n/aAna Teresa Reis is thankful for the financial support of FCT and FEDER-Fundo Europeu de Desenvolvimento Regional through the COMPETE 2020-POCI, in the framework of the project POCI-01-0145-FEDER-029651, and individual FCT Grant SFRH/BPD/122112/2016. Sonia Fraga acknowledges the funding from the Operational Program for Competitiveness and Internationalization (POCI) through the European Regional Development Funds (FEDER/FNR) and from the Foundation for Science and Technology (FCT) (grant refs. POCI-01-0145-FEDER-031162 and DL-57/INSA-06/2018). The authors also thank FCT/MCTES for the financial support to EPIUnit (UIDB/04750/2020) and ITR (LA/P/0064/2020)

Costa, C

Fraga, S

Reis, AT

International Journal of Molecular Sciences

English

Repositório Aberto da Universidade do Porto

Citation: Reis, A.T.; Costa, C.; Fraga, S.Editorial of Special Issue: The Toxicityof Nanomaterials and LegacyContaminants: Risks to theEnvironment and Human Health. Int.J. Mol. Sci. 2023, 24, 11723. https://doi.org/10.3390/ijms241411723Received: 13 July 2023Accepted: 18 July 2023Published: 21 July 2023Copyright: © 2023 by the authors.Licensee MDPI, Basel, Switzerland.This article is an open access articledistributed under the terms andconditions of the Creative CommonsAttribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). International Journal of Molecular SciencesEditorialEditorial of Special Issue: The Toxicity of Nanomaterials andLegacy Contaminants: Risks to the Environment andHuman HealthAna Teresa Reis 1,2,3,* , Carla Costa 1,2,3 and Sónia Fraga 1,2,31 Environmental Health Department, National Institute of Health Dr. Ricardo Jorge, 4000-055 Porto, Portugal;carla.trindade@insa.min-saude.pt (C.C.); sonia.fraga@insa.min-saude.pt (S.F.)2 EPIUnit—Instituto de Saúde Pública, Universidade do Porto, 4050-600 Porto, Portugal3 Laboratório Para a Investigação Integrativa e Translacional em Saúde Populacional (ITR),Universidade do Porto, 4050-600 Porto, Portugal* Correspondence: ana.reis@insa.min-saude.ptNanotechnology and the incorporation of nanomaterials (NM) into everyday prod-ucts help to solve problems in society and improve the quality of life, allowing for majoradvances in the technological, industrial, and medical fields. Despite this positive andencouraging side of nanotechnology, the potential risks of NM to human health and theenvironment, as well as the ethical, legal, and social implications associated with nanotech-nology, cannot be disregarded. Indeed, the same characteristics that make NM interestingfrom a technological application point of view may be undesirable upon their release intothe environment. In fact, hundreds of tons of NM are released into the environment everyyear. The reduced dimensions of NM facilitate their diffusion into and transport throughthe atmosphere, water, and soil, and as well as their uptake and (bio)accumulation inorganisms [1,2].Nanotoxicology has emerged as a discipline that seeks to assess the potential risk ofNM, integrating knowledge and resources from material science, biology, toxicology, andanalytical chemistry. Several studies have alerted us to the risks that certain NM representfor the environment and for our health, depending on their persistence and circulationin ecosystems, on the dose and responses of organisms to acute and chronic exposure tothese substances, and on the ability of organisms to (bio)accumulate and/or excrete them.However, knowledge of the harmful effects of these contaminants of emerging concernis still insufficient, including mixture effects [2–4]. Efforts to advance our knowledge onthe reactivity of NM and their effects have been made using mostly in vitro and in vivomodels; however, in recent years, in silico approaches and quantitative structure–activityrelationship (QSAR) modeling have been gaining more attention [5]. Nanotoxicity assess-ment using in vitro models gathers important information regarding the mechanism(s) ofaction of NM at the cellular and molecular levels. These models also offer the benefits ofreduced costs and ethical concerns over animal welfare (3Rs principle), usually resulting inthe faster toxicity screening of chemicals, an advantage considering the increasing numberof materials and contaminant combinations to be tested. However, they lack the complexityand metabolic capabilities that in vivo models provide, which is important in identifyingthe relationship between exposure dose and the occurrence of adverse effects, and in under-standing how the body handles NM in terms of their absorption, distribution, metabolism,and excretion (ADME) [6].Some of the aspects mentioned above have been explored in the papers included inthis Special Issue.Inhalation is one of the main pathways for xenobiotics to penetrate the human bodyand, consequently, the respiratory system is one of the most studied targets of the infiltra-tion of nanomaterials [6]. In this regard, Bessa et al. [7] addressed the effects of incidentalInt. J. Mol. Sci. 2023, 24, 11723. https://doi.org/10.3390/ijms241411723 https://www.mdpi.com/journal/ijmsInt. J. Mol. Sci. 2023, 24, 11723 2 of 4fine and nanosized airborne particles emitted during the industrial thermal spray coatingprocesses, in particular high velocity oxy fuel (HVOF) and atmospheric plasma spraying(APS). Overall, particles derived from both processes were found to be toxic to humanalveolar epithelial cells, though different mechanisms were involved in the induced re-sponses. HVOF particles were more cytotoxic compared to APS particles, most likely due todifferences in their elemental composition. However, particles derived from both processescaused DNA damage, with APS particles increasing the levels of H2AX phosphorylation,while HVOF particles caused 8-oxo-7,8-dihydro-20-deoxyguanosine (8-oxo-dG) oxidativeDNA lesions, with the effect being more evident at lower concentrations of the nanosizedparticles compared to the fine particles. This study highlights that workers from industriesemploying processes with a high potential for (nano)particle release may be at (increased)risk of adverse health effects, and therefore must be closely monitored in order to guaranteetheir health and safety.Ziglari et al. [8] also focused on the respiratory system, studying the mechanism oflysosomal membrane permeabilization triggered by NM in murine alveolar macrophages.Using a quick non-invasive method to directly measure lysosomal membrane potential,which was specifically developed for this study, the authors showed that nanoparticles(ZnO and TiO2) and crystalline SiO2 increase lysosomal permeability to cations (potassium),leading to lysosomal membrane hyperpolarization that may potentially damage the lysoso-mal membrane. The authors also explained that hyperpolarization must exceed 40 mV tocause lysosomal membrane permeabilization. These results provide additional insight intothe possible role of particle-induced membrane hyperpolarization on lysosomal membranepermeabilization and other cascade events, such as NLRP3 activation and cell death.One major knowledge gap that has been identified is the effect of concomitant exposureto NM with other contaminants. It is expected that, when released into the environment,NM will coexist and interact with other potentially toxic species. Although scarce, existingdata in the literature indicate that these interactions can affect the physicochemical charac-teristics of NM, as well as their toxicity and absorption by cells/organisms [9,10]. Naaszand colleagues [11] reviewed the available data from 151 studies on NM–chemical mixturesin environmental organisms and concluded that NM may modify the effects of chemicalson organisms in various ways.Rosário et al. [12] studied and discussed the differences resulting from the exposureof liver and neuronal cells to single nanomaterials (TiO2 and CeO2) and potentially toxicelements (As and Hg) or binary mixtures of these compounds. The authors addressedthe viability and proliferative capacity of the cells, as well as changes in their cell cy-cle. Compared to single exposures, and depending on the mixture, the concentration,the exposure time, and the cell, they observed: (1) no change in toxicological response;(2) potentiation effects, particularly after long-term exposure, proving that it is extremelyimportant to address chronic effects, especially if chemicals with a long half-life in humansare present in the mixture; and (3) antagonistic effects on specific conditions, such as theformation of large NP aggregates, that, in turn, hinder their uptake by the cells, block theother contaminants’ access to the cell, and/or if the NP (e.g., CeO2NPs) has the ability toact as an antioxidant and reduce oxidative stress in the cell.This complexity of responses after co-exposure to two compounds was also observedby Carvalhais et al. [13]. These authors studied the isolated and combined effects of two UVfilters, namely TiO2NPs and oxybenzone, conducting in vivo experiments on Scophthalmusmaximus (turbot). Simultaneous exposure to both UV filters resulted in either favorable orunfavorable outcomes, depending on the organ, parameter, and post-exposure time.Even though the respiratory