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Towards prospective identification of respiratory sensitizers
Journal
Archives of Toxicology
Keywords
Air–liquid interface, Calu-3 human bronchial epithelial cell line, IL-6, Epithelial barrier, AOP
Date of publication
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Exposure to respiratory sensitizers (RSs) is the leading cause of occupational asthma. Although the prospective identification of RSs is important, there currently exists no OECD-approved test guideline for this endpoint. The adverse outcome pathway for respiratory sensitization consists of key event (KE) 1: binding of the respiratory sensitizer to a protein, KE2: activation of lung epithelial cells, KE3: activation of dendritic cells, and KE4: T-cell response. Here, we focused on KE2 by investigating whether measuring this KE could contribute to prospectively identify respiratory sensitizers. To mimic real-life exposure, cells were exposed via the air. We used an air–liquid interface model comprising the human bronchial epithelial cell line Calu-3. Exposure to the RS piperazine (3, 18, and 100 mg/m3) dose-dependently increased IL-6 production at dose levels that did not affect the other parameters tested (barrier integrity, cell metabolism, cytotoxicity, and IL-8 production). IL-6 has been linked to asthma in humans. Exposure to the RS chloramine-T (30, 300, and 3000 ng/cm2) showed only minor effects on the parameters tested. Exposure to the RS 2,4-toluene diisocyanate (10, 33, and 100 mg/m3) at the highest dose level clearly affected all parameters tested. Disrupted barrier function has been linked to asthma. In conclusion, this study may possibly suggest that different respiratory sensitizers may differentially impact KE2. Further research is needed to elucidate this.

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Modeling zebrafish escape swim reveals maximum neuromuscular power output and efficient body movement adaptation to increased water viscosity
Authors
Ravel Guillaume, Mercé Théo, Bergmann Michel, Knoll-Gellida Anja, Bouharguane Afaf, Al Kassir Sara, Iollo Angelo, Babin Patrick J.
Journal
iScience
Vol. 28
No. 3
112056
Keywords
Kinematics, Neuroscience, Biophysics
Date of publication
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Under evolutionary pressure, the kinematic and energetic characteristics of animal locomotion have been optimized for survival. We investigated the kinematics and energetic performance of zebrafish eleutheroembryo escape swims triggered by electrical stimuli in fluids of increasing viscosity. Eleutheroembryos exhibited a decrease in both tail movement frequency and swimming velocity in more viscous environments, while the amplitude of body curvature remains constant. We then combined experimental imaging of freely swimming eleutheroembryos with Navier-Stokes numerical simulations. The results showed that the mechanical power output was initially maximal and remained essentially stable with increasing viscosity, while the cost of transport was linearly correlated with viscosity. Eleutheroembryos maximize neuromuscular power output during the fast-start escape response, enabling them to potentially escape predators under all circumstances in a natural environment. This model may be used to identify genetic and toxicological factors that reduce the mechanical power developed by the neuromuscular system or induce a loss of efficiency in its use.

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Motor and non-motor effects of acute MPTP in adult zebrafish: insights into Parkinson's disease
Authors
Tagkalidou Niki, Stevanović Marija, Romero Alfano Irene, Elizalde-Velazquez Gustavo Axel, Herrera-Vazquez Selene Elizabeth, Prats Eva, Gómez-Canela Cristian, Gómez-Oliván Leobardo Manuel, Raldúa Demetrio
Journal
International Journal of Molecular Sciences
Vol. 26
No. 4
1674
Keywords
MPTP, Adult zebrafish, Parkinson's disease, Prepulse inhibition, Psychosis, Turning difficulties, Hypokinesia
Date of publication
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Parkinson’s disease (PD), the second most common neurodegenerative disorder, is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, leading to motor and non-motor symptoms. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been extensively used in different animal species to develop chemical models of PD. This study aimed to evaluate the effects of acute exposure to MPTP (3 × 150 mg/kg, intraperitoneally) on adult zebrafish by assessing the neurochemical, transcriptional, and motor changes associated with PD pathogenesis. MPTP treatment resulted in a significant decrease in brain catecholamines, including dopamine, norepinephrine, and normetanephrine. Additionally, a trend towards decreased levels of dopamine precursors (tyrosine and L-DOPA) and degradation products (3-MT and DOPAC) was also observed, although these changes were not statistically significant. Gene expression analysis showed the downregulation of dbh, while the expression of other genes involved in catecholamine metabolism (th1, th2, mao, comtb) and transport (slc6a3 and slc18a2) remained unaltered, suggesting a lack of dopaminergic neuron degeneration. Behavioral assessments revealed that MPTP-exposed zebrafish exhibited reduced motor activity, consistent with the observed decrease in dopamine levels. In contrast, the kinematic parameters of sharp turning were unaffected. A significant impairment in the sensorimotor gating of the ASR was detected in the MPTP-treated fish, consistent with psychosis. Despite dopamine depletion and behavioral impairments, the absence of neurodegeneration and some hallmark PD motor symptoms suggests limitations in the validity of this model for fully recapitulating PD pathology. Further studies are needed to refine the use of MPTP in zebrafish PD models.

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MLinvitroTox reloaded for high‑throughput hazard‑based prioritization of high‑resolution mass spectrometry data
Authors
Hollender Juliane, Arturi Katarzyna, Harris Eliza J., Gasser Lilian, Escher Beate I., Braun Georg, Bosshard Robin
Journal
Journal of Cheminformatics
Vol. 17
No. 14
Keywords
ToxCast, Tox21, Toxicity, In vitro assay, Activity prediction, HRMS/MS, Binary classifcation, XGBoost, SIRIUS
Date of publication
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MLinvitroTox is an automated Python pipeline developed for high-throughput hazard-driven prioritization of toxicologically relevant signals detected in complex environmental samples through high-resolution tandem mass spectrometry (HRMS/MS). MLinvitroTox is a machine learning (ML) framework comprising 490 independent XGBoost classifiers trained on molecular fingerprints from chemical structures and target-specific endpoints from the ToxCast/ Tox21 invitroDBv4.1 database. For each analyzed HRMS feature, MLinvitroTox generates a 490-bit bioactivity fingerprint used as a basis for prioritization, focusing the time-consuming molecular identification efforts on features most likely to cause adverse effects. The practical advantages of MLinvitroTox are demonstrated for groundwater HRMS data. Among the 874 features for which molecular fingerprints were derived from spectra, including 630 nontargets, 185 spectral matches, and 59 targets, around 4% of the feature/endpoint relationship pairs were predicted to be active. Cross-checking the predictions for targets and spectral matches with invitroDB data confirmed the bioactivity of 120 active and 6791 nonactive pairs while mislabeling 88 active and 56 non-active relationships. By filtering according to bioactivity probability, endpoint scores, and similarity to the training data, the number of potentially toxic features was reduced by at least one order of magnitude. This refinement makes the analytical confirmation of the toxicologically most relevant features feasible, offering significant benefits for cost-efficient chemical risk assessment.

Scientific Contribution:
In contrast to the classical ML-based approaches for toxicity prediction, MLinvitroTox predicts bioactivity for HRMS features (i.e., distinct m/z signals) based on MS2 fragmentation spectra rather than the chemical structures from the identified features. While the original proof of concept study was accompanied by the release of a MLinvitroTox v1 KNIME workflow, in this study, we release a Python MLinvitroTox v2 package, which, in addition to automation, expands functionality to include predicting toxicity from structures, cleaning up and generating chemical fingerprints, customizing models, and retraining on custom data. Furthermore, as a result of improvements in bioactivity data processing, realized in the concurrently released pytcpl Python package for the custom processing of invitroDBv4.1 input data used for training MLinvitroTox, the current release introduces enhancements in model accuracy, coverage of biological mechanistic targets, and overall interpretability.

