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Hazard assessment of nanomaterials using in vitro toxicity assays: Guidance on potential assay interferences and mitigating actions to avoid biased results

Yamani, Naouale El; Rundén-Pran, Elise; Varet, Julia; Beus, Maja; Dusinska, Maria; Fessard, Valerie; Moschini, Elisa; Serchi, Tommaso; Cimpan, Mihaela Roxana; Lynch, Iseult; Vrček, ivana Vinković

The movement towards an animal-free testing approach for risk assessment represents a key paradigm shift in toxicology. Risk assessment of engineered and anthropogenic nanoscale materials (NM) is dependent on reliable hazard characterization, which requires validated test methods and models, and increasingly on mechanistic insights into the mode of action. The properties that make NMs so advantageous for a wide range of commercial and industrial applications also pose a challenge when it comes to safety testing under in vitro and in chemico experimental settings. Their large reactive surface area makes NMs prone to interactions with assay reagents, readout signals, or intermediate steps of many test assays, leading to the potential for biased results and data inconsistencies, collectively referred to as interferences. Therefore, methods and protocols developed and validated for conventional chemicals often require adaptation and checking for reliability in NMs' toxicity assessment. This review presents the collected scientific knowledge on NMs-induced interferences for the most common in vitro toxicity assays and methods related to cytotoxicity, oxidative stress and inflammatory response evaluation. Our analysis of existing scientific literature showed that the challenge of NMs-induced interference was not explicitly addressed in more than 90% of the papers published up to 2014 reporting the safety and toxicity of NMs. In later years, increasing number of studies tackled the interference challenge in toxicity testing of NMs, which initiated exhaustive work on standardization and validation of existing regulatory-relevant in vitro test protocols and guidelines. Due to the specificity of the different NMs and the range of ways they can potentially interfere with in vitro assays, interference and fit-for purpose controls should be included for each NM type and method applied, unless label-free assays are selected. Here, we provide a decision tree to guide researchers on how to design experiments to avoid interferences during in vitro testing by taking appropriate mitigation actions and how to include proper interference controls in their experimental design where complete avoidance is not possible. The application of this decision tree will improve the reliability, comparability and reusability of in vitro toxicity data on engineered NMs or ENMs, increasing the relevance of in silico hazard data for use in risk assessment and in science-based risk governance of NMs. The approach is applicable more broadly also, to advanced materials and to hazard assessment of anthropogenic nanoscale materials such as microplastic and tyre-wear particles.

2024

Validation practices for satellite soil moisture retrievals: What are (the) errors?

Gruber, Alexander; Lannoy, Gabriëlle J.M de; Albergel, Clément; Al-Yaari, Amen; Brocca, Luca; Calvet, Jean-Christophe; Colliander, Andreas; Cosh, Michael H.; Crow, Wade T.; Dorigo, Wouter Arnaud; Draper, Clara Sophie; Hirschi, Martin; Kerr, Yann H.; Konings, Alexandra G.; Lahoz, William A.; McColl, Kaighin Alexander; Montzka, Carsten; Muñoz-Sabater, Joaquín; Peng, Jian; Reichle, Rolf H.; Richaume, Philippe; Rüdiger, Christoph; Scanlon, Tracy; Schalie, Robin van der; Wigneron, Jean Pierre; Wagner, Wolfgang

This paper presents a community effort to develop good practice guidelines for the validation of global coarse-scale satellite soil moisture products. We provide theoretical background, a review of state-of-the-art methodologies for estimating errors in soil moisture data sets, practical recommendations on data pre-processing and presentation of statistical results, and a recommended validation protocol that is supplemented with an example validation exercise focused on microwave-based surface soil moisture products. We conclude by identifying research gaps that should be addressed in the near future.

2020

Insights into possibilities for grouping and read-across for nanomaterials in EU chemicals legislation

Mech, A.; Rasmussen, K.; Jantunen, P.; Aicher, L.; Alessandrelli, M.; Bernauer, U.; Bleeker, E. A. J.; Bouillard, J.; Fanghella, P. Di Prospero; Draisci, R.; Dusinska, Maria; Encheva, G.; Flament, G.; Haase, A.; Handzhiyski, Y.; Herzberg, F.; Huwyler, J.; Jacobsen, N.R.; Jeliazkov, V.; Jeliazkova, N.; Nymark, P.; Grafström, R.; Oomen, A. G.; Polci, M. L.; Riebeling, C.; Sandström, J.; Shivachev, B.; Stateva, S.; Tanasescu, S.; Tsekovska, R.; Wallin, Håkan; Wilks, M. F.; Zellmer, S.; Apostolova, M. D.

This paper presents a comprehensive review of European Union (EU) legislation addressing the safety of chemical substances, and possibilities within each piece of legislation for applying grouping and read-across approaches for the assessment of nanomaterials (NMs). Hence, this
review considers both the overarching regulation of chemical substances under REACH (Regulation (EC) No 1907/2006 on registration, evaluation, authorization, and restriction of chemicals) and CLP (Regulation (EC) No 1272/2008 on classification, labeling and packaging of substances and mixtures) and the sector-specific pieces of legislation for cosmetic, plant protection and biocidal products, and legislation addressing food, novel food, and food contact materials. The relevant supporting documents (e.g. guidance documents) regarding each piece of legislation were identified and reviewed, considering the relevant technical and scientific literature. Prospective regulatory needs for implementing grouping in the assessment of NMs were identi-
fied, and the question whether each particular piece of legislation permits the use of grouping and read-across to address information gaps was answered.

