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Adult neurotoxicity (ANT) and developmental neurotoxicity (DNT) assessments aim to understand the adverse effects and underlying mechanisms of toxicants on the human nervous system. In recent years, there has been an increasing focus on the so-called new approach methodologies (NAMs). The Organization for Economic Co-operation and Development (OECD), together with European and American regulatory agencies, promote the use of validated alternative test systems, but to date, guidelines for regulatory DNT and ANT assessment rely primarily on classical animal testing. Alternative methods include both non-animal approaches and test systems on non-vertebrates (e.g., nematodes) or non-mammals (e.g., fish). Therefore, this review summarizes the recent advances of NAMs focusing on ANT and DNT and highlights the potential and current critical issues for the full implementation of these methods in the future. The status of the DNT in vitro battery (DNT IVB) is also reviewed as a first step of NAMs for the assessment of neurotoxicity in the regulatory context. Critical issues such as (i) the need for test batteries and method integration (from in silico and in vitro to in vivo alternatives, e.g., zebrafish, C. elegans) requiring interdisciplinarity to manage complexity, (ii) interlaboratory transferability, and (iii) the urgent need for method validation are discussed.
2024
The Aerosol, Clouds and Trace Gases Research Infrastructure (ACTRIS) officially became the 33rd European Research Infrastructure Consortium (ERIC) on April 25, 2023 with the support of 17 founding member and observer countries. As a pan-European legal organization, ACTRIS ERIC will coordinate the provision of data and data products on short-lived atmospheric constituents and clouds relevant to climate and air pollution over the next 15-20 years. ACTRIS was designed more than a decade ago, and its development was funded at national and European levels. It was included in the European Strategy Forum on Research Infrastructures (ESFRI) Roadmap in 2016 and subsequently, in the national infrastructure roadmaps of European countries. It became a landmark of the ESFRI roadmap in 2021. The purpose of this paper is to describe the mission of ACTRIS, its added value to the community of atmospheric scientists, providing services to academia as well as the public and private sectors, and to summarize its main achievements. The present publication serves as a reference document for ACTRIS, its users and the scientific community as a whole. It provides the reader with relevant information and an overview on ACTRIS governance and services, as well as a summary of the main scientific achievements of the last 20 years. The paper concludes with an outlook on the upcoming challenges for ACTRIS and the strategy for its future evolution.
2024
We investigate the concentration fluctuations of passive scalar plumes emitted from small, localised (point-like) steady sources in a neutrally stratified turbulent boundary layer over a rough wall. The study utilises high-resolution large-eddy simulations for sources of varying sizes and heights. The numerical results, which show good agreement with wind-tunnel studies, are used to estimate statistical indicators of the concentration field, including spectra and moments up to the fourth order. These allow us to elucidate the mechanisms responsible for the production, transport and dissipation of concentration fluctuations, with a focus on the very near field, where the skewness is found to have negative values – an aspect not previously highlighted. The gamma probability density function is confirmed to be a robust model for the one-point concentration at sufficiently large distances from the source. However, for ground-level releases in a well-defined area around the plume centreline, the Gaussian distribution is found to be a better statistical model. As recently demonstrated by laboratory results, for elevated releases, the peak and shape of the pre-multiplied scalar spectra are confirmed to be independent of the crosswind location for a given downwind distance. Using a stochastic model and theoretical arguments, we demonstrate that this is due to the concentration spectra being directly shaped by the transverse and vertical velocity components governing the meandering of the plume. Finally, we investigate the intermittency factor, i.e. the probability of non-zero concentration, and analyse its variability depending on the thresholds adopted for its definition.
2024
Surface-Bioengineered Extracellular Vesicles Seeking Molecular Biotargets in Lung Cancer Cells
Personalized medicine is a new approach to modern oncology. Here, to facilitate the application of extracellular vesicles (EVs) derived from lung cancer cells as potent advanced therapy medicinal products in lung cancer, the EV membrane was functionalized with a specific ligand for targeting purposes. In this role, the most effective heptapeptide in binding to lung cancer cells (PTHTRWA) was used. The functionalization process of EV surface was performed through the C- or N-terminal end of the heptapeptide. To prove the activity of the EVs functionalized with PTHTRWA, both a model of lipid membrane mimicking normal and cancerous cell membranes as well as human adenocarcinomic alveolar basal epithelial cells (A549) and human normal bronchial epithelial cells (BEAS-2B) have been exposed to these bioconstructs. Magnetic resonance imaging (MRI) showed that the as-bioengineered PTHTRWA-EVs loaded with superparamagnetic iron oxide nanoparticle (SPIO) cargos reach the growing tumor when dosed intravenously in NUDE Balb/c mice bearing A549 cancer. Molecular dynamics (MD) in silico studies elucidated a high affinity of the synthesized peptide to the α5β1 integrin. Preclinical safety assays did not evidence any cytotoxic or genotoxic effects of the PTHTRWA-bioengineered EVs.