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Automated curation of spatial metadata in environmental monitoring data
Authors
Mutlu Ilhan, Hackermüller Jörg, Schor Jana
Journal
Ecological Informatics
Vol. 86
103038
Keywords
Environmental monitoring, Spatial data accuracy, Automated data curation, Big data analytics, AI applications in hydrology
Date of publication
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Spatial data accuracy in environmental monitoring is crucial for practical large-scale data analytics and the development of AI models. In this context, spatial data is metadata and faces the same challenges as any other metadata, like missing values, false or contradicting information, formatting problems of textual data and numbers, the usage of different languages, and more. These issues severely limit the usability of the data.
With this study, we provide an automatic approach, CleanGeoStreamR, to resolve as many of these issues as possible for the spatially annotated environmental monitoring database. We substantially increased the quality of the spatial metadata and, therefore, the quantity of data points that can be used in large-scale data analytics and AI applications.
Further, our goal is to raise awareness about the issues related to spatial metadata and promote the implementation of our concepts in other environmental monitoring data sources. Advanced understanding and the availability of automatic approaches like the presented method will substantially contribute to making environmental monitoring data FAIR and enhance its usability in the era of Big Data and AI.
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Toward product safety and circularity: Understanding the information structure of global databases on chemicals in products and articles
Authors
Olisah Chijioke, Melymuk Lisa, Vestergren Robin, Rumar Karin, Wickman Tonie, Melander Nina, Talasniemi Petteri, Brandsma Sicco, af Gennäs Urban Boije, Scheringer Martin
Journal
Environmental Science & Technology
Vol. 59
No. 4
1897–1908
Keywords
Consumer products, REACH, Compliance, Regulations, Enforcement
Date of publication
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Access to information about chemicals in products and articles is critical for supporting enforcement of chemical regulations, assessing risks from chemicals, allowing informed consumer choices, and enabling product circularity. In this work, we identified and evaluated available databases (DBs) on chemicals in products and articles from the literature using a defined protocol and from European national market surveillance authorities, nongovernmental agencies, and industrial sector groups using questionnaires. This is the first comprehensive review of DBs that provide information about chemicals in products and articles. A majority of these DBs are heterogeneous in terms of scope, ontologies, and data structures. Among the 57 identified DBs, 49 identified specific substances and only 30 reported their concentration in their products. In addition, 35 DBs included hazard information and 27 DBs provided safety information about products or chemicals. The analysis highlights the lack of comprehensive or accessible data on chemicals in products and articles for most categories of products/articles and jurisdictions. The limitations of existing DBs were attributed to scattered regulatory information requirements, a lack of data for unregulated substances, the complexity of supply chain communication, and confidentiality issues. In response to these challenges, we identified opportunities for improving existing information transfer structures and exploring alternative data sources to promote product and article safety and circularity.

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New approach methodologies in human health risk assessment across European regulatory frameworks: Status quo, barriers and drivers for regulatory acceptance and use
Authors
Bearth Angela, Roth Nicolas, Jansen Tom, Holden Laura, Cavoski Aleksandra, Di Consiglio Emma, Hauzenberger Ingrid, Lee Robert, Mombelli Enrico, Tcheremenskaia Olga, Wendt-Rasch Lina, Wilks Martin
Journal
Environment International
Vol. 196
No. February 2025
109279
Keywords
Next generation risk assessment, New approach methodologies, Chemical regulation, Barriers, Drivers, Perspectives, Social science, Survey
Date of publication
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The traditional approaches to chemical risk assessment for human health are continuously challenged by their limitations, such as validity concerns, societal pressure to use animal-free methods, and resource constraints. New Approach Methodologies (NAMs) are considered a promising avenue toward modernisation of chemical risk assessment practices but their implementation in practice has been slow. This article aims to investigate the perspectives of human health risk assessors on the status quo, barriers and drivers of the acceptance and use of NAMs across different regulatory frameworks. A mixed method design was applied: qualitative interviews (N = 19) and an online survey with human health risk assessors from industry, regulatory agencies/institutions and academia (N = 222). The results show heterogeneity in familiarity and use of specific NAMs (e.g., QSARs as well-known and used vs. −omics approaches that are seldom used), the risk assessors’ background (e.g., industry vs. regulatory agencies and institutions vs. academia) and the application context (e.g., screening/prioritisation vs. hazard identification/characterisation). The identified barriers and drivers offer pointers for the future integration and acceptance of NAMs in regulatory risk assessment. For instance, guidance documents can facilitate the use of NAMs, showcasing successful examples that increase trust in the methods and thus, the risk assessors’ confidence in using these methods. Among other things, the article highlights the importance of considering human health risk assessors’ needs and prerequisites to foster bottom-up coordinated efforts and to ensure the success of top-down legal and institutional change to incorporate NAMs in regulatory risk assessment.
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Collecting perspectives on project prioritisation process in the EU co-funded multinational partnership for the assessment of risks from chemicals (PARC) through focus group discussion
Authors
Permana Katya Manuella, Tannous Maria, Mouaziz Hanna, Sanders Pascal, Bonvallot Nathalie, Rousselle Christophe
Journal
Environmental Sciences Europe
Vol. 37
2
Keywords
PARC, Chemical risk assessment, Research and innovation need prioritisation, EU partnership coordination, Focus group discussion, Regulatory relevance
Date of publication
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Introduction
The European Partnership for the Assessment of Risks from Chemicals (PARC) is a 7-year multinational partnership aimed at consolidating and strengthening European Union’s (EU) research and innovation capacity for chemical risk assessment (RA) to protect human health and the environment. It consists of nine work packages (WP) involving more than 200 participating organisations from 29 countries. PARC is currently mapping the most relevant needs in the field of European chemical RA to steer PARC’s future activities in the coming years. The present study aims to gather the perspectives of WP/Task/Project Leaders of PARC to understand their experience during the first prioritisation round of PARC activities and to identify potential points of improvement for future rounds.

Methods
Three online 90-min focus group discussion (FGD) sessions were conducted between the 3rd and 9th of May 2023. Each session was attended by 4-5 participants with at least one representative from each PARC WPs 4, 5 and 6 (n = 13). The sessions were recorded and transcribed, then analysed in NVivo 12 software using thematic analysis.

Results
Some important aspects for the prioritisation of activities that were mentioned include: (1) having a transparent prioritisation process even though each WP might need different prioritisation criteria, (2) balancing the fulfilment of short-term regulatory needs and anticipating long-term needs in chemical RA, (3) maintaining alignment and synergy between the WPs and with other relevant EU initiatives to avoid duplication and to ensure continuity of work and (4) making sure that PARC can effectively respond to requests from different PARC stakeholders.

Conclusions
The next round of PARC research activity steering process will provide an opportunity to implement the various improvements identified. PARC should utilise the advantage of having stakeholders from different backgrounds (e.g., risk assessors, policymakers, regulatory bodies, academia, etc.) within its consortium and its advising bodies to prioritise projects and activities that will support its overall objectives. These recommendations could also be of interest outside PARC in the context of prioritising research and innovation needs related to chemical RA.