2019

NORMAN guidance on suspect and non-target screening in environmental monitoring

Hollender, Juliane; Schymanski, Emma L.; Ahrens, Lutz; Alygizakis, Nikiforos; Been, Frederic; Bijlsma, Lubertus; Brunner, Andrea M.; Celma, Alberto; Fildier, Aurelie; Fu, Qiuguo; Gago-Ferrero, Pablo; Gil-Solsona, Ruben; Haglund, Peter; Hansen, Martin; Kaserzon, Sarit; Kruve, Anneli; Lamoree, Marja; Margoum, Christelle; Meijer, Jeroen; Merel, Sylvain; Rauert, Cassandra; Rostkowski, Pawel; Samanipour, Saer; Schulze, Bastian; Shculze, Tobias; Singh, Randolph R.; Slobodnik, Jaroslav; Steininger-Mairinger, Teresa; Thomaidis, Nikolaos S.; Togola, Anne; Vorkamp, Katrin; Vulliet, Emmanuelle; Zhu, Linyan; Krauss, Martin

Increasing production and use of chemicals and awareness of their impact on ecosystems and humans has led to large interest for broadening the knowledge on the chemical status of the environment and human health by suspect and non-target screening (NTS). To facilitate effective implementation of NTS in scientific, commercial and governmental laboratories, as well as acceptance by managers, regulators and risk assessors, more harmonisation in NTS is required. To address this, NORMAN Association members involved in NTS activities have prepared this guidance document, based on the current state of knowledge. The document is intended to provide guidance on performing high quality NTS studies and data interpretation while increasing awareness of the promise but also pitfalls and challenges associated with these techniques. Guidance is provided for all steps; from sampling and sample preparation to analysis by chromatography (liquid and gas—LC and GC) coupled via various ionisation techniques to high-resolution tandem mass spectrometry (HRMS/MS), through to data evaluation and reporting in the context of NTS. Although most experience within the NORMAN network still involves water analysis of polar compounds using LC–HRMS/MS, other matrices (sediment, soil, biota, dust, air) and instrumentation (GC, ion mobility) are covered, reflecting the rapid development and extension of the field. Due to the ongoing developments, the different questions addressed with NTS and manifold techniques in use, NORMAN members feel that no standard operation process can be provided at this stage. However, appropriate analytical methods, data processing techniques and databases commonly compiled in NTS workflows are introduced, their limitations are discussed and recommendations for different cases are provided. Proper quality assurance, quantification without reference standards and reporting results with clear confidence of identification assignment complete the guidance together with a glossary of definitions. The NORMAN community greatly supports the sharing of experiences and data via open science and hopes that this guideline supports this effort.

2023

Genotoxicity of nanomaterials: Advanced in vitro models and high throughput methods for human hazard assessment—a review

Kohl, Yvonne; Rundén-Pran, Elise; Mariussen, Espen; Hesler, Michelle; Yamani, Naouale El; Longhin, Eleonora Marte; Dusinska, Maria

Changes in the genetic material can lead to serious human health defects, as mutations in somatic cells may cause cancer and can contribute to other chronic diseases. Genotoxic events can appear at both the DNA, chromosomal or (during mitosis) whole genome level. The study of mechanisms leading to genotoxicity is crucially important, as well as the detection of potentially genotoxic compounds. We consider the current state of the art and describe here the main endpoints applied in standard human in vitro models as well as new advanced 3D models that are closer to the in vivo situation. We performed a literature review of in vitro studies published from 2000–2020 (August) dedicated to the genotoxicity of nanomaterials (NMs) in new models. Methods suitable for detection of genotoxicity of NMs will be presented with a focus on advances in miniaturization, organ-on-a-chip and high throughput methods.

2020

The role of nature-based solutions for improving environmental quality, health and well-being

Liu, Hai Ying; Jay, Marion; Chen, Xianwen

Nature-based solutions (NbS) have been positioned and implemented in urban areas as solutions for enhancing urban resilience in the face of a wide range of urban challenges. However, there is a lack of recommendations of optimal NbS and appropriate typologies fitting to different contexts and urban design. The analytical frameworks for NbS implementation and impact evaluation, that integrate NbS into local policy frameworks, socio-economic transition pathways, and spatial planning, remain fragmented. In this article, the NbS concept and its related terminologies are first discussed. Second, the types of NbS implemented in Europe are reviewed and their benefits over time are explored, prior to categorizing them and highlighting the key methods, criteria, and indicators to identify and assess the NbS’s impacts, co-benefits, and trade-offs. The latter involved a review of the websites of 52 projects and some relevant publications funded by EU Research and Innovation programs and other relevant publications. The results show that there is a shared understanding that the NbS concept encompasses benefits of restoration and rehabilitation of ecosystems, carbon neutrality, improved environmental quality, health and well-being, and evidence for such benefits. This study also shows that most NbS-related projects and activities in Europe use hybrid approaches, with NbS typically developed, tested, or implemented to target specific types of environmental–social–economic challenges. The results of this study indicate that NbS as a holistic concept would be beneficial in the context of climate action and sustainable solutions to enhance ecosystem resilience and adaptive capacity within cities. As such, this article provides a snapshot of the role of NbS in urban sustainability development, a guide to the state-of-the-art, and key messages and recommendations of this rapidly emerging and evolving field.

