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Risk Assessment of Nanomaterials Toxicity

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A special issue of Nanomaterials (ISSN 2079-4991). This special issue belongs to the section "Biology and Medicines".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 39067

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Special Issue Editors

Prof. Dr. Andrea Hartwig

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Guest Editor

Karlsruhe Institute of Technology (KIT), 76131 Karlsruhe, Germany
Interests: nanotoxicology; genotoxicity; dissolution/biosolubility; gene expression profiling; air–liquid interface exposure
Special Issues, Collections and Topics in MDPI journals

Dr. Christoph van Thriel

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Guest Editor

Leibniz Research Centre for working environment and human factors (IFADO), 44139 Dortmund, Germany
Interests: nanotoxicology; nasal uptake; neurotoxicity; regulatory toxicology; alternative methods
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Regarding the increasing use of nanomaterials in almost every area of our daily life, toxicological risk assessment is one major requirement for their safe handling. Especially at workplaces, inhalation is the major route of exposure and potential toxicity, and the effect on the lungs needs to be considered. Furthermore, neurotoxicity associated with the exposure to nanomaterials is a growing field of scientific investigation. However, not every single nanomaterial can be assessed in long-term animal inhalation studies due to limited resources as well as political and societal efforts to reduce animal experiment according to the 3R principles. Thus, during the last years, much effort has been given to grouping nanomaterials, mainly based on advanced in vitro models. These new approach methodologies (NAMs) include detailed characterization of the respective materials in physiologically relevant media, but also more realistic exposure systems, such as co-cultures, also at the air–liquid interface, combined with comprehensive cellular investigations providing quite detailed toxicological profiles. Furthermore, the first results on long-term toxicity studies with selected nanoparticles are available. Thus, nanoparticles show differences in toxicity depending, e.g., on size, surface reactivity, and dissolution kinetics. Adverse cellular effects include inflammation, genotoxicity, oxidative stress, and epigenetic alterations.

This Special Issue aims to highlight recent advances in mechanisms of nanomaterial toxicity as well as approaches for risk assessment, linking nanoparticle characteristics as well as in vitro toxicity to in vivo observations for advanced risk assessment.

The Special Issue is open to original research articles as well as review papers that contribute to nanomaterial risk assessment.

Prof. Dr. Andrea Hartwig
Dr. Christoph van Thriel
Guest Editors

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Keywords

nanomaterials
inflammation
(oxidative) stress response
genotoxicity
lung toxicity
neurotoxicity

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Published Papers (14 papers)

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Editorial

Jump to: Research, Review

2 pages, 168 KiB

Open AccessEditorial

Risk Assessment of Nanomaterials Toxicity

by Andrea Hartwig and Christoph van Thriel

Nanomaterials 2023, 13(9), 1512; https://doi.org/10.3390/nano13091512 - 28 Apr 2023

Cited by 2 | Viewed by 1080

Abstract

The increasing use of nanomaterials in almost every area of our daily life renders toxicological risk assessment a major requirement for their safe handling [...] Full article

(This article belongs to the Special Issue Risk Assessment of Nanomaterials Toxicity)

Research

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19 pages, 5381 KiB

Open AccessArticle

Assessment of Carbon Nanotubes on Barrier Function, Ciliary Beating Frequency and Cytokine Release in In Vitro Models of the Respiratory Tract

by Claudia Meindl, Markus Absenger-Novak, Ramona Jeitler, Eva Roblegg and Eleonore Fröhlich

Nanomaterials 2023, 13(4), 682; https://doi.org/10.3390/nano13040682 - 9 Feb 2023