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Zebra_K, a kinematic analysis automated platform for assessing sensitivity, habituation and prepulse inhibition of the acoustic startle response in adult zebrafish
Authors
Stevanović Marija, Tagkalidou Niki, Multisanti Cristiana Roberta, Pujol Sergi, Aljabasini Ouwais, Prats Eva, Faggio Caterina, Porta Josep M, Barata Carlos, Raldua Demetrio
Journal
Science of The Total Environment
Vol. 958
No. January 2025
178028
Keywords
Acoustic startle response, Neuroplasticity, Habituation, Prepulse inhibition, Sensorimotor gating, Adult zebrafish, Kinematic analysis platform
Date of publication
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The acoustic startle response (ASR) is leaded by a sudden and intense acoustic stimulus. ASR has several forms of plasticity, including habituation and sensorimotor gating. Although ASR and its plasticity have been intensively studied in zebrafish (Danio rerio) larvae, information in adult zebrafish is still very scarce. In this manuscript we present Zebra_K, a new automated high-content kinematic analysis platform for assessing ASR, its habituation and prepulse inhibition (PPI), a quantitative measure of sensorimotor gating, in adult zebrafish. The analysis of the kinematic parameters of ASR in adult zebrafish has shown a single response wave consistent with the short-latency C-bend described in zebrafish larvae. Moreover, protocols have been designed and validated in Zebra_K for the analysis of sensitivity, habituation and PPI of this response. Then, the effect of the time of day and the gender on zebrafish ASR plasticity has been analyzed for the first time. Females exhibited higher responsiveness and a lower habituation and PPI than males, a result consistent with the gender effect described in other animal models and in humans. This platform has also been used to determine the effect of a pharmacological modulators of ASR plasticity, the NMDA-receptor antagonist ketamine. As described in other animal models, ketamine increased the responsiveness to the acoustic stimuli, decreasing habituation and leading to complete abolition of PPI. These results enhance the interest of using adult zebrafish to assess the potential effect of environmental pollutants on ASR plasticity.

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A cognitive and sensory approach based on workshops using the zebrafish model promotes the discovery of life sciences in the classroom
Journal
Biology Methods and Protocols
Vol. 9
No. 1
bpae092
Keywords
Cognitive and sensory approach, Biology education, Teacher-researcher partnership, Zebrafish
Date of publication
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The main objective of the ZebraCool programme was to create a positive attitude and curiosity towards science by bringing experimental activities within schools using an introductory cognitive and sensory approach. This innovative programme was offered at all levels of primary and secondary education including vocational high schools. Thematic workshops can be carried out on various themes such as comparative anatomy and embryology, molecular biology and evolution, or toxicology and endocrine disruptors. They were on an ad hoc basis or as part of an annual school project using zebrafish as a model. This animal was a very attractive entry point for the educator to motivate students to appreciate biology, in particular in the field of molecular biology and evolution. For each practical workshop, the student was an actor in his/her learning, which was intended to arouse the curiosity and desire to understand and learn. The programme was based on close collaboration between class teachers and programme educators to adapt workshops’ content to the school curriculum. Students conducted their own experiments, formulated and tested hypotheses, learned laboratory techniques, collected and analysed data. ZebraCool scientific activities fell within a conceptual framework of evolutionary biology through which participants perceived their own inner fish through the comparison of biological processes between humans and zebrafish.

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Association of environmental pollutants with asthma and allergy, and the mediating role of oxidative stress and immune markers in adolescents
Authors
Hassen Y. Hamid, Govarts Eva, Remy Sylvie, Cox Bianca, Iszatt Nina, Portengen Lützen, Covaci Adrian, Schoeters Greet, Den Hond Elly, De Henauw Stefaan, Bruckers Liesbeth, Koppen Gudrun, Verheyen Veerle J.
Journal
Environmental Research
Vol. 265
120445
Keywords
Asthma, Allergy, Airway inflammation, Oxidative stress, Immune biomarkers, Human biomonitoring, Mixture, Adolescents
Date of publication
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Background
Asthma and allergic diseases are among the common causes of morbidity and mortality globally. Various environmental pollutants are linked to the development of asthma and allergic diseases. Evidence on the role of oxidative stress and immune markers in the association of environmental pollutants with asthma and allergy is scant. We examined cross-sectional associations between environmental pollutants and asthma and allergy, investigated mixture effects and possible mediation by oxidative stress or immune markers.

Methods
We used data from the Flemish Environment and Health Study 2016–2020 (FLEHS IV), including 409 adolescents aged 13–16 years. Fifty-four pollutants, including metals, phthalates, Di(isononyl) cyclohexane-1,2-dicarboxylate (DINCH), bisphenols, currently used and legacy pesticides, flame retardants, per- and polyfluoroalkyl substances (PFAS), polyaromatic hydrocarbons (PAHs), and polychlorinated biphenyls (PCBs) were analyzed. Outcomes were self-reported asthma, rhinitis, eczema, allergies, respiratory infection, and airway inflammation, measured through fractional exhaled nitric oxide (FeNO). Single pollutant models using multiple regression analysis and multipollutant models using Bayesian Kernel Machine Regression (BKMR) were fitted. As sensitivity analysis, Bayesian model averaging (BMA) and elastic net (ENET) models were also performed. For Bayesian models, posterior inclusion probabilities (PIP) were used to identify the most important chemicals. Mediation analysis was performed to investigate the role of oxidative stress, measured by urinary 8-hydroxy-2' -deoxyguanosine (8-OHdG), and immune markers (eosinophils, basophils, InterLeukin 8, InterLeukin 6, and Interferon-ᵧ in blood).

Results
In single pollutant models, FeNO was significantly higher by 20% (95% CI: 6, 36%) and 13% (95% CI: 2, 25%) per interquartile range (IQR) fold in mono-n-butyl phthalate (MnBP) and mono-benzyl phthalate (MBzP), respectively. In BKMR analysis, the group PIPs indicated phthalates and DINCH as the most important group (group PIP = 0.509), with MnBP being the most important pollutant within that group (conditional PIP = 0.564; %change = 28%; 95%CI: 6, 54%). Similar patterns were observed in all multipollutant models. Eosinophil count mediated 37.8% (p = 0.018) and 27.9% (p = 0.045) of the association between MBzP and FeNO, and the association between MnBP and FeNO, respectively. 8-OHdG plays a significant mediating role in the association of 2,4-Dichlorophenoxyacetic acid (2,4-D) (55.4%), 3,5,6-Trichloro-2-pyridinol (TCPY) (48.1%), and 1-Naphthylamine (1-NAP) (32.7%) with rhinitis, while the total effects of these chemicals on rhinitis were not statistically significant.

Conclusions
This study found associations between phthalates, MnBP and MBzP, and elevated FeNO, which appeared to be mediated by eosinophil count. 8-OHdG plays a significant mediating role in the association between 2,4-D, TCPY, and 1-NAP with rhinitis, while their direct effects remain non-significant. Use of inflammatory and oxidative stress markers can enhance the understanding of inflammatory processes in asthma and allergic diseases due to environmental pollutants.

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A comprehensive library of lifetime physiological equations for PBK models
Authors
Gastellu Thomas, Karakoltzidis Achilleas, Ratier Aude, Bellouard Marie, Alavarez jean claude, Rivière Gilles, Le Bizec Bruno, Karakitsios Spyros, Sarigiannis Dimosthenis, Vogs Carolina
Journal
Environmental Research
Vol. 265
120393
Keywords
ADME toxicokinetics, Lifetime dietary exposure, Total mercury, Toxicological reference values
Date of publication
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Dietary risk assessment of food contaminants requires a well-established understanding of the exposure in a heterogeneous population. There are many methods for estimating human exposure to food contaminants, such as intake calculations and internal biomarkers of exposure measured in individuals. However, those methods are expensive, partly invasive, and often provide a momentary exposure snapshot. Physiologically Based Kinetic (PBK) modelling is increasingly used to overcome those challenges that traditional human exposure methods encounter. Still, PBK models are often restricted to certain life stages (e.g., children, adolescents, adults). This study outlines a strategy for implementing nonlinear organ growths in age-specific PBK models to enhance dietary risk assessment from lifetime exposure. To this end, lifetime physiological equations calculating organ growth for both sexes were inventoried from literature and a library was established for 24 organs. We then assessed total lifelong mercury exposure via foodstuff by combining two existing age-specific PBK models for methylmercury (MeHg) and inorganic mercury (iHg) that simulated internal exposure to total mercury, the speciation typically measured in hair and urine. We implemented a set of physiological equations in the PBK model that fitted best the total mercury measured in individuals' organs, hair, and urine from heterogeneous populations. For refined dietary risk assessment, we ultimately estimated total mercury concentration in hair and urine based on i) maximum limits defined by the regulation for MeHg in seafood, ii) the health-based guidance values for MeHg and iHg, and iii) realistic intakes considering French demographic parameters and food consumption data. These exposure scenarios demonstrated that total mercury concentrations in hair and urine estimated from realistic intakes are below critical effect level measures at all ages. The result of this study is the creation of easily accessible tools in Excel and R that facilitate the implementation of physiological equations in Next Generation PBK models.