2024
2024
Metal pollution is a global environmental issue with adverse biological effects on wildlife. Long-term studies that span declines in metal emissions due to regulation, resulting in varying levels of environmental contamination, are therefore well-suited to investigate effects of toxic metals, while also facilitating robust analysis by incorporating fluctuating environmental conditions and food availability. Here, we examined a resident population of tawny owls in Norway between 1986 and 2019. Tail feathers from females were collected annually, resulting in over 1000 feathers. Each feather served as an archive of local environmental conditions during molt, including the presence of metals, and their dietary ecology, proxied by stable isotopes of nitrogen (δ15N) and carbon (δ13C), as well as corticosterone levels (CORTf), the primary avian glucocorticoid and a measure of physiological stress. We analyzed feathers to examine how exposure to toxic metal(loid)s (Al, As, Cd, Hg, and Pb) and variability in dietary proxies modulate CORTf. Using structural equation modelling, we found that increased Al concentrations and δ15N values, linked directly to increased CORTf. In opposite, we found that increased Hg concentrations and δ13C related to decreased CORTf concentrations. δ15N was indirectly linked to CORTf through Al and Hg, while δ13C was indirectly linked to CORTf through Hg. This supports our hypothesis that metal exposure and dietary ecology may individually or jointly influence physiological stress. Notably, our results suggest that dietary ecology has the potential to mediate the impact of metals on CORTf, highlighting the importance of considering multiple variables, direct and indirect effects, when assessing stress in wildlife. In conclusion, feathers represent an excellent non-destructive biomonitoring strategy in avian wildlife, providing valuable insights not easily accessible using other methods. Further research is warranted to fully comprehend implications of alterations in CORTf on the tawny owl's health and fitness.
2024
This paper presents the results of a multidisciplinary study with the aim of assessing the potential combined risk from consuming locally harvested food products in the Euro-Arctic region of Norway, Finland, and Russia. The three important contaminant groups—radioactive substances, heavy metals, and persistent organic pollutants (POPs)—were measured in food samples such as berries, mushrooms, fish, birds, reindeer, and moose; they were sampled in 2013–2015. To assess the combined pollution levels and investigate the trends, similarities, and variations between different contaminant groups, subsequent multivariate statistical analysis was performed. The results showed that, in general, the levels of radioactive substances, toxic elements, and POPs were below the permitted EU maximum content in food products. However, statistical analysis revealed some correlations, similarities, and peculiarities between the accumulation of different contaminants in various species, which allowed for a better understanding of the mechanisms of accumulation and interaction between different contaminant groups. It also gave a better insight into the possible added risks and helped pinpoint species that could serve as reference markers for the accumulation of different contaminants in food. Mushrooms, fish, and reindeer were found to be important markers in the combined risk assessments for the contents of metals and radioactive substances. Further research, as well as the development of methodologies for combined assessments, are recommended.
2024
This study investigates the efficacy of supramolecular solvent (SUPRAS) in extracting a diverse spectrum of organic contaminants from indoor dust. Initially, seven distinct SUPRAS were assessed across nine categories of contaminants to identify the most effective one. A SUPRAS comprising Milli-Q water, tetrahydrofuran, and hexanol in a 70:20:10 ratio, respectively, demonstrated the best extraction performance and was employed for testing a wider array of organic contaminants. Furthermore, we applied the selected SUPRAS for the extraction of organic compounds from the NIST Standard Reference Material (SRM) 2585. In parallel, we performed the extraction of NIST SRM 2585 with conventional extraction methods using hexane:acetone (1:1) for non-polar contaminants and methanol (100%) extraction for polar contaminants. Analysis from two independent laboratories (in Norway and the Czech Republic) demonstrated the viability of SUPRAS for the simultaneous extraction of twelve groups of organic contaminants with a broad range of physico-chemical properties including plastic additives, pesticides, and combustion by-products. However, caution is advised when employing SUPRAS for highly polar contaminants like current-use pesticides or volatile substances like naphthalene.