Cited by 3 | Viewed by 1695

Abstract

The exposure to inhaled carbon nanotubes (CNT) may have adverse effects on workers upon chronic exposure. In order to assess the toxicity of inhaled nanoparticles in a physiologically relevant manner, an air–liquid interface culture of mono and cocultures of respiratory cells and assessment in reconstructed bronchial and alveolar tissues was used. The effect of CNT4003 reference particles applied in simulated lung fluid was studied in bronchial (Calu-3 cells, EpiAirway™ and MucilAir™ tissues) and alveolar (A549 +/−THP-1 and EpiAlveolar™ +/−THP-1) models. Cytotoxicity, transepithelial electrical resistance, interleukin 6 and 8 secretion, mucociliary clearance and ciliary beating frequency were used as readout parameters. With the exception of increased secretion of interleukin 6 in the EpiAlveolar™ tissues, no adverse effects of CNT4003 particles, applied at doses corresponding to the maximum estimated lifetime exposure of workers, in the bronchial and alveolar models were noted, suggesting no marked differences between the models. Since the doses for whole-life exposure were applied over a shorter time, it is not clear if the interleukin 6 increase in the EpiAlveolar™ tissues has physiological relevance. Full article

(This article belongs to the Special Issue Risk Assessment of Nanomaterials Toxicity)

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15 pages, 3219 KiB

Open AccessArticle

The Effects of Titanium Dioxide Nanoparticles on Osteoblasts Mineralization: A Comparison between 2D and 3D Cell Culture Models

by Gabriela de Souza Castro, Wanderson de Souza, Thais Suelen Mello Lima, Danielle Cabral Bonfim, Jacques Werckmann, Braulio Soares Archanjo, José Mauro Granjeiro, Ana Rosa Ribeiro and Sara Gemini-Piperni

Nanomaterials 2023, 13(3), 425; https://doi.org/10.3390/nano13030425 - 20 Jan 2023

Cited by 2 | Viewed by 2525

Abstract

Although several studies assess the biological effects of micro and titanium dioxide nanoparticles (TiO₂ NPs), the literature shows controversial results regarding their effect on bone cell behavior. Studies on the effects of nanoparticles on mammalian cells on two-dimensional (2D) cell cultures display several disadvantages, such as changes in cell morphology, function, and metabolism and fewer cell–cell contacts. This highlights the need to explore the effects of TiO₂ NPs in more complex 3D environments, to better mimic the bone microenvironment. This study aims to compare the differentiation and mineralized matrix production of human osteoblasts SAOS-2 in a monolayer or 3D models after exposure to different concentrations of TiO₂ NPs. Nanoparticles were characterized, and their internalization and effects on the SAOS-2 monolayer and 3D spheroid cells were evaluated with morphological analysis. The mineralization of human osteoblasts upon exposure to TiO₂ NPs was evaluated by alizarin red staining, demonstrating a dose-dependent increase in mineralized matrix in human primary osteoblasts and SAOS-2 both in the monolayer and 3D models. Furthermore, our results reveal that, after high exposure to TiO₂ NPs, the dose-dependent increase in the bone mineralized matrix in the 3D cells model is higher than in the 2D culture, showing a promising model to test the effect on bone osteointegration. Full article

(This article belongs to the Special Issue Risk Assessment of Nanomaterials Toxicity)

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27 pages, 3218 KiB

Open AccessArticle

Different Sensitivity of Advanced Bronchial and Alveolar Mono- and Coculture Models for Hazard Assessment of Nanomaterials

by Elisabeth Elje, Espen Mariussen, Erin McFadden, Maria Dusinska and Elise Rundén-Pran

Nanomaterials 2023, 13(3), 407; https://doi.org/10.3390/nano13030407 - 19 Jan 2023

Cited by 6 | Viewed by 2416

Abstract

For the next-generation risk assessment (NGRA) of chemicals and nanomaterials, new approach methodologies (NAMs) are needed for hazard assessment in compliance with the 3R’s to reduce, replace and refine animal experiments. This study aimed to establish and characterize an advanced respiratory model consisting of human epithelial bronchial BEAS-2B cells cultivated at the air–liquid interface (ALI), both as monocultures and in cocultures with human endothelial EA.hy926 cells. The performance of the bronchial models was compared to a commonly used alveolar model consisting of A549 in monoculture and in coculture with EA.hy926 cells. The cells were exposed at the ALI to nanosilver (NM-300K) in the VITROCELL^® Cloud. After 24 h, cellular viability (alamarBlue assay), inflammatory response (enzyme-linked immunosorbent assay), DNA damage (enzyme-modified comet assay), and chromosomal damage (cytokinesis-block micronucleus assay) were measured. Cytotoxicity and genotoxicity induced by NM-300K were dependent on both the cell types and model, where BEAS-2B in monocultures had the highest sensitivity in terms of cell viability and DNA strand breaks. This study indicates that the four ALI lung models have different sensitivities to NM-300K exposure and brings important knowledge for the further development of advanced 3D respiratory in vitro models for the most reliable human hazard assessment based on NAMs. Full article