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Developing quantitative Adverse Outcome Pathways: An ordinary differential equation-based computational framework
Journal
Computational Toxicology
Vol. 32
100330
Keywords
Ordinary differential equations (ODEs), Quantitative Adverse Outcome Pathway (qAOP), Key event relationships (KERs), Adverse outcome (AO), Response–response modeling, Predictive toxicology, Markov chain Monte Carlo (MCMC), Population variability
Date of publication
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The Adverse Outcome Pathway (AOP) biological framework was introduced in 2012, yet defining a mathematical/computational framework for quantitative AOP (qAOP) development remains an open problem. In order to properly unravel the intricate biological mechanisms described by AOPs and provide quantitative predictions to support risk assessment, a computational model should provide a clear time-course prediction of key events (KEs), as well as describe the key event relationships (KERs) linking a molecular initiating event (MIE) to an adverse outcome (AO). Ultimately, the mathematical description of those links entails the possibility of quantitatively predicting adverse effects based on early events.
 
Here, we propose an ordinary differential equation (ODE) - based qAOP framework, as ODEs provide a time-course description of KEs and KERs. We illustrate how the application of computational techniques, such as Bayesian inference and Leave-one-out cross-validation (LOO-CV), can assist AOP development, introducing concepts of qAOP model selection and qAOP updating. Furthermore, we compare ODE and response–response based qAOP models, showing that ODE-based qAOPs can avoid erroneous predictions potentially resulting from response–response qAOPs. Finally, we show how ODE parameter variability can be linked to AO variability across a population. Overall, this framework serves as a valuable mathematical and computational tool for the development of qAOP models, enhancing our comprehension of intricate biological pathways associated with adverse outcomes.
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A comprehensive item bank of internal validity issues of relevance to in vitro toxicology studies
Authors
Vist Gunn E., Ames Heather M., Mathisen Gro H., Husøy Trine, Svendsen Camilla, Beronius Anna, Di Consiglio Emma, Druwe Ingrid, Hartung Thomas, Hoffmann Sebastian, Hooijmans Carlijn R., Machera Kyriaki, Prieto Pilar, Robinson Joshua F., Roggen Erwin, Rooney Andrew A., Roth Nicolas, Spilioti Eliana, Spyropoulou Anastasia, Tcheremenskaia Olga, Testai Emanuela, Vinken Mathieu, Whaley Paul
Journal
Evidence-Based Toxicology
Vol. 2
No. 1
2418045
Keywords
In vitro methods, Toxicology, NAMs, Risk of bias, Internal validity
Date of publication
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Context: In vitro toxicology studies are increasingly being included as evidence in systematic reviews and chemical risk assessments. INVITES-IN, a tool for assessing the internal validity of in vitro studies, is currently under development. The first step in developing INVITES-IN involves the creation of an “item bank”, an overview of study assessment concepts that may be relevant to evaluating the internal validity of in vitro toxicology studies. The item bank and methodology for its creation presented in this manuscript are intended to be a general resource for supporting the development of appraisal tools for in vitro toxicology studies and potentially other study designs.

Methods: We derived the item bank from seven literature sources (one existing item bank created from a systematic review of assessment criteria for in vitro studies, and six purposively sampled study appraisal tools) and the transcripts of three focus groups. Assessment criteria plausibly relating to internal validity were abstracted from the literature sources and focus group transcripts, disaggregated into individual criteria, then normalised to express in the simplest achievable language the core issue in each criterion – an “item bank” of assessment concepts. The items were then mapped onto a set of bias domains. We conducted simple descriptive statistical analyses and visualisations to describe patterns in the dataset and developed recommendations for the use and development of the item bank.

Results: The item bank contains 405 items of potential relevance to evaluating the internal validity of in vitro toxicology studies.

Discussion: To our knowledge, this is the second item bank of any kind to have been created for toxicology studies, and the first to use focus groups as a data source alongside literature analysis. The large number of items contributed by focus group discussions suggests this is an efficient method for capturing internal validity issues that are not easily identifiable in the literature. We believe our item bank and methodology for its creation will be a useful resource for supporting the development of appraisal tools. Due to the broad applicability of many items in the item bank, it may be informative for study designs beyond the in vitro domain.

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A preliminary estimate of the environmental burden of disease associated with exposure to pyrethroid insecticides and ADHD in Europe based on human biomonitoring
Authors
Purece Anthony, Thomsen Sofie Theresa, Plass Dietrich, Spyropoulou Anastasia, Machera Kyriaki, Palmont Philippe, Crépet Amélie, Benchrih Rafiqa, Devleesschauwer Brecht, Wieland Nina, Scheepers Paul, Deepika Deepika, Kumar Vikas, Sanchez Gerardo, Bessems Jos, Piselli Dario, Buekers Jurgen
Journal
Environmental Health
Vol. 23
91
Date of publication
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Human biomonitoring (HBM) data indicate that exposure to pyrethroids is widespread in Europe, with significantly higher exposure observed in children compared to adults. Epidemiological, toxicological, and mechanistic studies raise concerns for potential human health effects, particularly, behavioral effects such as attention deficit
hyperactivity disorder (ADHD) in children at low levels of exposure. Based on an exposure-response function from a single European study and on available quality-assured and harmonized HBM data collected in France, Germany, Iceland, Switzerland, and Israel, a preliminary estimate of the environmental burden of disease for ADHD associated with pyrethroid exposure was made for individuals aged 0–19 years. The estimated annual number of prevalencebased disability-adjusted life years (DALYs) per million inhabitants were 27 DALYs for Israel, 21 DALYs for France, 12 DALYs for both Switzerland and Iceland, and 3 DALYs for Germany; while the annual ADHD cases per million inhabitants attributable to pyrethroids were 2189 for Israel, 1710 for France, 969 for Iceland, 944 for Switzerland, and 209 for Germany. Direct health costs related to ADHD ranged between 0.3 and 2.5 million EUR yearly per million inhabitants for the five countries. Additionally, a substantial number of ADHD cases, on average 18%, were
associated with pyrethroid exposure. Yet, these figures should be interpreted with caution given the uncertainty of the estimation. A sensitivity analysis showed that by applying a different exposure-response function from outside the EU, the population attributable fraction decreased from an average of 18 to 7%. To ensure more robust disease burden estimates and adequate follow-up of policy measures, more HBM studies are needed, along with increased efforts to harmonize the design of epidemiological studies upfront to guarantee meta-analysis of exposureresponse functions. This is particularly important for pyrethroids as evidence of potential adverse health effects is continuously emerging.