system is one the main direct targets (the gastro-intestinalsystem is also considered one in the case of ingestion), NM can reach the circulatory system,cross blood–organ barriers, and cause toxicity to other organs [14]. Nanoparticle exposurehas been associated with an elevated risk of cardiovascular dysfunction [15,16]. Klinovaet al. [17] investigated in their well-designed study the single and mixture toxicity of lead(PbO) and cadmium oxide (CdO) NP, with a focus on the cardiac inotropic effects, followingInt. J. Mol. Sci. 2023, 24, 11723 3 of 4repeated intraperitoneal administration in rats. Using a combination of classical biochemi-cal, physiological, and pharmacological methods, these authors demonstrated that bothNP, particularly when administered as a mixture, induced marked toxicity as evidencedby cardiac, hepatic, and renal morphometric changes, increased DNA fragmentation inblood nucleated cells, decreased sliding velocity of myofilaments, and changes upon rightventricle trabeculae and papillary muscles’ mechanical work, most likely associated withalterations in intracellular calcium kinetics.Finally, the lack of harmonized protocols for nanotoxicity testing has been high-lighted [18], and it has been shown that NP themselves may interfere with biologicalassays [19], leading to inaccurate results and hindering developments in nanotoxicology.In this context, and considering the existing evidence that cytochalasin-B, used in in vitrocytokinesis-block micronucleus (CBMN), affects the uptake of nanomaterials, hinderingits use in the genotoxicity testing of nanomaterials. Fernández-Bertólez et al. [20] testedTiO2NP uptake and induced genotoxicity in neuroblastoma (SH-SY5Y) cells using flowcytometry and CBMN, after three different treatment options with cytochalasin-B, as recom-mended by the Organisation for Economic Co-operation and Development (OECD). Theresults showed that, even though there was no interference of cytochalasin-B in the uptake,micronuclei induction was affected by the presence of cytochalasin-B in the medium, possi-bly causing false positive results. Once again, it becomes clear that the identification andestablishment of alternative protocols for the assessment of nanomaterials’ genotoxicity areurgently required.The works presented in this Special Issue are intended to advance our knowledgeon NM toxicity. Both occupational and environmental exposure were considered, and thetoxic potential in several target organs (lungs, brain, liver, heart, and intestine) as wellas multiple biomarkers were measured through in vitro and in vivo experiments. Someimportant demands in the field of nanotoxicology have not been adequately met, suchas the co-exposure of NM and other contaminants and the optimization of protocols toconduct toxicity assessments of NPs, highlighting the need for more studies dedicated tothis complex issue in future. Altogether, the results presented by the contributing authorsreinforce the evidence base for preventive actions and the development of safe-by-designNM, while also furthering the analytical progress of new methodologies to assess thetoxicity of pollutants, either as single contaminants or in mixtures. Overall, this SpecialIssue offers scientific evidence and background for researchers working in the field ofepidemiology, toxicology, biochemistry, and nanomedicine.Author Contributions: Conceptualization, A.T.R., C.C. and S.F.; writing—original draft preparation,A.T.R., C.C. and S.F.; writing—review and editing, A.T.R., C.C. and S.F. All authors have read andagreed to the published version of the manuscript.Funding: Ana Teresa Reis is thankful for the financial support of FCT and FEDER—Fundo Eu-ropeu de Desenvolvimento Regional through the COMPETE 2020—POCI, in the framework of theproject POCI-01-0145-FEDER-029651, and individual FCT Grant SFRH/BPD/122112/2016. SóniaFraga acknowledges the funding from the Operational Program for Competitiveness and Interna-tionalization (POCI) through the European Regional Development Funds (FEDER/FNR) and fromthe Foundation for Science and Technology (FCT) (grant refs. POCI-01-0145-FEDER-031162 andDL-57/INSA-06/2018). The authors also thank FCT/MCTES for the financial support to EPIUnit(UIDB/04750/2020) and ITR (LA/P/0064/2020).Conflicts of Interest: The authors declare no conflict of interest.References1. Yang, W.; Wang, L.; Mettenbrink, E.M.; DeAngelis, P.L.; Wilhelm, S. Nanoparticle Toxicology. Annu. Rev. Pharmacol. Toxicol. 