2021

Oceanic long-range transport of organic additives present in plastic products: an overview

Andrade, Helena; Glüge, Juliane; Herzke, Dorte; Ashta, Narain Maharaj; Nayagar, Shwetha Manohar; Scheringer, Martin

Most plastics are made of persistent synthetic polymer matrices that contain chemical additives in significant amounts. Millions of tonnes of plastics are produced every year and a significant amount of this plastic enters the marine environment, either as macro- or microplastics. In this article, an overview is given of the presence of marine plastic debris globally and its potential to reach remote locations in combination with an analysis of the oceanic long-range transport potential of organic additives present in plastic debris. The information gathered shows that leaching of hydrophobic substances from plastic is slow in the ocean, whereas more polar substances leach faster but mostly from the surface layers of the particle. Their high content used in plastic of several percent by weight allows also these chemicals to be transported over long distances without being completely depleted along the way. It is therefore likely that various types of additives reach remote locations with plastic debris. As a consequence, birds or other wildlife that ingest plastic debris are exposed to these substances, as leaching is accelerated in warm-blooded organisms and in hydrophobic fluids such as stomach oil, compared to leaching in water. Our estimates show that approximately 8100–18,900 t of various organic additives are transported with buoyant plastic matrices globally with a significant portion also transported to the Arctic. For many of these chemicals, long-range transport (LRT) by plastic as a carrier is their only means of travelling over long distances without degrading, resulting in plastic debris enabling the LRT of chemicals which otherwise would not reach polar environments with unknown consequences. The transport of organic additives via plastic debris is an additional long-range transport route that should also be considered under the Stockholm Convention.

2021

What is the effect of phasing out long-chain per- and polyfluoroalkyl substances on the concentrations of perfluoroalkyl acids and their precursors in the environment? A systematic review

Land, Magnus; Wit, Cynthia A. de; Bignert, Anders; Cousins, Ian T.; Herzke, Dorte; Johansson, Jana H.; Martin, Jonathan W.

There is a concern that continued emissions of man-made per- and polyfluoroalkyl substances (PFASs) may cause environmental and human health effects. Now widespread in human populations and in the environment, several PFASs are also present in remote regions of the world, but the environmental transport and fate of PFASs are not well understood. Phasing out the manufacture of some types of PFASs started in 2000 and further regulatory and voluntary actions have followed. The objective of this review is to understand the effects of these actions on global scale PFAS concentrations.

2018

Technical recommendations to perform the alkaline standard and enzyme-modified comet assay in human biomonitoring studies

Azqueta, Amaya; Muruzabal, Damian; Boutet-Robinet, Elisa; Milic, Mirta; Dusinska, Maria; Brunborg, Gunnar; Møller, Peter; Collins, Andrew R.

The comet assay (single cell gel electrophoresis) is widely used as a biomonitoring tool to assess DNA damage – strand breaks, as well as oxidised bases; it can also be adapted to measure DNA repair. It is based on the ability of breaks in the DNA to relax supercoiling, allowing DNA loops to extend from the nuclear core (nucleoid) under an electric field to form a comet-like tail. Most commonly, it is applied to white blood cells. The range of detection is between a few hundred breaks per cell and a few thousand, encompassing levels of damage that can be repaired and tolerated by human cells. Its applications include monitoring various diseases, studying the influence of nutrition on DNA stability, and investigating effects of environmental and occupational mutagens. Here we address the issue of inter-laboratory variation in comet assay results. This variation is largely due to differences in methods. Imposing a standard protocol is not practical, but users should be aware of the crucial parameters that affect performance of the assay. These include the concentration of agarose in which the cells are embedded; the duration of cell lysis, and of enzyme incubation when oxidised bases are being measured; the duration of alkaline unwinding; the duration of electrophoresis and the voltage gradient applied; and the method used to score the comets. Including reference standards in each experiment allows experimental variability to be monitored – and if variation is not extreme, results can be normalised using reference standard values. Reference standards are also essential for inter-laboratory comparison. Finally, we offer recommendations which, we believe, will limit variability and increase the usefulness of this assay in molecular epidemiology.

2019

Applications of low-cost sensing technologies for air quality monitoring and exposure assessment: How far have they gone?