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A critical review to identify data gaps and improve risk assessment of bisphenol A alternatives for human health
Authors
Mhaouty-Kodja Sakina, Zalko Daniel, Tait Sabrina, Testai Emanuela, Viguié Catherine, Corsini Emanuela, Grova Nathalie, Buratti Franca Maria, Cabaton Nicolas J., Coppola Lucia, De la Vieja Antonio, Dusinska Maria, El Yamani Naouale, Galbiati Valentina, Iglesias-Hernández Patricia, Kohl Yvonne, Maddalon Ambra, Marcon Francesca, Naulé Lydie, Rundén-Pran Elise, Salani Francesca, Santori Nicoletta, Torres-Ruiz Mónica, Turner Jonathan D., Adamovsky Ondrej, Aiello-Holden Kiara, Dirven Hubert, Louro Henriqueta, Silva Maria Joao
Journal
Critical Reviews in Toxicology
1-58
Keywords
Bisphenol A alternatives, Endocrine disruption, Metabolism, Toxicokinetic, Immunotoxicity, Developmental neurotoxicity, Genotoxicity, Carcinogenesis, Human health
Date of publication
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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).

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Extremely high levels of PBDEs in children’s toys from European markets: causes and implications for the circular economy
Authors
Olisah Chijioke , Melymuk Lisa, Audy Ondrej , Kukucka Petr , Pribylova Petra, Boudot Martin
Journal
Environmental Sciences Europe
Vol. 36
183
Keywords
Flame retardants, Consumer products, Plastic recycling, E-waste, Enforcement, Compliance
Date of publication
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Background

With the high influx of low-cost plastic toys on the market, there is growing concern about the safety of such toys. Some of these plastic toys contains hazardous chemicals like polybrominated diphenyl ethers (PBDEs) due to the use of recycled plastics in new toy manufacturing. Here, we investigated if toys marketed in Europe are compliant with EU directives to assess the safety of currently used children's toys and identify implications of PBDE content in toys.

Results

Eighty-four toys purchased from international toy retailers were screened for bromine using X-ray fluorescence (XRF), and 11 of those with bromine content higher than 500 µg/g were analyzed for ten PBDEs using GC–HRMS. PBDEs were detected in all 11 toys. Ʃ10PBDE concentrations ranged up to 23.5 mg/g (with a median concentration of 8.61 mg/g), with BDE-209 being the most abundant compound (4.40 mg/g). Eight samples exceeded the EU’s Low POP Content Limit (LPCL) of 500 µg/g for the Ʃ10PBDEs by 6–47 times and the Unintentional Trace Contaminant (UTC) limits of 10 µg/g for Deca-BDE by 12–800 times.

Conclusions

PBDEs were up to percent levels, suggesting direct recycling of flame retarded plastic, e.g., e-waste plastics, into toy components. This is a call for concern and requires intervention from all stakeholders involved in the toy market. Overall, the occurrence of non-compliant toys in the EU market, as indicated in this study is primarily attributed to gaps in regulations, inadequate legislation for recycled plastics, the rise of online sales, complexities in global and national supply chains, and economic challenges. Failure to address these issues will hinder the efforts of the plastics industry to transition into a circular economy. This suggests that more actions are needed to address gaps in cross-border enforcement, and stricter sanctions are required for toy manufacturers who fail to adhere to regulations and safety standards.

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Computational tools to facilitate early warning of new emerging risk chemicals
Authors
Farina Tariq, Lutz Ahrens, Nikiforos A. Alygizakis, Karine Audouze, Emilio Benfenati, Pedro N. Carvalho, Ioana Chelcea, Spyros Karakitsios, Achilleas Karakoltzidis, Vikas Kumar, Liadys Mora Lagares, Dimosthenis Sarigiannis, Gianluca Selvestrel, Olivier Taboureau, Katrin Vorkamp, Patrik L. Andersson
Journal
Toxics
Vol. 12
No. 10
736
Keywords
Early warning system (EWS), New and emerging risk chemicals (NERCs), Computational toxicology, Risk assessment, Artificial intelligence (AI), QSAR, Exposure assessment, Effect assessment
Date of publication
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Innovative tools suitable for chemical risk assessment are being developed in numerous domains, such as non-target chemical analysis, omics, and computational approaches. These methods will also be critical components in an efficient early warning system (EWS) for the identification of potentially hazardous chemicals. Much knowledge is missing for current use chemicals and thus computational methodologies complemented with fast screening techniques will be critical. This paper reviews current computational tools, emphasizing those that are accessible and suitable for the screening of new and emerging risk chemicals (NERCs). The initial step in a computational EWS is an automatic and systematic search for NERCs in literature and database sources including grey literature, patents, experimental data, and various inventories. This step aims at reaching curated molecular structure data along with existing exposure and hazard data. Next, a parallel assessment of exposure and effects will be performed, which will input information into the weighting of an overall hazard score and, finally, the identification of a potential NERC. Several challenges are identified and discussed, such as the integration and scoring of several types of hazard data, ranging from chemical fate and distribution to subtle impacts in specific species and tissues. To conclude, there are many computational systems, and these can be used as a basis for an integrated computational EWS workflow that identifies NERCs automatically.

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A conceptual framework for landscape-based environmental risk assessment (ERA) of pesticides
Authors
Tarazona Jose V., de Alba-Gonzalez Mercedes, Bedos Carole, Benoit Pierre, Bertrand Colette, Crouzet Olivier, Dagès Cécile, CM Dorne Jean-Lou, Fernandez-Agudo Ana, Focks Andreas, Gonzalez-Caballero Maria del Carmen, Kroll Alexandra, Liess Matthias, Loureiro Susana, Ortiz-Santaliestra Manuel E., Rasmussen Jes J., Royauté Raphaël, Rundlöf Maj, Schäfer Ralf B., Short Stephen, Siddique Ayesha, Sousa José Paulo, Spurgeon Dave, Staub Pierre-François, Topping Chris J., Voltz Marc, Axelman Johan, Aldrich Annette, Duquesne Sabine, Mazerolles Vanessa, Devos Yann
Journal
Environment International
Vol. 191
108999
Keywords
Functional ecotoxicology, Landscape, Modelling, Pesticide exposure and effects, Biodiversity, Ecological framework
Date of publication
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While pesticide use is subject to strict regulatory oversight worldwide, it remains a main concern for environmental protection, including biodiversity conservation. This is partly due to the current regulatory approach that relies on separate assessments for each single pesticide, crop use, and non-target organism group at local scales. Such assessments tend to overlook the combined effects of overall pesticide usage at larger spatial scales. Integrative landscape-based approaches are emerging, enabling the consideration of agricultural management, the environmental characteristics, and the combined effects of pesticides applied in a same or in different crops within an area. These developments offer the opportunity to deliver informative risk predictions relevant for different decision contexts including their connection to larger spatial scales and to combine environmental risks of pesticides, with those from other environmental stressors. We discuss the needs, challenges, opportunities and available tools for implementing landscape-based approaches for prospective and retrospective pesticide Environmental Risk Assessments (ERA). A set of “building blocks” that emerged from the discussions have been integrated into a conceptual framework. The framework includes elements to facilitate its implementation, in particular: flexibility to address the needs of relevant users and stakeholders; means to address the inherent complexity of environmental systems; connections to make use of and integrate data derived from monitoring programs; and options for validation and approaches to facilitate future use in a regulatory context. The conceptual model can be applied to existing ERA methodologies, facilitating its comparability, and highlighting interoperability drivers at landscape level. The benefits of landscape-based pesticide ERA extend beyond regulation. Linking and validating risk predictions with relevant environmental impacts under a solid science-based approach will support the setting of protection goals and the formulation of sustainable agricultural strategies. Moreover, landscape ERA offers a communication tool on realistic pesticide impacts in a multistressors environment for stakeholders and citizens.