(This article belongs to the Special Issue Risk Assessment of Nanomaterials Toxicity)

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18 pages, 2146 KiB

Open AccessArticle

Impact of Nano- and Micro-Sized Chromium(III) Particles on Cytotoxicity and Gene Expression Profiles Related to Genomic Stability in Human Keratinocytes and Alveolar Epithelial Cells

by Paul Schumacher, Franziska Fischer, Joachim Sann, Dirk Walter and Andrea Hartwig

Nanomaterials 2022, 12(8), 1294; https://doi.org/10.3390/nano12081294 - 11 Apr 2022

Cited by 4 | Viewed by 2242

Abstract

Exposure to Cr(VI) compounds has been consistently associated with genotoxicity and carcinogenicity, whereas Cr(III) is far less toxic, due to its poor cellular uptake. However, contradictory results have been published in relation to particulate Cr₂O₃. The aim of the present study was to investigate whether Cr(III) particles exerted properties comparable to water soluble Cr(III) or to Cr(VI), including two nano-sized and one micro-sized particles. The morphology and size distribution were determined by TEM, while the oxidation state was analyzed by XPS. Chromium release was quantified via AAS, and colorimetrically differentiated between Cr(VI) and Cr(III). Furthermore, the toxicological fingerprints of the Cr₂O₃ particles were established using high-throughput RT-qPCR and then compared to water-soluble Cr(VI) and Cr(III) in A549 and HaCaT cells. Regarding the Cr₂O₃ particles, two out of three exerted only minor or no toxicity, and the gene expression profiles were comparable to Cr(III). However, one particle under investigation released considerable amounts of Cr(VI), and also resembled the toxicity profiles of Cr(VI); this was also evident in the altered gene expression related to DNA damage signaling, oxidative stress response, inflammation, and cell death pathways. Even though the highest toxicity was found in the case of the smallest particle, size did not appear to be the decisive parameter, but rather the purity of the Cr(III) particles with respect to Cr(VI) content. Full article

(This article belongs to the Special Issue Risk Assessment of Nanomaterials Toxicity)

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33 pages, 6477 KiB

Open AccessArticle

PLATOX: Integrated In Vitro/In Vivo Approach for Screening of Adverse Lung Effects of Graphene-Related 2D Nanomaterials

by Otto Creutzenberg, Helena Oliveira, Lucian Farcal, Dirk Schaudien, Ana Mendes, Ana Catarina Menezes, Tatjana Tischler, Sabina Burla and Christina Ziemann

Nanomaterials 2022, 12(8), 1254; https://doi.org/10.3390/nano12081254 - 7 Apr 2022

Cited by 4 | Viewed by 2551

Abstract

Graphene-related two-dimensional nanomaterials possess very technically promising characteristics, but gaps exist regarding their potential adverse health effects. Based on their nano-thickness and lateral micron dimensions, nanoplates exhibit particular aerodynamic properties, including respirability. To develop a lung-focused, in vitro/in vivo screening approach for toxicological hazard assessment, various graphene-related nanoplates, i.e., single-layer graphene (SLG), graphene nanoplatelets (GNP), carboxyl graphene, graphene oxide, graphite oxide and Printex 90^® (particle reference) were used. Material characterization preceded in vitro (geno)toxicity screening (membrane integrity, metabolic activity, proliferation, DNA damage) with primary rat alveolar macrophages (AM), MRC-5 lung fibroblasts, NR8383 and RAW 264.7 cells. Submerse cell exposure and material-adapted methods indicated material-, cell type-, concentration-, and time-specific effects. SLG and GNP were finally chosen as in vitro biologically active or more inert graphene showed eosinophils in lavage fluid for SLG but not GNP. The subsequent 28-day inhalation study (OECD 412) confirmed a toxic, genotoxic and pro-inflammatory potential for SLG at 3.2 mg/m³ with an in vivo-ranking of lung toxicity: SLG > GNP > Printex 90^®. The in vivo ranking finally pointed to AM (lactate dehydrogenase release, DNA damage) as the most predictive in vitro model for the (geno)toxicity screening of graphene nanoplates. Full article