Morawska, Lidia; Thai, Phong K.; Liu, Xiaoting; Asumadu-Sakyi, Akwasi; Ayoko, Godwin; Bartonova, Alena; Bedini, Andrea; Chai, Fahe; Christensen, Bryce; Dunbabin, Matthew; Gao, Jian; Hagler, Gayle S. W.; Jayaratne, Rohan; Kumar, Prashant; Lau, Alexis K. H.; Louie, Peter K. K.; Mazaheri, Mandana; Ning, Zhi; Motta, Nunzio; Mullins, Ben; Rahman, Md Mahmudur; Ristovski, Zoran; Shafiei, Mahnaz; Tjondronegoro, Dian; Westerdahl, Dane; Williams, Ron

2018

Comparison of observation- and inventory-based methane emissions for eight large global emitters

Petrescu, Ana Maria Roxana; Peters, Glen Philip; Engelen, Richard; Houweling, Sander; Brunner, Dominik; Tsuruta, Aki; Matthews, Bradley; Patra, Prabir K.; Belikov, Dmitry; Thompson, Rona Louise; Hoglund-Isaksson, Lena; Zhang, Wenxin; Segers, Arjo; Etiope, Giuseppe; Ciotoli, Giancarlo; Peylin, Philippe; Chevallier, Frédéric; Aalto, Tuula; Andrew, Robbie; Bastviken, David; Berchet, Antoine; Broquet, Gregoire; Conchedda, Giulia; Dellaert, Stijn N. C.; Gon, Hugo Denier van der; Gütschow, Johannes; Haussaire, Jean-Matthieu; Lauerwald, Ronny; Markkanen, Tiina; Peet, Jacob C. A. van; Pison, Isabelle; Regnier, Pierre; Sollum, Espen; Scholze, Marko; Tenkanen, Maria; Tubiello, Francesco N.; Werf, Guido R. van der; Worden, John R.

Monitoring the spatial distribution and trends in surface greenhouse gas (GHG) fluxes, as well as flux attribution to natural and anthropogenic processes, is essential to track progress under the Paris Agreement and to inform its global stocktake. This study updates earlier syntheses (Petrescu et al., 2020, 2021, 2023), provides a consolidated synthesis of CH4 emissions using bottom-up (BU) and top-down (TD) approaches for the European Union (EU), and is expanded to include seven additional countries with large anthropogenic and/or natural emissions (the USA, Brazil, China, India, Indonesia, Russia, and the Democratic Republic of the Congo (DR Congo)). Our aim is to demonstrate the use of different emission estimates to help improve national GHG emission inventories for a diverse geographical range of stakeholders.

We use updated national GHG inventories (NGHGIs) reported by Annex I parties under the United Nations Framework Convention on Climate Change (UNFCCC) in 2023 and the latest available biennial update reports (BURs) reported by non-Annex I parties. Comparing NGHGIs with other approaches highlights that different system boundaries are a key source of divergence. A key system boundary difference is whether anthropogenic and natural fluxes are included and, if they are, how fluxes belonging to these two sources are partitioned.

Over the studied period, the total CH4 emission estimates in the EU, the USA, and Russia show a steady decreasing trend since 1990, while for the non-Annex I emitters analyzed in this study, Brazil, China, India, Indonesia, and DR Congo, CH4 emissions have generally increased. Quantitatively, in the EU the mean of 2015–2020 anthropogenic UNFCCC NGHGIs (15±1.8 Tg CH4 yr−1) and the mean of the BU CH4 emissions (17.8 (16–19) Tg CH4 yr−1) generally agree on the magnitude, while inversions show higher emission estimates (medians of 21 (19–22) Tg CH4 yr−1 and 24 (22–25) Tg CH4 yr−1 for the three regional and six global inversions, respectively), as they include natural emissions, which for the EU were quantified at 6.6 Tg CH4 yr−1 (Petrescu et al., 2023). Similarly, for the other Annex I parties in this study (the USA and Russia), the gap between the BU anthropogenic and total TD emissions is partly explained by the natural emissions.

For the non-Annex I parties, anthropogenic CH4 estimates from UNFCCC BURs show large differences compared to the other global-inventory-based estimates and even more compared to atmospheric ones. This poses an important potential challenge to monitoring the progress of the global CH4 pledge and the global stocktake. Our analysis provides a useful baseline to prepare for the influx of inventories from non-Annex I parties as regular reporting starts under the enhanced transparency framework of the Paris Agreement.

By systematically comparing the BU and TD methods, this study provides recommendations for more robust comparisons of available data sources and hopes to steadily engage more parties in using observational methods to complement their UNFCCC inventories, as well as considering their natural emissions. With anticipated improvements in atmospheric modeling and observations, as well as modeling of natural fluxes, future development needs to resolve knowledge gaps in the BU and TD approaches and to better quantify the remaining uncertainty. TD methods may emerge as a powerful tool to help improve NGHGIs of CH4 emissions, but further confidence is needed in the comparability and robustness of the estimates.

The referenced datasets related to figures are available at https://doi.org/10.5281/zenodo.12818506 (Petrescu et al., 2024).