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Associations between urinary phthalate metabolites with BDNF and behavioral function among european children from five HBM4EU aligned studies
Authors
Salamanca-Fernandez Elena, Espín-Moreno Lydia, Olivas-Martínez Alicia, Pérez-Cantero Ainhoa, Martín-Rodríguez José L., Poyatos Rafael M., Barbone Fabio, Rosolen Valentina, Mariuz Marika, Ronfani Luca, Palkovičová Murínová Ľubica, Fábelová Lucia, Szigeti Tamás, Kakucs Réka, Sakhi Amrit K., Haug Line S., Lindeman Birgitte, Snoj Tratnik Janja, Kosjek Tina, Jacobs Griet, Voorspoels Stefan, Jurdáková Helena, Górová Renáta, Petrovičová Ida, Kolena Branislav, Esteban Marta, Pedraza-Díaz Susana, Kolossa-Gehring Marike, Remy Sylvie, Govarts Eva, Schoeters Greet, Fernández Mariana F., Mustieles Vicente
Journal
Toxics
Vol. 12
No. 9
642
Keywords
Phthalate, Behavior, BDNF, Effect biomarker, Exposure biomarker, HBM4EU, PARC
Date of publication
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Based on toxicological evidence, children’s exposure to phthalates may contribute to altered neurodevelopment and abnormal regulation of brain-derived neurotrophic factor (BDNF). We analyzed data from five aligned studies of the Human Biomonitoring for Europe (HBM4EU) project. Ten phthalate metabolites and protein BDNF levels were measured in the urine samples of 1148 children aged 6–12 years from Italy (NACII-IT cohort), Slovakia (PCB-SK cohort), Hungary (InAirQ-HU cohort) and Norway (NEBII-NO). Serum BDNF was also available in 124 Slovenian children (CRP-SLO cohort). Children’s total, externalizing and internalizing behavioral problems were assessed using the Child Behavior Checklist at 7 years of age (only available in the NACII-IT cohort). Adjusted linear and negative binomial regression models were fitted, together with weighted quantile sum (WQS) regression models to assess phthalate mixture associations. Results showed that, in boys but not girls of the NACII-IT cohort, each natural-log-unit increase in mono-n-butyl phthalate (MnBP) and Mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) was cross-sectionally associated with higher externalizing problems [incidence rate ratio (IRR): 1.20; 95% CI: 1.02, 1.42 and 1.26; 95% CI: 1.03, 1.55, respectively]. A suggestive mixture association with externalizing problems was also observed per each tertile mixture increase in the whole population (WQS—IRR = 1.15; 95% CI: 0.97, 1.36) and boys (IRR = 1.20; 95% CI: 0.96, 1.49). In NACII-IT, PCB-SK, InAirQ-HU and NEBII-NO cohorts together, urinary phthalate metabolites were strongly associated with higher urinary BDNF levels, with WQS regression confirming a mixture association in the whole population (percent change (PC) = 25.9%; 95% CI: 17.6, 34.7), in girls (PC = 18.6%; 95% CI: 7.92, 30.5) and mainly among boys (PC = 36.0%; 95% CI: 24.3, 48.9). Among CRP-SLO boys, each natural-log-unit increase in ∑DINCH concentration was associated with lower serum BDNF levels (PC: −8.8%; 95% CI: −16.7, −0.3). In the NACII-IT cohort, each natural-log-unit increase in urinary BDNF levels predicted worse internalizing scores among all children (IRR: 1.15; 95% CI: 1.00, 1.32). Results suggest that (1) children’s exposure to di-n-butyl phthalate (DnBP) and di(2-ethylhexyl) phthalate (DEHP) metabolites is associated with more externalizing problems in boys, (2) higher exposure to DINCH may associate with lower systemic BDNF levels in boys, (3) higher phthalate exposure is associated with higher urinary BDNF concentrations (although caution is needed since the possibility of a “urine concentration bias” that could also explain these associations in noncausal terms was identified) and (4) higher urinary BDNF concentrations may predict internalizing problems. Given this is the first study to examine the relationship between phthalate metabolite exposure and BDNF biomarkers, future studies are needed to validate the observed associations.

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A short-term exposure to saxitoxin triggers a multitude of deleterious effects in Daphnia magna at levels deemed safe for human health
Authors
Ribeiro Pinto Albano, Asselman Jana, Pereira Patricia, Pereira Joana Luisa, Macário Inês P.E., Marques Sérgio M, Lourenço Joana, Domingues Inês, Botelho Maria João
Journal
Science of The Total Environment
Vol. 951
175431
Keywords
Neurotoxins, Harmful algal blooms, Cyanotoxins, Saxitoxins, Oxidative stress biomarkers, Epigenetic biomarkers
Date of publication
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Harmful algal blooms and the toxins produced during these events are a human and environmental health concern worldwide. Saxitoxin and its derivatives are potent natural aquatic neurotoxins produced by certain freshwater cyanobacteria and marine algae species during these bloom events. Saxitoxins effects on human health are well studied, however its effects on aquatic biota are still largely unexplored. This work aims at evaluating the effects of a pulse acute exposure (24 h) of the model cladoceran Daphnia magna to 30 μg saxitoxin L−1, which corresponds to the safety guideline established by the World Health Organization (WHO) for these toxins in recreational freshwaters. Saxitoxin effects were assessed through a comprehensive array of biochemical (antioxidant enzymes activity and lipid peroxidation), genotoxicity (alkaline comet assay), neurotoxicity (total cholinesterases activity), behavioral (swimming patterns), physiological (feeding rate and heart rate), and epigenetic (total 5-mC DNA methylation) biomarkers. Exposure resulted in decreased feeding rate, heart rate, total cholinesterases activity and catalase activity. Contrarily, other antioxidant enzymes, namely glutathione-S-transferases and selenium-dependent Glutathione peroxidase had their activity increased, together with lipid peroxidation levels. The enhancement of the antioxidant enzymes was not sufficient to prevent oxidative damage, as underpinned by lipid peroxidation enhancement. Accordingly, average DNA damage level was significantly increased in STX-exposed daphnids. Total DNA 5-mC level was significantly decreased in exposed organisms. Results showed that even a short-term exposure to saxitoxin causes significant effects on critical molecular and cellular pathways and modulates swimming patterns in D. magna individuals. This study highlights sub-lethal effects caused by saxitoxin in D. magna, suggesting that these toxins may represent a marked challenge to their thriving even at a concentration deemed safe for humans by the WHO.

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Pioneering an effect-based early warning system for hazardous chemicals in the environment
Authors
Niarchos Georgios, Alygizakis Nikiforos, Carere Mario, Dulio Valeria, Engwall Magnus, Hyötyläinen Tuulia, Kallenborn Roland, Karakitsios Spyros, Karakoltzidis Achilleas, Kärrman Anna, Lamoree Marja, Larsson Maria, Lundqvist Johan, Mancini Laura, Mottaghipisheh Javad, Rostkowski Pawel, Sarigiannis Dimosthenis, Vorkamp Katrin, Ahrens Lutz
Journal
TrAC Trends in Analytical Chemistry
Vol. 180
No. November 2024
117901
Keywords
Contaminants of emerging concern, Bioassays, Effect-based methods, Effect-directed analysis, Environmental monitoring, Toxicity
Date of publication
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Existing regulatory frameworks often prove inadequate in identifying contaminants of emerging concern (CECs) and determining their impacts on biological systems at an early stage. The establishment of Early Warning Systems (EWSs) for CECs is becoming increasingly relevant for policy-making, aiming to proactively detect chemical hazards and implement effective mitigation measures. Effect-based methodologies, including bioassays and effect-directed analysis (EDA), offer valuable input to EWSs with a view to pinpointing the relevant toxicity drivers and prioritizing the associated risks. This review evaluates the analytical techniques currently available to assess biological effects, and provides a structured plan for their systematic integration into an EWS for hazardous chemicals in the environment. Key scientific advancements in effect-based approaches and EDA are discussed, underscoring their potential for early detection and management of chemical hazards. Additionally, critical challenges such as data integration and regulatory alignment are addressed, emphasizing the need for continuous improvement of the EWS and the incorporation of analytical advancements to safeguard environmental and public health from emerging chemical threats.