(This article belongs to the Special Issue Risk Assessment of Nanomaterials Toxicity)

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20 pages, 3913 KiB

Open AccessFeature PaperArticle

How Structured Metadata Acquisition Contributes to the Reproducibility of Nanosafety Studies: Evaluation by a Round-Robin Test

by Linda Elberskirch, Adriana Sofranko, Julia Liebing, Norbert Riefler, Kunigunde Binder, Christian Bonatto Minella, Matthias Razum, Lutz Mädler, Klaus Unfried, Roel P. F. Schins, Annette Kraegeloh and Christoph van Thriel

Nanomaterials 2022, 12(7), 1053; https://doi.org/10.3390/nano12071053 - 24 Mar 2022

Cited by 2 | Viewed by 2582

Abstract

It has been widely recognized that nanosafety studies are limited in reproducibility, caused by missing or inadequate information and data gaps. Reliable and comprehensive studies should be performed supported by standards or guidelines, which need to be harmonized and usable for the multidisciplinary field of nanosafety research. The previously described minimal information table (MIT), based on existing standards or guidelines, represents one approach towards harmonization. Here, we demonstrate the applicability and advantages of the MIT by a round-robin test. Its modular structure enables describing individual studies comprehensively by a combination of various relevant aspects. Three laboratories conducted a WST-1 cell viability assay using A549 cells to analyze the effects of the reference nanomaterials NM101 and NM110 according to predefined (S)OPs. The MIT contains relevant and defined descriptive information and quality criteria and thus supported the implementation of the round-robin test from planning, investigation to analysis and data interpretation. As a result, we could identify sources of variability and justify deviating results attributed to differences in specific procedures. Consequently, the use of the MIT contributes to the acquisition of reliable and comprehensive datasets and therefore improves the significance and reusability of nanosafety studies. Full article

(This article belongs to the Special Issue Risk Assessment of Nanomaterials Toxicity)

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18 pages, 3668 KiB

Open AccessArticle

Cellular Uptake of Silica and Gold Nanoparticles Induces Early Activation of Nuclear Receptor NR4A1

by Mauro Sousa de Almeida, Patricia Taladriz-Blanco, Barbara Drasler, Sandor Balog, Phattadon Yajan, Alke Petri-Fink and Barbara Rothen-Rutishauser

Nanomaterials 2022, 12(4), 690; https://doi.org/10.3390/nano12040690 - 18 Feb 2022

Cited by 10 | Viewed by 3330

Abstract

The approval of new nanomedicines requires a deeper understanding of the interaction between cells and nanoparticles (NPs). Silica (SiO₂) and gold (Au) NPs have shown great potential in biomedical applications, such as the delivery of therapeutic agents, diagnostics, and biosensors. NP-cell interaction and internalization can trigger several cellular responses, including gene expression regulation. The identification of differentially expressed genes in response to NP uptake contributes to a better understanding of the cellular processes involved, including potential side effects. We investigated gene regulation in human macrophages and lung epithelial cells after acute exposure to spherical 60 nm SiO₂ NPs. SiO₂ NPs uptake did not considerably affect gene expression in epithelial cells, whereas five genes were up-regulated in macrophages. These genes are principally related to inflammation, chemotaxis, and cell adhesion. Nuclear receptor NR4A1, an important modulator of inflammation in macrophages, was found to be up-regulated. The expression of this gene was also increased upon 1 h of macrophage exposure to spherical 50 nm AuNPs and 200 nm spherical SiO₂ NPs. NR4A1 can thus be an important immediate regulator of inflammation provoked by NP uptake in macrophages. Full article