2024

New Approach Methods (NAMs) for genotoxicity assessment of nano- and advanced materials; Advantages and challenges

Gutleb, Arno; Murugadoss, Sivakumar; Stepnik, Maciej; SenGupta, Tanima; Yamani, Naouale El; Longhin, Eleonora Marta; Olsen, Ann-Karin Hardie; Wyrzykowska, Ewelina; Jagiello, Karolina; Judzinska, Beata; Cambier, Sebastien; Honza, Tatiana; McFadden, Erin; Shaposhnikov, Sergey; Puzyn, Tomasz; Serchi, Tommaso; Weber, Pamina; Arnesdotter, Emma; Skakalova, Vier; Jirsova, Katerina; Grudzinski, Ireneusz; Collins, Andrew; Rundén-Pran, Elise; Dusinska, Maria

Genotoxicity assessment is essential for ensuring chemical safety and mitigating risks to human health and the environment. Traditional methods, reliant on animal models, are time-consuming, costly, and raise ethical concerns. New Approach Methods (NAMs) offer innovative, cost-effective, and ethical alternatives, playing a pivotal role in both traditional and next-generation risk assessment (NGRA) by minimizing the need for animal testing, particularly in genotoxicity evaluations. However, the development of NAMs often overlooks the particular physicochemical properties of nanomaterials (NMs), which significantly influence their toxicological behaviour and can interfere with genotoxicity evaluation. This underscores an urgent need for the standardization and adaptation of NAMs to address nano- and advanced material-specific genotoxicity challenges. In this review, we summarize the challenges associated with genotoxicity testing of NMs and highlight the suitability of existing in vitro and in silico NAMs for NMs and advanced materials, enabling genotoxicity testing across various exposure routes and organ systems. Despite considerable progress, regulatory validation remains constrained by the absence of approved test guidelines and standardized protocols. To achieve regulatory acceptance, it is crucial to adapt NAMs to NM-specific exposure scenarios, refine test systems to better mimic human biology, develop tailored in vitro protocols, and ensure thorough characterisation of NMs both in pristine form and dispersed in culture medium. Collaborative efforts among scientists, regulators, industry, and advocacy groups are vital to improving the reliability and regulatory acceptance of NAMs. By addressing these challenges, NAMs have the potential to revolutionize genotoxicity risk assessment, advancing it towards a more sustainable, efficient and ethical framework.

2025

Transitioning to building integration of photovoltaics and greenery (BIPVGREEN): case studies up-scaling from cities informal settlements

Karamanis, Dimitrios; Liu, Hai Ying; Skandalos, Nikolaos; Makis, Achilleas; Kapsalis, Vasileios; D’Agostino, Delia; Maduta, Carmen; Tolis, Athanasios; Trandafir, Simona; Parker, Danny

To achieve the objectives of COP28 for transitioning away from fossil fuels and phasing these out, both natural and technological solutions are essential, necessitating a step-change in how we implement social innovation. Given the significant CO2 emissions produced by the building sector, there is an urgent need for a transformative shift towards a net-zero building stock by mid-century. This transition to zero-energy and zero-emission buildings is difficult due to complex processes and substantial costs. Building integrated photovoltaics (BIPV) offers a promising solution due to the benefits of enhanced energy efficiency and electricity production. The availability of roof and façade space in offices and other types of buildings, especially in large cities, permits photovoltaic integration in both opaque and transparent surfaces. This study investigates the synergistic relationship between solar conversion technologies and nature-based components. Through a meta-analysis of peer-reviewed literature and critical assessment, effective BIPVs with greenery (BIPVGREEN) combinations suitable for various climatic zones are identified. The results highlight the multi-faceted benefits of this integration across a range of techno-economic and social criteria and underscore the feasibility of up-scaling these solutions for broader deployment. Applying a SWOT analysis approach, the internal strengths and weaknesses, as well as the external opportunities and threats for BIPVGREEN deployment, are investigated. The analysis reveals key drivers of synergistic effects and multi-benefits, while also addressing the challenges associated with optimizing performance and reducing investment costs. The strengths of BIPVGREEN in terms of energy efficiency and sustainable decarbonization, along with its potential to mitigate urban and climate temperature increases, enhance its relevance to the built environment, especially for informal settlements. The significance of prioritizing this BIPVGREEN climate mitigation action in low-income vulnerable regions and informal settlements is crucial through the minimum tax financing worldwide and citizen's engagement in architectural BIPVGREEN co-integration.

2024

Hazard characterization of the mycotoxins enniatins and beauvericin to identify data gaps and improve risk assessment for human health

Behr, Anne-Cathrin; Fæste, Christiane Kruse; Azqueta, Amaya; Tavares, Ana M.; Spyropoulou, Anastasia; Solhaug, Anita; Olsen, Ann-Karin Hardie; Vettorazzi, Ariane; Mertens, Birgit; Zegura, Bojana; Streel, Camille; Ndiaye, Dieynaba; Spilioti, Eliana; Dubreil, Estelle; Buratti, Franca Maria; Crudo, Francesco; Eriksen, Gunnar Sundstøl; Snapkov, Igor; Teixeira, João Paulo; Rasinger, Josef; Sanders, Julie; Machera, Kyriaki; Ivanova, Lada; Gaté, Laurent; Hegarat, Ludovic Le; Novak, Matjaz; Smith, Nicola Margareta; Tait, Sabrina; Fraga, Sónia; Hager, Sonja; Marko, Doris; Braeuning, Albert; Louro, Henriqueta; Silva, Maria João; Dirven, Hubert; Dietrich, Jessica

