a number of studies have discussed the toxicity of GO sheets, the in vivo impact of their lateral dimensions is still not clear. Here, we compared the effects of large GO sheets (l-GO, 1-20 µm) with those of small GO sheets (s-GO, < 1 µm) in terms of mesothelial damage and peritoneal inflammation, after intraperitoneal (i.p.) injection in mice. To benchmark the outcomes, long and rigid multi-walled carbon nanotubes (MWCNTs) that were shown to be associated with asbestos-like pathogenicity on the mesothelium were also tested. Our aim was to assess whether lateral dimensions can be a predictor of inflammogenicity for GO sheets in a similar fashion as length is for MWCNTs. While long MWCNTs dispersed in 0.5% BSA induced a granulomatous response on the diaphragmatic mesothelium and immune cell recruitment to the peritoneal cavity, GO sheets dispersed under similar conditions did not cause any response, regardless of their lateral dimensions. We further interrogated whether tuning the surface reactivity of GO by testing different dispersions (5% dextrose instead of 0.5% BSA) may change the biological outcome. Although the change of dispersion did not alter the impact of GO on the mesothelium (i.e. no granuloma), we observed that, when dispersed in protein-free 5% dextrose solution, s-GO elicited a greater recruitment of monocytic cells to the peritoneal cavity than l-GO, or when dispersed in protein-containing solution. Such recruitment coincided with the greater ability of s-GO to interact in vivo with peritoneal macrophages and was associated with a greater surface reactivity in comparison to l-GO. In conclusion, large dimension was not a determining factor of the immunological impact of GO sheets after i.p. administration. For an equal dose, GO sheets with lateral dimensions similar to the length of long MWCNTs were less pathogenic than the MWCNTs. On the other hand, surface reactivity and the ability of some smaller GO sheets to interact more readily with immune cells seem to be key parameters that can be tuned to improve the safety profile of GO. In particular, the choice of dispersion modality, which affected these two parameters, was found to be of crucial importance in the assessment of GO impact in this model. Overall, these findings are essential for a better understanding of the parameters governing GO toxicity and inflammation, and the rational design of safe GO-based formulations for various applications, including biomedicine.

• Environmental risk factors for pancreatic cancer: an update. E. Barone, A. Corrado, F. Gemignani, et al. 2016;90(11):2617-2642. Review PubMed · Publisher

  Abstract

  Pancreatic cancer (PC) is one of the most aggressive diseases. Only 10 % of all PC cases are thought to be due to genetic factors. Here, we analyzed the most recently published case-control association studies, meta-analyses, and cohort studies with the aim to summarize the main environmental factors that could have a role in PC. Among the most dangerous agents involved in the initiation phase, there are the inhalation of cigarette smoke, and the exposure to mutagenic nitrosamines, organ-chlorinated compounds, heavy metals, and ionizing radiations. Moreover, pancreatitis, high doses of alcohol drinking, the body microbial infections, obesity, diabetes, gallstones and/or cholecystectomy, and the accumulation of asbestos fibers seem to play a crucial role in the progression of the disease. However, some of these agents act both as initiators and promoters in pancreatic acinar cells. Protective agents include dietary flavonoids, marine omega-3, vitamin D, fruit, vegetables, and the habit of regular physical activity. The identification of the factors involved in PC initiation and progression could be of help in establishing novel therapeutic approaches by targeting the molecular signaling pathways responsive to these stimuli. Moreover, the identification of these factors could facilitate the development of strategies for an early diagnosis or measures of risk reduction for high-risk people.

• The role of Rho-kinases in IL-1β release through phagocytosis of fibrous particles in human monocytes. S. Kanno, S. Hirano, S. Chiba, et al. 2015;89(1):73-85. PubMed · Publisher