(This article belongs to the Special Issue Risk Assessment of Nanomaterials Toxicity)

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17 pages, 2264 KiB

Open AccessArticle

Collection of Controlled Nanosafety Data—The CoCoN-Database, a Tool to Assess Nanomaterial Hazard

by Harald F. Krug

Nanomaterials 2022, 12(3), 441; https://doi.org/10.3390/nano12030441 - 28 Jan 2022

Cited by 9 | Viewed by 2265

Abstract

Hazard assessment is the first step in nanomaterial risk assessment. The overall number of studies on the biological effects of nanomaterials or innovative materials is steadily increasing and is above 40,000. Several databases have been established to make the amount of data manageable, but these are often highly specialized or can be used only by experts. This paper describes a new database which uses an already existing data collection of about 35,000 publications. The collection from the first phase between the years 2000 and 2013 contains about 11,000 articles and this number has been reduced by specific selection criteria. The resulting publications have been evaluated for their quality regarding the toxicological content and the experimental data have been extracted. In addition to material properties, the most important value to be extracted is the no-observed-adverse-effect-level (NOAEL) for in vivo and the no-observed-effect-concentration (NOEC) for in vitro studies. The correlation of the NOAEL/NOEC values with the nanomaterial properties and the investigated endpoints has been tested in projects such as the OECD-AOP project, where the available data for inflammatory responses have been analysed. In addition, special attention was paid to titanium dioxide particles and this example is used to show with searches for in vitro and in vivo experiments on possible lung toxicity what a typical result of a database query can look like. In this review, an emerging database is described that contains valuable information for nanomaterial hazard estimation and should aid in the progress of nanosafety research. Full article

(This article belongs to the Special Issue Risk Assessment of Nanomaterials Toxicity)

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24 pages, 6542 KiB

Open AccessArticle

Assessing Genotoxicity of Ten Different Engineered Nanomaterials by the Novel Semi-Automated FADU Assay and the Alkaline Comet Assay

by Sarah May, Cordula Hirsch, Alexandra Rippl, Alexander Bürkle and Peter Wick

Nanomaterials 2022, 12(2), 220; https://doi.org/10.3390/nano12020220 - 10 Jan 2022

Cited by 8 | Viewed by 2714

Abstract

Increased engineered nanomaterial (ENM) production and incorporation in consumer and biomedical products has raised concerns about the potential adverse effects. The DNA damaging capacity is of particular importance since damaged genetic material can lead to carcinogenesis. Consequently, reliable and robust in vitro studies assessing ENM genotoxicity are of great value. We utilized two complementary assays based on different measurement principles: (1) comet assay and (2) FADU (fluorimetric detection of alkaline DNA unwinding) assay. Assessing cell viability ruled out false-positive results due to DNA fragmentation during cell death. Potential structure–activity relationships of 10 ENMs were investigated: three silica nanoparticles (SiO₂-NP) with varying degrees of porosity, titanium dioxide (TiO₂-NP), polystyrene (PS-NP), zinc oxide (ZnO-NP), gold (Au-NP), graphene oxide (GO) and two multi-walled carbon nanotubes (MWNT). SiO₂-NPs, TiO₂-NP and GO were neither cytotoxic nor genotoxic to Jurkat E6-I cells. Quantitative interference corrections derived from GO results can make the FADU assay a promising screening tool for a variety of ENMs. MWNT merely induced cytotoxicity, while dose- and time-dependent cytotoxicity of PS-NP was accompanied by DNA fragmentation. Hence, PS-NP served to benchmark threshold levels of cytotoxicity at which DNA fragmentation was expected. Considering all controls revealed the true genotoxicity for Au-NP and ZnO-NP at early time points. Full article

(This article belongs to the Special Issue Risk Assessment of Nanomaterials Toxicity)