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High precision blood lead radiogenic isotope signatures in a community exposed to Pb contaminated soils and implications for the current Pb exposure of the European population
Authors
Petit Jérôme C.J., Mattielli Nadine , De Jong Jeroen , Bouhoulle Elodie , Debouge Wendy , Maggi Patrick , Hublet Geneviève , Fagel Nathalie , Pirard Catherine , Charlier Corinne , Suzanne Remy
Journal
Science of The Total Environment
Vol. 950
174763
Keywords
Epidemiology, Biokinetic model, Urban environment, Allotment garden, Historical metallurgy, Isotope forensics
Date of publication
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Our study provides the most comprehensive dataset for high-precision radiogenic isotopes of lead (Pb) in blood for the western European population. It investigates their potential for elucidating the contribution of soil Pb to blood Pb using a human biomonitoring survey involving 81 adults and 4 children living in the urban area of Liège (Belgium). Soils in the area show moderate (median of 360 mg/kg) to high (95th percentile of 1000 mg/kg) Pb concentrations, due to former metal processing activities. Blood lead levels (BLL) measured in the study population are, on average, quantitatively consistent with a ∼ 20 % increase due to the exposure to Pb from soils, as estimated by a single-compartment biokinetic model. Consistently, its isotopic composition does not represent an endmember that fully accounts for the variability of Blood lead isotope (BLI) compositions measured in the study population. While some individuals show more thorogenic BLI ratios (relatively more enriched in 208Pb), which could be consistent with a greater exposure to local soils and/or by their country of birth, the BLI data mostly follow a trend roughly parallel to the European Standard Lead Pollution (ESLP) line, within the European leaded gasoline field, even two decades after the withdrawal of this source. Differences in BLI are probably associated with factors related to the presence of Pb in dwellings (pipes, paint) and drinking water distribution system, suggesting that the anthropogenic Pb in use, relevant to human exposure, may contain ore components of different origins, including the Australian Pb ore signature.

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Chemical respiratory sensitization
Authors
Hargitai Rita, Parráková Lucia, Szatmári Tünde, Monfort-Lanzas Pablo, Galbiati Valentina, Audouze Karine, Jornod Florence, Staal Yvonne C. M., Burla Sabina, Chary Aline, Gutleb Arno C., Lumniczky Katalin, Vandebriel Rob J., Gostner Johanna M.
Journal
Frontiers in Toxicology
Vol. 6
1331803
Keywords
Adverse outcome pathway (AOP), Chemical respiratory allergy, Chemical sensitizer, Chemical-induced hypersensitivity, Key event, New approach methodology (NAM), Occupational asthma, Respiratory sensitization
Date of publication
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Respiratory sensitization is a complex immunological process eventually leading to hypersensitivity following re-exposure to the chemical. A frequent consequence is occupational asthma, which may occur after long latency periods. Although chemical-induced respiratory hypersensitivity has been known for decades, there are currently no comprehensive and validated approaches available for the prospective identification of chemicals that induce respiratory sensitization, while the expectations of new approach methodologies (NAMs) are high. A great hope is that due to a better understanding of the molecular key events, new methods can be developed now. However, this is a big challenge due to the different chemical classes to which respiratory sensitizers belong, as well as because of the complexity of the response and the late manifestation of symptoms. In this review article, the current information on respiratory sensitization related processes is summarized by introducing it in the available adverse outcome pathway (AOP) concept. Potentially useful models for prediction are discussed. Knowledge gaps and gaps of regulatory concern are identified.

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Cross-mapping of terms used in chemical risk assessment with those used in systematic review: research protocol
Authors
Svendsen Camilla, Mathisen Gro Haarklou, Vist Gunn E., Husøy Trine, Ames Heather, Beronius Anna, Di Consiglio Emma, Druwe Ingrid, Hartung Thomas, Hoffmann Sebastian, Hooijmans Carlijn R., Machera Kyriaki, Robinson Joshua F. , Roggen Erwin, Rooney Andrew A., Roth Nicolas, Spilioti Eliana, Spyropoulou Anastasia, Tcheremenskaia Olga, Testai Emanuela, Vinken Mathieu, Whaley Paul
Journal
Evidence-Based Toxicology
Vol. 2
No. 1
22371285
Keywords
Conceptual overlap, Cross-mapping, Definitions, Interoperability, Terminology
Date of publication
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The focus on implementation of systematic review (SR) principles in chemical risk assessments (CRAs) is growing as it has the potential to advance the rigour and transparency of the CRAs. However, the SR and CRA communities use their own specific terminologies. Understanding the meaning of core SR and CRA terms and where they overlap is critical for application of SR methods and principles in CRAs. Moreover, it will increase the possibility for cross-sectorial collaboration, avoid misunderstandings, and improve communication among risk assessors, researchers, and policy makers.

We present a process for the cross-mapping of core CRA terms and core SR terms. Core terms for study appraisal, evidence synthesis and integration used in the SR and CRA communities will be included. The outcome will be an overview of how core SR terms map onto core CRA terms and vice versa, and a description of the relationship and conceptual overlap between the terms.

The cross-mapping is divided in three phases, where in the first phase the core SR and CRA terms will be identified. In the second phase, existing SR and CRA definitions will be mapped. In the third phase, descriptions of the relationship and conceptual overlap between the terms will be derived. The third phase will include weekly one-hour online meetings for SR and CRA experts.

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Progress, applications, and challenges in high-throughput effect-directed analysis for toxicity driver identification
Authors
Alvarez Mora Iker, Arturi Katarzyna, Béen Frederic, Buchinger Sebastian, El Mais Abd El Rahman, Gallampois Christine, Hahn Meike, Hollender Juliane, Houtman Corine, Johann Sarah, Krauss Martin, Lamoree Marja, Margalef Maria, Massei Riccardo, Brack Werner, Muz Melis
Journal
Analytical and Bioanalytical Chemistry
Vol. 417
451-472
Keywords
HT-EDA, NTS, Bioanalytical methods, Mass spectrometry
Date of publication
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The rapid increase in the production and global use of chemicals and their mixtures has raised concerns about their potential impact on human and environmental health. With advances in analytical techniques, in particular, high-resolution mass spectrometry (HRMS), thousands of compounds and transformation products with potential adverse effects can now be detected in environmental samples. However, identifying and prioritizing the toxicity drivers among these compounds remain a significant challenge. Effect-directed analysis (EDA) emerged as an important tool to address this challenge, combining biotesting, sample fractionation, and chemical analysis to unravel toxicity drivers in complex mixtures. Traditional EDA workflows are labor-intensive and time-consuming, hindering large-scale applications. The concept of high-throughput (HT) EDA has recently gained traction as a means of accelerating these workflows. Key features of HT-EDA include the combination of microfractionation and downscaled bioassays, automation of sample preparation and biotesting, and efficient data processing workflows supported by novel computational tools. In addition to microplate-based fractionation, high-performance thin-layer chromatography (HPTLC) offers an interesting alternative to HPLC in HT-EDA. This review provides an updated perspective on the state-of-the-art in HT-EDA, and novel methods/tools that can be incorporated into HT-EDA workflows. It also discusses recent studies on HT-EDA, HT bioassays, and computational prioritization tools, along with considerations regarding HPTLC. By identifying current gaps in HT-EDA and proposing new approaches to overcome them, this review aims to bring HT-EDA a step closer to monitoring applications.