2021,61, 269–289. [CrossRef] [PubMed]2. Bundschuh, M.; Filser, J.; Lüderwald, S.; McKee, M.S.; Metreveli, G.; Schaumann, G.E.; Schulz, R.; Wagner, S. Nanoparticles in theEnvironment: Where Do We Come from, Where Do We Go To? Environ. Sci. Eur. 2018, 30, 6. [CrossRef] [PubMed]3. Sengul, A.B.; Asmatulu, E. Toxicity of Metal and Metal Oxide Nanoparticles: A Review. Environ. Chem. Lett. 2020, 18, 1659–1683.[CrossRef]Int. J. Mol. Sci. 2023, 24, 11723 4 of 44. Saleh, T.A. Nanomaterials: Classification, Properties, and Environmental Toxicities. Environ. Technol. Innov. 2020, 20, 101067.[CrossRef]5. Huang, H.J.; Lee, Y.H.; Hsu, Y.H.; Liao, C.T.; Lin, Y.F.; Chiu, H.W. Current Strategies in Assessment of Nanotoxicity: Alternativesto in Vivo Animal Testing. Int. J. Mol. Sci. 2021, 22, 4216. [CrossRef] [PubMed]6. Bessa, M.J.; Brandão, F.; Rosário, F.; Moreira, L.; Reis, A.T.; Valdiglesias, V.; Laffon, B.; Fraga, S.; Teixeira, J.P. Assessing the in VitroToxicity of Airborne (Nano)Particles to the Human Respiratory System: From Basic to Advanced Models. J. Toxicol. Environ.Health B Crit. Rev. 2023, 26, 67–96. [CrossRef] [PubMed]7. Bessa, M.J.; Brandão, F.; Fokkens, P.H.B.; Leseman, D.L.A.C.; Boere, A.J.F.; Cassee, F.R.; Salmatonidis, A.; Viana, M.; Monfort, E.;Fraga, S.; et al. Unveiling the Toxicity of Fine and Nano-Sized Airborne Particles Generated from Industrial Thermal SprayingProcesses in Human Alveolar Epithelial Cells. Int. J. Mol. Sci. 2022, 23, 4278. [CrossRef] [PubMed]8. Ziglari, T.; Wang, Z.; Holian, A. Contribution of Particle-Induced Lysosomal Membrane Hyperpolarization to LysosomalMembrane Permeabilization. Int. J. Mol. Sci. 2021, 22, 2277. [CrossRef] [PubMed]9. Zhang, F.; Wang, Z.; Peijnenburg, W.J.G.M.; Vijver, M.G. Review and Prospects on the Ecotoxicity of Mixtures of Nanoparticlesand Hybrid Nanomaterials. Environ. Sci. Technol. 2022, 56, 15238–15250. [CrossRef] [PubMed]10. Deng, R.; Lin, D.; Zhu, L.; Majumdar, S.; White, J.C.; Gardea-Torresdey, J.L.; Xing, B. Nanoparticle Interactions with Co-ExistingContaminants: Joint Toxicity, Bioaccumulation and Risk. Nanotoxicology 2017, 11, 591–612. [CrossRef] [PubMed]11. Naasz, S.; Altenburger, R.; Kühnel, D. Environmental Mixtures of Nanomaterials and Chemicals: The Trojan-Horse Phenomenonand Its Relevance for Ecotoxicity. Sci. Total Environ. 2018, 635, 1170–1181. [CrossRef]12. Rosário, F.; Costa, C.; Lopes, C.B.; Estrada, A.C.; Tavares, D.S.; Pereira, E.; Teixeira, J.P.; Reis, A.T. In Vitro Hepatotoxic andNeurotoxic Effects of Titanium and Cerium Dioxide Nanoparticles, Arsenic and Mercury Co-Exposure. Int. J. Mol. Sci. 2022,23, 2737. [CrossRef] [PubMed]13. Carvalhais, A.; Pereira, B.; Sabato, M.; Seixas, R.; Dolbeth, M.; Marques Guilherme, A.S.; Pereira, P.; Pacheco, M.; Mieiro, C. MildEffects of Sunscreen Agents on a Marine Flatfish: Oxidative Stress, Energetic Profiles, Neurotoxicity and Behaviour in Responseto Titanium Dioxide Nanoparticles and Oxybenzone. Int. J. Mol. Sci. 2021, 22, 1567. [CrossRef]14. Raftis, J.B.; Miller, M.R. Nanoparticle Translocation and Multi-Organ Toxicity: A Particularly Small Problem. Nano Today 2019,26, 8–12. [CrossRef]15. Cao, Y.; Gong, Y.; Liao, W.; Luo, Y.; Wu, C.; Wang, M.; Yang, Q. A Review of Cardiovascular Toxicity of TiO2, ZnO and AgNanoparticles (NPs). BioMetals 2018, 31, 457–476. [CrossRef]16. Yu, X.; Hong, F.; Zhang, Y.Q. Bio-Effect of Nanoparticles in the Cardiovascular System. J. Biomed. Mater. Res. A 2016,104, 2881–2897. [CrossRef]17. Klinova, S.V.; Katsnelson, B.A.; Minigalieva, I.A.; Gerzen, O.P.; Balakin, A.A.; Lisin, R.V.; Butova, K.A.; Nabiev, S.R.; Lookin,O.N.; Katsnelson, L.B.; et al. Cardioinotropic Effects in Subchronic Intoxication of Rats with Lead and/or Cadmium OxideNanoparticles. Int. J. Mol. Sci. 2021, 22, 3466. [CrossRef] [PubMed]18. Krug, H.F.; Nau, K. Editorial: Methods and Protocols in Nanotoxicology. Front. Toxicol. 2022, 4, 1093765. [CrossRef] [PubMed]19. Ong, K.J.; MacCormack, T.J.; Clark, R.J.; Ede, J.D.; Ortega, V.A.; Felix, L.C.; Dang, M.K.M.; Ma, G.; Fenniri, H.; Veinot, J.G.C.; et al.Widespread Nanoparticle-Assay Interference: Implications for Nanotoxicity Testing. PLoS ONE 2014, 9, e90650. [CrossRef]20. Fernández-Bertólez, N.; Brandão, F.; Costa, C.; Pásaro, E.; Teixeira, J.P.; Laffon, B.; Valdiglesias, V. Suitability of the in VitroCytokinesis-Block Micronucleus Test for Genotoxicity Assessment of TiO2 Nanoparticles on SH-SY5Y Cells. Int. J. Mol. Sci. 2021,22, 8558. [CrossRef]Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individualauthor(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury topeople or property resulting from any ideas, methods, instructions or products referred to in the content.