  Abstract

  Long fibers, such as asbestos and carbon nanotubes (CNTs), are more potent activators of inflammatory and genotoxicity than short or tangled fibers. Fibrous particles trigger interleukin (IL)-1β secretion and cause inflammatory diseases through NLRP3 inflammasomes in phagocytotic cells. However, the mechanism involved in fibrous particle-induced inflammation has not been well documented. In this study, we focused on GTPase effector Rho-kinases (ROCK1, and 2), which are known to be involved in a wide range of cellular functions such as adhesion, regulation of cytoskeleton, and phagocytosis. We examined whether ROCKs are associated with multi-walled CNT (MWCNT)- or asbestos-induced IL-1β secretion in human monocytic THP-1 cells using a selective inhibitor and small interfering RNA. THP-1 cells were differentiated to macrophages by PMA and were exposed to MWCNTs, crocidolite asbestos or lipopolysaccharide (LPS) in the presence or absence of Y27632 (ROCK inhibitor) or Z-YVAD (caspase-1 inhibitor). Exposure of the cells to MWCNTs or asbestos provoked IL-1β secretion, but this secretion was suppressed by both Y27632 and Z-YVAD, whereas LPS-induced IL-1β secretion was inhibited only by Z-YVAD and not by Y27632. siRNA designed for knockdown of both ROCK1 and ROCK2 suppressed MWCNT- and asbestos-induced IL-1β secretion, but did not change LPS-induced IL-1β secretion. Moreover, Y27632 suppressed pro-IL-1β protein levels and the release of activated-cathepsin B and activated-caspase-1 induced by MWCNTs or asbestos. In contrast, LPS-induced pro-IL-1β protein was not suppressed by Y27632. These results suggest that ROCKs are involved in fibrous particle-induced inflammasome responses in THP-1 cells.

• Manufactured nanomaterials: categorization and approaches to hazard assessment. T. Gebel, H. Foth, G. Damm, et al. 2014;88(12):2191-211. Review PubMed · Publisher

  Abstract

  Nanotechnology offers enormous potential for technological progress. Fortunately, early and intensive efforts have been invested in investigating toxicology and safety aspects of this new technology. However, despite there being more than 6,000 publications on nanotoxicology, some key questions still have to be answered and paradigms need to be challenged. Here, we present a view on the field of nanotoxicology to stimulate the discussion on major knowledge gaps and the critical appraisal of concepts or dogma. First, in the ongoing debate as to whether nanoparticles may harbour a specific toxicity due to their size, we support the view that there is at present no evidence of 'nanospecific' mechanisms of action; no step-change in hazard was observed so far for particles below 100 nm in one dimension. Therefore, it seems unjustified to consider all consumer products containing nanoparticles a priori as hazardous. Second, there is no evidence so far that fundamentally different biokinetics of nanoparticles would trigger toxicity. However, data are sparse whether nanoparticles may accumulate to an extent high enough to cause chronic adverse effects. To facilitate hazard assessment, we propose to group nanomaterials into three categories according to the route of exposure and mode of action, respectively: Category 1 comprises nanomaterials for which toxicity is mediated by the specific chemical properties of its components, such as released ions or functional groups on the surface. Nanomaterials belonging to this category have to be evaluated on a case-by-case basis, depending on their chemical identity. Category 2 focuses on rigid biopersistent respirable fibrous nanomaterials with a specific geometry and high aspect ratio (so-called WHO fibres). For these fibres, hazard assessment can be based on the experiences with asbestos. Category 3 focuses on respirable granular biodurable particles (GBP) which, after inhalation, may cause inflammation and secondary mutagenicity that may finally lead to lung cancer. After intravenous, oral or dermal exposure, nanoscaled GBPs investigated apparently did not show 'nanospecific' effects so far. Hazard assessment of GBPs may be based on the knowledge available for granular particles. In conclusion, we believe the proposed categorization system will facilitate future hazard assessments.

• Toxicogenomic comparison of multi-wall carbon nanotubes (MWCNTs) and asbestos. J.S. Kim, K.S. Song, J.K. Lee, et al. 2012;86(4):553-62. PubMed · Publisher

  Abstract

  Carbon nanotubes (CNTs) have specific properties, including electrical and thermal conductivity, great strength, and rigidity, that allow them to be used in many fields. However, this increasing contact with humans and the environment is also raising health and safety concerns. Thus, research on the safety of CNTs has attracted much interest, including a comparison of the toxic effects of asbestos and carbon nanotubes, due to their physical similarity of a high aspect ratio (length/diameter). Nonetheless, there has not yet been a toxicogenomic comparison. Therefore, to examine toxicogenomic effects, the 50% growth inhibition (GI(50)) concentration was determined for multi-wall carbon nanotubes (MWCNTs) and asbestos (crocidolite) and found to be approximately 0.0135 and 0.066%, respectively, in the case of 24-h treatment of normal human bronchial epithelia (NHBE) cells. Using these GI(50) concentrations, NHBE cells were then treated with MWCNTs and asbestos for 6 and 24 h, followed by a DNA microarray analysis. Among 31,647 genes, 1,201 and 1,252 were up-regulated by both asbestos and MWCNTs after 6 and 24 h of exposure, respectively. Meanwhile, 1,977 and 1,542 genes were down-regulated by both asbestos and MWNCTs after 6 and 24 h of exposure, respectively. In particular, the asbestos and MWCNTs both induced an over twofold up- and down-regulated expression of 12 mesothelioma-related genes and 22 lung cancer-related genes when compared with the negative control. Plus, the genes induced by the MWCNT exposure were expressed in the brain, lungs, epithelium, liver, and colon.