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19 pages, 2546 KiB

Open AccessArticle

Comparison of Metal-Based Nanoparticles and Nanowires: Solubility, Reactivity, Bioavailability and Cellular Toxicity

by Johanna Wall, Didem Ag Seleci, Feranika Schworm, Ronja Neuberger, Martin Link, Matthias Hufnagel, Paul Schumacher, Florian Schulz, Uwe Heinrich, Wendel Wohlleben and Andrea Hartwig

Nanomaterials 2022, 12(1), 147; https://doi.org/10.3390/nano12010147 - 31 Dec 2021

Cited by 8 | Viewed by 3746

Abstract

While the toxicity of metal-based nanoparticles (NP) has been investigated in an increasing number of studies, little is known about metal-based fibrous materials, so-called nanowires (NWs). Within the present study, the physico-chemical properties of particulate and fibrous nanomaterials based on Cu, CuO, Ni, and Ag as well as TiO₂ and CeO₂ NP were characterized and compared with respect to abiotic metal ion release in different physiologically relevant media as well as acellular reactivity. While none of the materials was soluble at neutral pH in artificial alveolar fluid (AAF), Cu, CuO, and Ni-based materials displayed distinct dissolution under the acidic conditions found in artificial lysosomal fluids (ALF and PSF). Subsequently, four different cell lines were applied to compare cytotoxicity as well as intracellular metal ion release in the cytoplasm and nucleus. Both cytotoxicity and bioavailability reflected the acellular dissolution rates in physiological lysosomal media (pH 4.5); only Ag-based materials showed no or very low acellular solubility, but pronounced intracellular bioavailability and cytotoxicity, leading to particularly high concentrations in the nucleus. In conclusion, in spite of some quantitative differences, the intracellular bioavailability as well as toxicity is mostly driven by the respective metal and is less modulated by the shape of the respective NP or NW. Full article

(This article belongs to the Special Issue Risk Assessment of Nanomaterials Toxicity)

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15 pages, 1711 KiB

Open AccessArticle

Agglomeration State of Titanium-Dioxide (TiO₂) Nanomaterials Influences the Dose Deposition and Cytotoxic Responses in Human Bronchial Epithelial Cells at the Air-Liquid Interface

by Sivakumar Murugadoss, Sonja Mülhopt, Silvia Diabaté, Manosij Ghosh, Hanns-Rudolf Paur, Dieter Stapf, Carsten Weiss and Peter H. Hoet

Nanomaterials 2021, 11(12), 3226; https://doi.org/10.3390/nano11123226 - 27 Nov 2021

Cited by 11 | Viewed by 2928

Abstract

Extensive production and use of nanomaterials (NMs), such as titanium dioxide (TiO₂), raises concern regarding their potential adverse effects to humans. While considerable efforts have been made to assess the safety of TiO₂ NMs using in vitro and in vivo studies, results obtained to date are unreliable, possibly due to the dynamic agglomeration behavior of TiO₂ NMs. Moreover, agglomerates are of prime importance in occupational exposure scenarios, but their toxicological relevance remains poorly understood. Therefore, the aim of this study was to investigate the potential pulmonary effects induced by TiO₂ agglomerates of different sizes at the air–liquid interface (ALI), which is more realistic in terms of inhalation exposure, and compare it to results previously obtained under submerged conditions. A nano-TiO₂ (17 nm) and a non-nano TiO₂ (117 nm) was selected for this study. Stable stock dispersions of small agglomerates and their respective larger counterparts of each TiO₂ particles were prepared, and human bronchial epithelial (HBE) cells were exposed to different doses of aerosolized TiO₂ agglomerates at the ALI. At the end of 4h exposure, cytotoxicity, glutathione depletion, and DNA damage were evaluated. Our results indicate that dose deposition and the toxic potential in HBE cells are influenced by agglomeration and exposure via the ALI induces different cellular responses than in submerged systems. We conclude that the agglomeration state is crucial in the assessment of pulmonary effects of NMs. Full article

(This article belongs to the Special Issue Risk Assessment of Nanomaterials Toxicity)