Editorial of Special Issue: The Toxicity of Nanomaterials and Legacy Contaminants: Risks to the Environment and Human Health

Editorial of Special Issue Toxicity of Nanomaterials and Legacy Contaminants: Risks to the Environment and Human Health.Nanotechnology and the incorporation of nanomaterials (NM) into everyday products help to solve problems in society and improve the quality of life, allowing for major advances in the technological, industrial, and medical fields. Despite this positive and encouraging side of nanotechnology, the potential risks of NM to human health and the environment, as well as the ethical, legal, and social implications associated with nanotechnology, cannot be disregarded. Indeed, the same characteristics that make NM interesting from a technological application point of view may be undesirable upon their release into the environment. In fact, hundreds of tons of NM are released into the environment every year. The reduced dimensions of NM facilitate their diffusion into and transport through the atmosphere, water, and soil, and as well as their uptake and (bio)accumulation in organisms.
Nanotoxicology has emerged as a discipline that seeks to assess the potential risk of NM, integrating knowledge and resources from material science, biology, toxicology, and analytical chemistry. Several studies have alerted us to the risks that certain NM represent for the environment and for our health, depending on their persistence and circulation in ecosystems, on the dose and responses of organisms to acute and chronic exposure to these substances, and on the ability of organisms to (bio)accumulate and/or excrete them. However, knowledge of the harmful effects of these contaminants of emerging concern is still insufficient, including mixture effects. Efforts to advance our knowledge on the reactivity of NM and their effects have been made using mostly in vitro and in vivo models; however, in recent years, in silico approaches and quantitative structure–activity relationship (QSAR) modeling have been gaining more attention. Nanotoxicity assessment using in vitro models gathers important information regarding the mechanism(s) of action of NM at the cellular and molecular levels. These models also offer the benefits of reduced costs and ethical concerns over animal welfare (3Rs principle), usually resulting in the faster toxicity screening of chemicals, an advantage considering the increasing number of materials and contaminant combinations to be tested. However, they lack the complexity and metabolic capabilities that in vivo models provide, which is important in identifying the relationship between exposure dose and the occurrence of adverse effects, and in understanding how the body handles NM in terms of their absorption, distribution, metabolism, and excretion (ADME). (...)Ana Teresa Reis is thankful for the financial support of FCT and FEDER—Fundo Europeu de Desenvolvimento Regional through the COMPETE 2020—POCI, in the framework of the project POCI-01-0145-FEDER-029651, and individual FCT Grant SFRH/BPD/122112/2016. Sónia Fraga acknowledges the funding from the Operational Program for Competitiveness and Internationalization (POCI) through the European Regional Development Funds (FEDER/FNR) and from the Foundation for Science and Technology (FCT) (grant refs. POCI-01-0145-FEDER-031162 and DL-57/INSA-06/2018). The authors also thank FCT/MCTES for the financial support to EPIUnit (UIDB/04750/2020) and ITR (LA/P/0064/2020)info:eu-repo/semantics/publishedVersio

Reis, Ana Teresa

Costa, Carla

Fraga, Sónia

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The Toxicity of Nanomaterials and Legacy Contaminants: Risks to the Environment and Human Health

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Editorial of Special Issue: The Toxicity of Nanomaterials and Legacy Contaminants: Risks to the Environment and Human Health

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