2024
Atmospheric volatile organic compounds (VOCs) constitute a wide range of species, acting as precursors to ozone and aerosol formation. Atmospheric chemistry and transport models (CTMs) are crucial to understanding the emissions, distribution, and impacts of VOCs. Given the uncertainties in VOC emissions, lack of evaluation studies, and recent changes in emissions, this work adapts the European Monitoring and Evaluation Programme Meteorological Synthesizing Centre – West (EMEP MSC-W) CTM to evaluate emission inventories in Europe. Here we undertake the first intensive model–measurement comparison of VOCs in 2 decades. The modelled surface concentrations are evaluated both spatially and temporally, using measurements from the regular EMEP monitoring network in 2018 and 2019, as well as a 2022 campaign. To achieve this, we utilised the UK National Atmospheric Emissions Inventory to derive explicit emission profiles for individual species and employed a tracer method to produce pure concentrations that are directly comparable to observations.
The degree to which the modelled and measured VOCs agree varies depending on the specific species. The model successfully captures the overall spatial and temporal variations of major alkanes (e.g. ethane, n-butane) and unsaturated species (e.g. ethene, benzene) but less so for propane, i-butane, and ethyne. This discrepancy underscores potential issues in the boundary conditions for the latter species and in their primary emissions from, in particular, the solvent and road transport sectors. Specifically, potential missing propane emissions and issues with its boundary conditions are highlighted by large model underestimations and smaller propane-to-ethane ratios compared to the measurement. Meanwhile, both the model and measurements show strong linear correlations among butane isomers and among pentane isomers, indicating common sources for these pairs of isomers. However, modelled ratios of i-butane to n-butane and i-pentane to n-pentane are approximately one-third of the measured ratios, which is largely driven by significant emissions of n-butane and n-pentane from the solvent sector. This suggests issues with the speciation profile of the solvent sector, underrepresented contributions from transport and fuel evaporation sectors in current inventories, or both. Furthermore, the modelled ethene-to-ethyne and benzene-to-ethyne ratios differ significantly from measured ratios. The different model performance strongly points to shortcomings in the spatial and temporal patterns and magnitudes of ethyne emissions, especially during winter. For OVOCs, the modelled and measured concentrations of methanal and methylglyoxal show a good agreement, despite a moderate underestimation by the model in summer. This discrepancy could be attributed to an underestimation of contributions from biogenic sources or possibly a model overestimation of their photolytic loss in summer. However, the insufficiency of suitable measurements limits the evaluation of other OVOCs. Finally, model simulations employing the CAMS inventory show slightly better agreements with measurements than those using the Centre on Emission Inventories and Projections (CEIP) inventory. This enhancement is likely due to the CAMS inventory's detailed segmentation of the road transport sector, including its associated sub-sector-specific emission profiles. Given this improvement, alongside the previously mentioned concerns about the model's biased estimations of various VOC ratios, future efforts should focus on a more detailed breakdown of dominant emission sectors (e.g. solvents) and the refinement of their speciation profiles to improve model accuracy.
2024
Bisphenol A (BPA), a synthetic chemical widely used in the production of polycarbonate plastic and epoxy resins, has been associated with a variety of adverse effects in humans including metabolic, immunological, reproductive, and neurodevelopmental effects, raising concern about its health impact. In the EU, it has been classified as toxic to reproduction and as an endocrine disruptor and was thus included in the candidate list of substances of very high concern (SVHC). On this basis, its use has been banned or restricted in some products. As a consequence, industries turned to bisphenol alternatives, such as bisphenol S (BPS) and bisphenol F (BPF), which are now found in various consumer products, as well as in human matrices at a global scale. However, due to their toxicity, these two bisphenols are in the process of being regulated. Other BPA alternatives, whose potential toxicity remains largely unknown due to a knowledge gap, have also started to be used in manufacturing processes. The gradual restriction of the use of BPA underscores the importance of understanding the potential risks associated with its alternatives to avoid regrettable substitutions. This review aims to summarize the current knowledge on the potential hazards related to BPA alternatives prioritized by European Regulatory Agencies based on their regulatory relevance and selected to be studied under the European Partnership for the Assessment of Risks from Chemicals (PARC): BPE, BPAP, BPP, BPZ, BPS-MAE, and TCBPA. The focus is on data related to toxicokinetic, endocrine disruption, immunotoxicity, developmental neurotoxicity, and genotoxicity/carcinogenicity, which were considered the most relevant endpoints to assess the hazard related to those substances. The goal here is to identify the data gaps in BPA alternatives toxicology and hence formulate the future directions that will be taken in the frame of the PARC project, which seeks also to enhance chemical risk assessment methodologies using new approach methodologies (NAMs).
2024