Enniatins (ENNs) and beauvericin (BEA) are cyclic hexadepsipeptide fungal metabolites which have demonstrated antibiotic, antimycotic, and insecticidal activities. The substantial toxic potentials of these mycotoxins are associated with their ionophoric molecular properties and relatively high lipophilicities. ENNs occur extensively in grain and grain-derived products and are considered a food safety issue by the European Food Safety Authority (EFSA). The tolerable daily intake and maximum levels for ENNs in humans and animals remain unestablished due to key toxicological and toxicokinetic data gaps, preventing full risk assessment. Aiming to find critical data gaps impeding hazard characterization and risk evaluation, this review presents a comprehensive summary of the existing information from in vitro and in vivo studies on toxicokinetic characteristics and cytotoxic, genotoxic, immunotoxic, endocrine, reproductive and developmental effects of the most prevalent ENN analogues (ENN A, A1, B, B1) and BEA. The missing information identified showed that additional studies on ENNs and BEA have to be performed before sufficient data for an in-depth hazard characterisation of these mycotoxins become available.

2025

The concept of essential use for determining when uses of PFASs can be phased out

Cousins, Ian T.; Goldenman, Gretta; Herzke, Dorte; Lohmann, Rainer; Miller, Mark; Ng, Carla A.; Patton, Sharyle; Scheringer, Martin; Trier, Xenia; Vierke, Lena; Wang, Zhanyun; DeWitt, Jamie

Because of the extreme persistence of per- and polyfluoroalkyl substances (PFASs) and their associated risks, the Madrid Statement argues for stopping their use where they are deemed not essential or when safer alternatives exist. To determine when uses of PFASs have an essential function in modern society, and when they do not, is not an easy task. Here, we: (1) develop the concept of “essential use” based on an existing approach described in the Montreal Protocol, (2) apply the concept to various uses of PFASs to determine the feasibility of elimination or substitution of PFASs in each use category, and (3) outline the challenges for phasing out uses of PFASs in society. In brief, we developed three distinct categories to describe the different levels of essentiality of individual uses. A phase-out of many uses of PFASs can be implemented because they are not necessary for the betterment of society in terms of health and safety, or because functional alternatives are currently available that can be substituted into these products or applications. Some specific uses of PFASs would be considered essential because they provide for vital functions and are currently without established alternatives. However, this essentiality should not be considered as permanent; rather, constant efforts are needed to search for alternatives. We provide a description of several ongoing uses of PFASs and discuss whether these uses are essential or non-essential according to the three essentiality categories. It is not possible to describe each use case of PFASs in detail in this single article. For follow-up work, we suggest further refining the assessment of the use cases of PFASs covered here, where necessary, and expanding the application of this concept to all other uses of PFASs. The concept of essential use can also be applied in the management of other chemicals, or groups of chemicals, of concern.

2019

The comet assay applied to cells of the eye

Azqueta, Amaya; Rundén-Pran, Elise; Elje, Elisabeth; Nicolaissen, Bjørn; Haug, Kristiane; Smeringaiova, Ingrida; Jirsova, Katerina; Collins, Andrew Richard

2018

Extracellular Vesicles as Next-Generation Diagnostics and Advanced Therapy Medicinal Products

Stawarska, Agnieszka; Bamburowicz-Klimkows, Magdalena; Rundén-Pran, Elise; Dusinska, Maria; Cimpan, Mihaela Roxana; Mondragon, Ivan Rios; Grudzinski, Ireneusz P.

Extracellular vesicles (EVs) hold great promise for clinical application as new diagnostic and therapeutic modalities. This paper describes major GMP-based upstream and downstream manufacturing processes for EV large-scale production, also focusing on post-processing technologies such as surface bioengineering and uploading studies to yield novel EV-based diagnostics and advanced therapy medicinal products. This paper also focuses on the quality, safety, and efficacy issues of the bioengineered EV drug candidates before first-in-human studies. Because clinical trials involving extracellular vesicles are on the global rise, this paper encompasses different clinical studies registered on clinical-trial register platforms, with varying levels of advancement, highlighting the growing interest in EV-related clinical programs. Navigating the regulatory affairs of EVs poses real challenges, and obtaining marketing authorization for EV-based medicines remains complex due to the lack of specific regulatory guidelines for such novel products. This paper discusses the state-of-the-art regulatory knowledge to date on EV-based diagnostics and medicinal products, highlighting further research and global regulatory needs for the safe and reliable implementation of bioengineered EVs as diagnostic and therapeutic tools in clinical settings. Post-marketing pharmacovigilance for EV-based medicinal products is also presented, mainly addressing such topics as risk assessment and risk management.

2024

Overview of methods for production of sterile salmonids, their applicability in aquaculture and possible implications to wild salmon populations and biodiversity in Norway

Hindar, Kjetil; Bodin, Johanna Eva; Dalen, Knut Tomas; Duale, Nur; Garseth, Åse Helen; Malmstrøm, Martin; Sipinen, Ville Erling; Thorstad, Eva Bonsak; Berg, Paul Ragnar; Mo, Tor Atle; Olesen, Ingrid; Olsen, Ann-Karin Hardie; Rimstad, Espen; Velle, Gaute

VKM has assessed the positive and negative effects on biodiversity were sterile salmon to be used in Norwegian aquaculture. Triploidisation is assessed as the most effective method for sterilising fish, but it can affect the welfare and health of the fish.