• A single intratracheal instillation of single-walled carbon nanotubes induced early lung fibrosis and subchronic tissue damage in mice. E.J. Park, J. Roh, S.N. Kim, et al. 2011;85(9):1121-31. PubMed · Publisher

  Abstract

  Large amounts of nanomaterials may reach both the natural and occupational environments. This represents a potential health hazard. People have forecasted that CNTs may lead to the toxicity such as mesothelioma and fibrosis like asbestos. To identify dominant immune responses induced by SWCNTs, we investigated the composition of bronchioalveolar lavage (BAL) cells, the secretion of cytokine and collagen, histopathology, protein expression, and cell phenotypes over time after a single administration of single-walled carbon nanotubes (SWCNT). In our results, the number of total cells and macrophages remained at the up-regulated level until Day 28, neutrophils rapidly increased at Day 1, and lymphocytes increased from Day 7. In the BAL fluid, pro-inflammatory cytokines rapidly increased at Day 1 and remained at an up-regulated level throughout the experimental period. IL-12 and IL-10 rapidly increased at Day 1 after administration and remained at a similar level until Day 28. IFN-γ and IL-4 reached the maximum at Day 1, and IL-5, TGF-β, and collagen reached the maximum at Day 7. IL-13 and IL-17 increased in a time-dependent manner. The distribution of B cells and cytotoxic T cells markedly increased at Days 7 and 14, and fibrotic lesions were histopathologically observed at Days 7 and 14. The expressions of caspase-3, p53, COL1A1, COX-2, iNOS, MMP-9, and MMP-2 were also markedly increased at Days 7 and 14. In addition, the expression of mesothelin, iNOS, MMP-9, and p53 was up-regulated until Day 28. Based on these findings, we suggest that a single intratracheal instillation of SWCNTs may induce early lung fibrosis and subchronic tissue damage.

• Aspect ratio has no effect on genotoxicity of multi-wall carbon nanotubes. J.S. Kim, K. Lee, Y.H. Lee, et al. 2011;85(7):775-86. PubMed · Publisher

  Abstract

  Carbon nanotubes (CNTs) have specific physico-chemical and electrical properties that are useful for telecommunications, medicine, materials, manufacturing processes and the environmental and energy sectors. Yet, despite their many advantages, it is also important to determine whether CNTs may represent a hazard to the environment and human health. Like asbestos, the aspect ratio (length:diameter) and metal components of CNTs are known to have an effect on the toxicity of carbon nanotubes. Thus, to evaluate the toxic potential of CNTs in relation to their aspect ratio and metal contamination, in vivo and in vitro genotoxicity tests were conducted using high-aspect-ratio (diameter: 10-15 nm, length: ~10 μm) and low-aspect-ratio multi-wall carbon nanotubes (MWCNTs, diameter: 10-15 nm, length: ~150 nm) according to OECD test guidelines 471 (bacterial reverse mutation test), 473 (in vitro chromosome aberration test), and 474 (in vivo micronuclei test) with a good laboratory practice system. To determine the treatment concentration for all the tests, a solubility and dispersive test was performed, and a 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) solution found to be more suitable than distilled water. Neither the high- nor the low-aspect-ratio MWCNTs induced any genotoxicity in a bacterial reverse mutation test (~1,000 μg/plate), in vitro chromosome aberration test (without S9: ~6.25 μg/ml, with S9: ~50 μg/ml), or in vivo micronuclei test (~50 mg/kg). However, the high-aspect-ratio MWCNTs were found to be more toxic than the low-aspect-ratio MWCNTs. Thus, while high-aspect-ratio MWCNTs do not induce direct genotoxicity or metabolic activation-mediated genotoxicity, genotoxicity could still be induced indirectly through oxidative stress or inflammation.