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13 pages, 12134 KiB

Open AccessArticle

Assessing the Toxicological Relevance of Nanomaterial Agglomerates and Aggregates Using Realistic Exposure In Vitro

by Sivakumar Murugadoss, Lode Godderis, Manosij Ghosh and Peter H. Hoet

Nanomaterials 2021, 11(7), 1793; https://doi.org/10.3390/nano11071793 - 9 Jul 2021

Cited by 7 | Viewed by 2707

Abstract

Low dose repeated exposures are considered more relevant/realistic in assessing the health risks of nanomaterials (NM), as human exposure such as in workplace occurs in low doses and in a repeated manner. Thus, in a three-week study, we assessed the biological effects (cell viability, cell proliferation, oxidative stress, pro-inflammatory response, and DNA damage) of titanium-di-oxide nanoparticle (TiO₂ NP) agglomerates and synthetic amorphous silica (SAS) aggregates of different sizes in human bronchial epithelial (HBE), colon epithelial (Caco2), and human monocytic (THP-1) cell lines repeatedly exposed to a non-cytotoxic dose (0.76 µg/cm²). We noticed that neither of the two TiO₂ NPs nor their agglomeration states induced any effects (compared to control) in any of the cell lines tested while SAS aggregates induced some significant effects only in HBE cell cultures. In a second set of experiments, HBE cell cultures were exposed repeatedly to different SAS suspensions for two weeks (first and second exposure cycle) and allowed to recover (without SAS exposure, recovery period) for a week. We observed that SAS aggregates of larger sizes (size ~2.5 µm) significantly affected the cell proliferation, IL-6, IL-8, and total glutathione at the end of both exposure cycle while their nanosized counterparts (size less than 100 nm) induced more pronounced effects only at the end of the first exposure cycle. As noticed in our previous short-term (24 h) exposure study, large aggregates of SAS did appear to be similarly potent as nano sized aggregates. This study also suggests that aggregates of SAS of size greater than 100 nm are toxicologically relevant and should be considered in risk assessment. Full article

(This article belongs to the Special Issue Risk Assessment of Nanomaterials Toxicity)

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Review

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47 pages, 6170 KiB

Open AccessEditor’s ChoiceReview

The State of the Art and Challenges of In Vitro Methods for Human Hazard Assessment of Nanomaterials in the Context of Safe-by-Design

by Nienke Ruijter, Lya G. Soeteman-Hernández, Marie Carrière, Matthew Boyles, Polly McLean, Julia Catalán, Alberto Katsumiti, Joan Cabellos, Camilla Delpivo, Araceli Sánchez Jiménez, Ana Candalija, Isabel Rodríguez-Llopis, Socorro Vázquez-Campos, Flemming R. Cassee and Hedwig Braakhuis

Nanomaterials 2023, 13(3), 472; https://doi.org/10.3390/nano13030472 - 24 Jan 2023

Cited by 10 | Viewed by 4705

Abstract

The Safe-by-Design (SbD) concept aims to facilitate the development of safer materials/products, safer production, and safer use and end-of-life by performing timely SbD interventions to reduce hazard, exposure, or both. Early hazard screening is a crucial first step in this process. In this review, for the first time, commonly used in vitro assays are evaluated for their suitability for SbD hazard testing of nanomaterials (NMs). The goal of SbD hazard testing is identifying hazard warnings in the early stages of innovation. For this purpose, assays should be simple, cost-effective, predictive, robust, and compatible. For several toxicological endpoints, there are indications that commonly used in vitro assays are able to predict hazard warnings. In addition to the evaluation of assays, this review provides insights into the effects of the choice of cell type, exposure and dispersion protocol, and the (in)accurate determination of dose delivered to cells on predictivity. Furthermore, compatibility of assays with challenging advanced materials and NMs released from nano-enabled products (NEPs) during the lifecycle is assessed, as these aspects are crucial for SbD hazard testing. To conclude, hazard screening of NMs is complex and joint efforts between innovators, scientists, and regulators are needed to further improve SbD hazard testing. Full article

(This article belongs to the Special Issue Risk Assessment of Nanomaterials Toxicity)

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