Several other techniques for producing sterile salmon are being tested, but it is too early to determine whether they can be used in large-scale farming.

This is the key message in a knowledge summary VKM has prepared for the Norwegian Environment Agency.

Background
Escaped farmed salmon poses a major threat to wild salmon in Norway. hey can interbreed with wild salmon, genetically alter them, and make the populations less adaptable and more vulnerable to disease and environmental changes. A possible solution to the problem may be to use sterile salmon in farming.

To date, only triploidisation has been tested. Newly fertilised eggs are given a hydrostatic pressure shock, thereby retaining an extra set of chromosomes which render the fish sterile. This method is currently the only one tested on a large scale. Triploidisation is effective but can also pose health and welfare challenges to fish.

Methods
VKM has reviewed available scientific literature regarding methods that can be used to produce sterile salmon. VKM has assessed whether these methods work as well, or better, than triploidy and whether they are likely to have fewer negative effects on fish welfare. Assessments have also been made of whether farmed fish treated with other sterilisation methods pose a greater or lesser threat to wild salmon than traditional farmed salmon.

VKM has looked at the possibilities for further development of the triploidisation technique and has also assessed various methods currently being tested for producing sterile fish. Some of these are still at the laboratory-testing stage, while others are approaching trials with release into sea-pens. VKM has grouped the different methods based on whether they cause permanent changes in the genome (so-called "knock-out" of important genes) or whether the changes only result in temporary blocking or downregulation of gene expression (so-called "knock-down").

Results
VKM concludes that triploidisation remains the most effective method and that there are possibilities to further develop this methodology through targeted breeding and adjustments in how the fish are kept. These measures can potentially solve the challenges for fish health and welfare. Using pure triploid female lines can also reduce some of the other challenges by preventing spawning interactions in rivers and reducing disease transmission to wild salmon.

Alternative sterilisation methods, such as gene editing, vaccination, and temporary downregulation of proteins for gonad development using antisense oligomers and egg immersion, are promising but still under development.

VKM assesses that methods causing permanent changes in the genome of diploid fish have a higher inherent risk than methods that only affect gene expression.

Hope in egg-bathing
Perhaps the most promising technique for safe production of sterile salmon is to add synthetic oligonucleotides to the eggs at an early stage, thereby preventing germ cell development without causing any inheritable changes. Such oligonucleotides can be injected into the eggs or absorbed by the eggs through bathing (immersion) in a special solution.

"Especially the method involving targeted 'tools,' such as oligonucleotides that prevent germ cell development and can be added to the eggs in a water bath, seems promising," says Johanna Bodin, member of the Panel for Genetically Modified organisms and spokesperson for the report.

(...)

2025

Plastics as a carrier of chemical additives to the Arctic: Possibilities for strategic monitoring across the circumpolar North

Hamilton, Bonnie M.; Baak, Julia E.; Vorkamp, Katrin; Hammer, Sjúrður; Granberg, Maria; Herzke, Dorte; Provencher, Jennifer F.

Plastic pollution (including microplastics) has been reported in a variety of biotic and abiotic compartments across the circumpolar Arctic. Due to their environmental ubiquity, there is a need to understand not only the fate and transport of physical plastic particles, but also the fate and transport of additive chemicals associated with plastic pollution. Further, there is a fundamental research gap in understanding long-range transport of chemical additives to the Arctic via plastics as well as their behavior under environmentally relevant Arctic conditions. Here, we comment on the state of the science of plastic as carriers of chemical additives to the Arctic, and highlight research priorities going forward. We suggest further research on the transport pathways of chemical additives via plastics from both distant and local sources and laboratory experiments to investigate chemical behavior of plastic additives under Arctic conditions, including leaching, uptake, and bioaccumulation. Ultimately, chemical additives need to be included in strategic monitoring efforts to fully understand the contaminant burden of plastic pollution in Arctic ecosystems.

2023

Multi-Scale Soil Salinization Dynamics From Global to Pore Scale: A Review

Shokri, Nima; Hassani, Amirhossein; Sahimi, Muhammad

Soil salinization refers to the accumulation of water-soluble salts in the upper part of the soil profile. Excessive levels of soil salinity affects crop production, soil health, and ecosystem functioning. This phenomenon threatens agriculture, food security, soil stability, and fertility leading to land degradation and loss of essential soil ecosystem services that are fundamental to sustaining life. In this review, we synthesize recent advances in soil salinization at various spatial and temporal scales, ranging from global to core, pore, and molecular scales, offering new insights and presenting our perspective on potential future research directions to address key challenges and open questions related to soil salinization. Globally, we identify significant challenges in understanding soil salinity, which are (a) the considerable uncertainty in estimating the total area of salt-affected soils, (b) geographical bias in ground-based measurements of soil salinity, and (c) lack of information and data detailing secondary salinization processes, both in dry- and wetlands, particularly concerning responses to climate change. At the core scale, the impact of salt precipitation with evolving porous structure on the evaporative fluxes from porous media is not fully understood. This knowledge is crucial for accurately predicting soil water loss due to evaporation. Additionally, the effects of transport properties of porous media, such as mixed wettability conditions, on the saline water evaporation and the resulting salt precipitation patterns remain unclear. Furthermore, effective continuum equations must be developed to accurately represent experimental data and pore-scale numerical simulations.