• Performance of biomarkers SMRP, CA125, and CYFRA 21-1 as potential tumor markers for malignant mesothelioma and lung cancer in a cohort of workers formerly exposed to asbestos. M. Gube, D. Taeger, D.G. Weber, et al. 2011;85(3):185-92. PubMed · Publisher

  Abstract

  The aim of the study is to examine the cancer-predictive values of SMRP (soluble mesothelin-related peptides), CA125, and CYFRA21-1 as potential tumor markers for lung cancer and malignant mesothelioma in a cohort of workers formerly exposed to asbestos. A voluntary surveillance program has been established for German workers with former asbestos exposure. A subgroup of 626 subjects with a mean age of 63 years (range 53-70 years) at baseline was enrolled in an extended health examination program with high-resolution computer tomography (HRCT) of the chest and blood drawing between 1993 and 1997. Serum concentrations of SMRP, CA125, and CYFRA21-1 were measured in archived serum samples in 2005 and 2006. A mortality follow-up was conducted through 2007. So far, 12 cases with lung cancer and 20 cases with malignant mesothelioma have been observed in this cohort. The average time between sample collection and diagnosis was 4.7 years. Analyzed biomarkers showed low sensitivities (5-25%) and positive predictive values (4-30%) for both cancer sites. Marker combinations resulted in sensitivities between 5 and 50% and positive predictive values ranging from 3 to 14%. Even in those cases, where biomarker concentrations were available within 36 months before diagnosis, no trend for increasing biomarker levels was observed. The analyzed tumor markers were characterized by high specificities, but low sensitivities. SMRP, CA125, and CYFRA21-1 alone or in combination were less suitable to serve as predictors for the diagnosis of lung cancer or malignant mesothelioma. However, a prospective study with annual sampling might reveal a better predictive value of these markers.

2000s

• A new in vitro cellular system for the analysis of mineral fiber biopersistence. H. Dika Nguea, A. de Reydellet, P. Lehuédé, et al. 2008;82(7):435-43. PubMed · Publisher

  Abstract

  The toxicity of mineral fibers, whether they are natural or man made (MMMF), is usually evaluated in vivo using biopersistence tests in rodents. Development of an in vitro cellular model would be worthwhile in order to reduce, refine and finally replace animal models. For this purpose, we developed an in vitro assay using human monocytic cell line (U-937) to evaluate a new manufactured rock wool fiber (HDN) biodegradation. Experiments on earlier known mineral fibers asbestos (crocidolite) and glass wool fibers (CM44) were also performed. U-937 responded to HDN and CM44 only if they were activated. Among the different activators we used, Escherichia coli living cells as well as FS were the most efficient as evidenced by alterations of HDN and CM44 surface, detected by scanning electron microscopy, and by the measure of silicon released from the rock wool fibers. Asbestos fibers were not degraded when incubated in the presence of living bacteria. The MMMF modifications were function of the fiber composition, the time of exposure to activated cells and the concentration of activators. The pattern of MMMF degradation by our in vitro system was in accordance with those observed in an in vivo study, thus indicating that the fiber degradation by macrophage cells activated by E. coli living cells as well as FS is a valuable system to assess mineral fibers' biopersistence.

• Developments in industrial and occupational toxicology: REACH, toxicogenomics, mycotoxins, lead, asbestos, boron, bitumen, deletions polymorphisms and SNP interactions: meeting report of the 16th EUROTOX training and discussion session. G.H. Degen, J.G. Hengstler. 2008;82(7):483-7. PubMed · Publisher

  Summary

  This meeting report summarised the 16th EUROTOX Training and Discussion Session, held in Dortmund, Germany, on 31 January 2008 to mark the retirement of Professor Hermann M. Bolt. With emphasis on carcinogenesis, it covered recent developments in industrial and occupational toxicology in sessions entitled "The 3 R," "Genotoxicity and Carcinogenesis" and "Current and Future Problems." Talks addressed alternatives to animal testing and EU cosmetics legislation. One talk covered the classification of carcinogens by toxicogenomics; in a rat liver study, prediction signatures correctly classified 14 of 16 validation compounds. Others covered ochratoxin A and HLA haplotypes in a Tunisian household of 21 persons, and cytogenetic effects in 50 lead-exposed storage battery workers compared with 30 controls, where high-frequency cell analysis seemed more sensitive than sister chromatid exchange analysis. Further talks dealt with deletion polymorphisms of glutathione S-transferases and with statistical tools for SNP interactions in breast cancer. A talk on current problems in occupational toxicology in Germany explained the legal compensation system using the example of asbestos exposure leading to lung cancer and peritoneal mesothelioma, and also discussed benzene-related neoplasms. Another talk covered the EU classification of boron compounds. The last talk reported a cross-shift study of 74 mastic asphalt workers and 49 reference construction workers, which found irritative effects of bitumen fumes and aerosols on the upper and lower airways, especially above 10 mg/m3.

  PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

• Production of nitric oxide elevates nitrosothiol formation resulting in decreased glutathione in macrophages exposed to asbestos or asbestos substitutes. T. Nishiike, Y. Nishimura, Y. Wada, et al. 2005;79(2):83-9. PubMed · Publisher

  Abstract

  The purpose of this study was to investigate the effects of pneumoconiogenic particles, such as asbestos, on nitrosothiol formation in macrophages. In addition, the effects of man-made mineral fibers (MMMFs) were also evaluated, because they have come into heavy use as substitutes for asbestos. RAW264.7 cells and J774 cells of murine macrophage cell lines were cultured with chrysotile B (CH) asbestos, crocidolite (CR) asbestos, or MMMFs comprised of glass wool (GW), rock wool (RW), or ceramic (RF1). All of these fibers significantly increased nitric oxide (NO) production in the culture with macrophages. Chrysotile B, CR, and GW significantly decreased the level of reduced glutathione (GSH) in RAW264.7 cells. S-nitrosothiol (RS-NO) formation was increased by both types of cells on exposure to every fiber. A large portion of this increased RS-NO may be in the form of S-nitrosoglutathione (GS-NO), because GSH is the most abundant thiol substance in the cell. Both CH and GW significantly increased superoxide anion in the media cultured of RAW264.7 cells. These results indicate that macrophages exposed to asbestos or MMMFs are subject to oxidative stress, not only through the generation of reactive oxygen and nitrogen species, but also through decreases in the level of the cellular antioxidant, GSH, by GS-NO formation. The increase of RS-NO in macrophages exposed to asbestos or MMMFs may deserve more attention as the indicator of continuous oxidative stress by NO on cells and tissues, which causes inflammation and involves the development of asbestos-induced diseases.

1990s

• Biological durability and oxidative potential of a stonewool mineral fibre compared to crocidolite asbestos fibres. S. Hippeli, K. Dornisch, S. Kaiser, et al. 1997;71(8):532-5. PubMed · Publisher

  Abstract

  Experiments are described concerning the differences in redox properties and biodurability of natural asbestos fibres and an experimental stonewool fibre incubated in Gamble solution and reconstructed surfactant fluid. Crocidolite exhibits a significantly higher oxidative potential compared to the tested stonewool fibres. The oxidative activity of both types of fibres is not constant during incubation over several weeks, but rather shows a sinoidal curve including reactivities much higher than those at the beginning of the incubation. A continuous loss of mass is concluded not to be definitively connected with a continuous loss of toxicity.

• Induction of macrophage plasminogen activator by asbestos is independent of PKC activation. D. Lison, F. Raguzzi, R. Lauwerys. 1991;65(5):386-9. PubMed · Publisher

  Abstract

  This study was undertaken to assess whether plasminogen activator (PA) induction in macrophages exposed to chrysotile fibers is mediated by protein kinase C (PKC) activation. In PKC depleted J774 cells, PA induction could be elicited by chrysotile whereas, as expected, the response to phorbol myristate acetate (PMA) was abolished. The effect of PMA and chrysotile on the distribution of PKC activity in the J774 cell line was also compared by measuring the enzyme catalytic activity and phorbol dibutyrate (PDBu) binding sites. No redistribution of PKC was observed after stimulation with PA inducing doses of chrysotile, whereas a clear translocation was observed with PMA. It is concluded that the mechanism of PA induction by chrysotile in this macrophage-like cell line is independent of PKC activation.

1980s

• Cooperative stimulation by sulfite and crocidolite asbestos fibres of enzyme catalyzed production of reactive oxygen species. E.F. Elstner, W. Schütz, G. Vogl. 1988;62(6):424-7. PubMed · Publisher

  Abstract

  Methylthioketobutyric acid has been used as an indicator for the production of reactive oxygen species during incubation with xanthine oxidase or NADH diaphorase in the presence of an autooxidizable quinone. The production of OH-radical-type oxidants is enhanced in the presence of crocidolite but not by the asbestos types chrysotile or amosite. This activity of crocidolite in the diaphorase system is further stimulated by bisulfite. Crocidolite-dependent ethylene formation from methylthioketo-butyric acid is inhibited by both superoxide dismutase and catalase. In the presence of both crocidolite and bisulfite, however, the inhibition by superoxide dismutase is preserved, but the inhibition by catalase is lost. Since in some respect the NADH-diaphorase quinone system may reflect the situation in the activated macrophage, crocidolite activation may represent a biochemical model system describing potential asbestos toxicity.

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