2024

Fifteen years of airborne particulates in vitro toxicology in Milano: Lessons and perspectives learned

Longhin, Eleonora Marte; Mantecca, Paride; Gualtieri, Maurizio

Air pollution is one of the world’s leading environmental causes of death. The epidemiological relationship between outdoor air pollution and the onset of health diseases associated with death is now well established. Relevant toxicological proofs are now dissecting the molecular processes that cause inflammation, reactive species generation, and DNA damage. In addition, new data are pointing out the role of airborne particulates in the modulation of genes and microRNAs potentially involved in the onset of human diseases. In the present review we collect the relevant findings on airborne particulates of one of the biggest hot spots of air pollution in Europe (i.e., the Po Valley), in the largest urban area of this region, Milan. The different aerodynamic fractions are discussed separately with a specific focus on fine and ultrafine particles that are now the main focus of several studies. Results are compared with more recent international findings. Possible future perspectives of research are proposed to create a new discussion among scientists working on the toxicological effects of airborne particles.

2020

Dust in the arctic: a brief review of feedbacks and interactions between climate change, aeolian dust and ecosystems

Meinander, Outi; Uppstu, Andreas; Dagsson-Waldhauserova, Pavla; Zwaaftink, Christine Groot; Jørgensen, Christian Juncher; Baklanov, Alexander; Kristensson, Adam; Massling, Andreas; Sofiev, Mikhail

Climatic feedbacks and ecosystem impacts related to dust in the Arctic include direct radiative forcing (absorption and scattering), indirect radiative forcing (via clouds and cryosphere), semi-direct effects of dust on meteorological parameters, effects on atmospheric chemistry, as well as impacts on terrestrial, marine, freshwater, and cryospheric ecosystems. This review discusses our recent understanding on dust emissions and their long-range transport routes, deposition, and ecosystem effects in the Arctic. Furthermore, it demonstrates feedback mechanisms and interactions between climate change, atmospheric dust, and Arctic ecosystems.

2025

High-Resolution Mass Spectrometry for Human Exposomics: Expanding Chemical Space Coverage

Lai, Yunjia; Koelmel, Jeremy P.; Walker, Douglas I; Price, Elliott J.; Papazian, Stefano; Manz, Katherine E.; Castilla-Fernández, Delia; Bowden, John A.; Nikiforov, Vladimir; David, Arthur; Bessonneau, Vincent; Amer, Bashar; Seethapathy, Suresch; Hu, Xin; Lin, Elizabeth Z.; Jbebli, Akrem; McNeil, Brooklynn R.; Barupal, Dinesh Kumar; Cerasa, Marina; Xie, Hongyu; Kalia, Vrinda; Nandakumar, Renu; Singh, Randolph R.; Tian, Zhenyu; Gao, Peng; Zhao, Yujia; Froment, Jean Francois; Rostkowski, Pawel; Dubey, Saurabh; Coufalíková, Kateřina; Seličová, Hana; Hecht, Helge; Liu, Sheng; Udhani, Hanisha H.; Restituito, Sophie; Tchou-Wong, Kam-Meng; Lu, Kun; Martin, Jonathan W.; Warth, Benedikt; Pollitt, Krystal J. Godri; Klánová, Jana; Fiehn, Oliver; Metz, Thomas O.; Pennell, Kurt D.; Jones, Dean P.

In the modern “omics” era, measurement of the human exposome is a critical missing link between genetic drivers and disease outcomes. High-resolution mass spectrometry (HRMS), routinely used in proteomics and metabolomics, has emerged as a leading technology to broadly profile chemical exposure agents and related biomolecules for accurate mass measurement, high sensitivity, rapid data acquisition, and increased resolution of chemical space. Non-targeted approaches are increasingly accessible, supporting a shift from conventional hypothesis-driven, quantitation-centric targeted analyses toward data-driven, hypothesis-generating chemical exposome-wide profiling. However, HRMS-based exposomics encounters unique challenges. New analytical and computational infrastructures are needed to expand the analysis coverage through streamlined, scalable, and harmonized workflows and data pipelines that permit longitudinal chemical exposome tracking, retrospective validation, and multi-omics integration for meaningful health-oriented inferences. In this article, we survey the literature on state-of-the-art HRMS-based technologies, review current analytical workflows and informatic pipelines, and provide an up-to-date reference on exposomic approaches for chemists, toxicologists, epidemiologists, care providers, and stakeholders in health sciences and medicine. We propose efforts to benchmark fit-for-purpose platforms for expanding coverage of chemical space, including gas/liquid chromatography–HRMS (GC-HRMS and LC-HRMS), and discuss opportunities, challenges, and strategies to advance the burgeoning field of the exposome.

2024

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