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Occupational exposure limits for reproductive toxicants – A comparative analysis
Authors
Schenk Linda, Ho Meng-Rung, Taxell Piia, Huuskonen Pasi, Leite Mimmi, Martinsone Inese, Nordby Karl-Christian, Paegle Linda, Strumylaite Loreta
Journal
Reproductive Toxicology
Vol. 128
108649
Keywords
Health risk assessment, Industrial hygiene, Maximum allowable concentration, Route-to-route extrapolation, Uncertainty factors, TLV, DNEL, Reproductive toxicology
Date of publication
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We investigated the level of protection of reproductive and developmental toxicity offered through occupational exposure limits (OELs) and Derived No-Effect Levels for workers’ inhalation exposure (wDNELs). We compared coverage of substances that have a harmonised classification as reproductive toxicant 1 A or 1B (Repr.1 A/B), numerical values and scientific basis of 12 lists of OELs and wDNELs from REACH Registrants’ and the Committee for Risk Assessment. Across the 14 sources of OELs and wDNELs, 53 % of the Repr1A/B-substances had at least one exposure limit (counting groups of metals as one entry). Registrants’ wDNELs covered the largest share, 40 %. The numerical values could be highly variable for the same substance across the lists. How often reproductive toxicity is identified as the critical effect varies between the examined lists, both due to different assessments of the same substance and different substance coverage. Reviewing the margin of safety to reproductive toxicity cited in the documents, we found that 15 % of safety margins were lower to reproductive toxicity than the critical effect. To conclude, neither the REACH nor work environment legislation supply wDNELs or OELs for a substantial share of known reproductive toxicants. EU OELs cover among the fewest substances in the range, and in many cases national OELs or wDNELs are set at more conservative levels.

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Internal flames: Metal(loid) exposure linked to alteration of the lipid profile in Czech male firefighters (CELSPAC-FIREexpo study)
Authors
Pálešová Nina, Řiháčková Katarína, Kuta Jan, Pindur Aleš, Šebejová Ludmila, Čupr Pavel
Journal
Environmental Science & Technology Letters
Vol. 7
No. 11
679–686
Keywords
Firefighters, Occupational exposure, Metals, Cholesterol, Cardiovascular disease, Mixture analysis
Date of publication
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Increased wildfire activity increases the demands onfire rescue services and firefighters’ contact with harmful chemicals.This study aimed to determine firefighters’ exposure to toxicmetal(loid)s and its association with the lipid profile. CELSPAC-FIREexpo study participants (including 110 firefighters) providedurine and blood samples to quantify urinary levels of metal(loid)s (arsenic, cadmium (Cd), mercury and lead (Pb)) and serum lipidbiomarkers (cholesterol (CHOL), low-density lipoprotein choles-terol (LDL), high-density lipoprotein cholesterol (HDL), and triglycerides (TG)). The associations were investigated by usingmultiple linear regression and Bayesian weighted quantile sum(BWQS) regression. Higher levels of Pb were observed infirefighters. Pb was positively associated with CHOL and TG.Cd was negatively associated with HDL. In the BWQS model, the mixture of metal(loid)s was associated positively with CHOL (β =14.75, 95% CrI = 2.45−29.08), LDL (β = 15.14, 95% CrI = 3.39−29.35) and TG (β = 14.79, 95% CrI = 0.73−30.42), whilenegatively with HDL (β = −14.96, 95% CrI = −25.78 to −1.8). Pb emerged as a key component in a metal(loid) mixture. Theresults suggest that higher exposure to lead and the mixture of metal(loid)s is associated with the alteration of the lipid profile, whichcan result in an unfavorable cardiometabolic profile, especially in occupationally exposed firefighters.

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Effects of metabolic disruption on lipid metabolism and yolk retention in zebrafish embryos
Journal
Environmental Toxicology and Chemistry
Vol. 43
No. 8
1880-1893
Keywords
Aquatic toxicology, Developmental toxicity, Endocrine-disrupting compounds, Toxicity mechanisms
Date of publication
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A subgroup of endocrine-disrupting chemicals have the ability to disrupt metabolism. These metabolism-disrupting chemicals (MDCs) can end up in aquatic environments and lead to adverse outcomes in fish. Although molecular and physiological effects of MDCs have been studied in adult fish, few studies have investigated the consequences of metabolic disruption in fish during the earliest life stages. To investigate the processes affected by metabolic disruption, zebrafish embryos were exposed to peroxisome proliferator–activated receptor gamma (PPARγ) agonist rosiglitazone, the PPARγ antagonist T0070907, and the well-known environmentally relevant MDC bisphenol A. Decreased apolipoprotein Ea transcript levels indicated disrupted lipid transport, which was likely related to the observed dose-dependent increases in yolk size across all compounds. Increased yolk size and decreased swimming activity indicate decreased energy usage, which could lead to adverse outcomes because the availability of energy reserves is essential for embryo survival and growth. Exposure to T0070907 resulted in a darkened yolk. This was likely related to reduced transcript levels of genes involved in lipid transport and fatty acid oxidation, a combination of responses that was specific to exposure to this compound, possibly leading to lipid accumulation and cell death in the yolk. Paraoxonase 1 (Pon1) transcript levels were increased by rosiglitazone and T0070907, but this was not reflected in PON1 enzyme activities. The present study shows how exposure to MDCs can influence biochemical and molecular processes involved in early lipid metabolism and may lead to adverse outcomes in the earliest life stages of fish.

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How wastewater reflects human metabolism - Suspect screening of pharmaceutical metabolites in wastewater influent
Journal
Environmental Science & Technology
Vol. 58
No. 22
9828-9839
Keywords
Drug Metabolites, Human Pharmaceutical Metabolism, Suspect Screening, Wastewater, High Resolution Mass Spectrometry, Sirius/csi:fingerid, Metfrag, Molecular Network
Date of publication
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Pharmaceuticals and their human metabolites are contaminants of emerging concern in the aquatic environment. Most monitoring studies focus on a limited set of parent compounds and even fewer metabolites. However, more than 50% of the most consumed pharmaceuticals are excreted in higher amounts as metabolites than as parents, as confirmed by a literature analysis within this study. Hence, we applied a wide-scope suspect screening approach to identify human pharmaceutical metabolites in wastewater influent from three Swiss treatment plants. Based on consumption amounts and human metabolism data, a suspect list comprising 268 parent compounds and over 1500 metabolites was compiled. Online solid phase extraction combined with liquid chromatography coupled to high-resolution tandem mass spectrometry was used to analyze the samples. Data processing, annotation, and structure elucidation were achieved with various tools, including molecular networking as well as SIRIUS/CSI:FingerID and MetFrag for MS2 spectra rationalization. We confirmed 37 metabolites with reference standards and 16 by human liver S9 incubation experiments. More than 25 metabolites were detected for the first time in influent wastewater. Semiquantification with MS2Quant showed that metabolite to parent concentration ratios were generally lower compared to literature expectations, probably due to further metabolite transformation in the sewer system or limitations in the metabolite detection. Nonetheless, metabolites pose a large fraction to the total pharmaceutical contribution in wastewater, highlighting the need for metabolite inclusion in chemical risk assessment.

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Exploring BPA alternatives – Environmental levels and toxicity review
Authors
Adamovsky Ondrej, Groh Ksenia J., Białk-Bielińska Anna, Escher Beate I., Beaudouin R., Lagares Liadys Mora, Tollefsen Knut Erik, Fenske Martina, Mulkiewicz Ewa, Creusot Nicolas, Sosnowska Anita, Loureiro Susana, Beyer Jonny, Repetto Guillermo, Štern Alja, Lopes Isabel, Monteiro Marta, Zikova-Kloas Andrea, Eleršek Tina, Vračko Marjan, Kyriakopoulou Katerina, Zdybel Szymon, Puzyn Tomasz, Koczur Weronika, Morthorst Jane Ebsen, Holbech Henrik, Carlsson Gunnar, Örn Stefan, Herrero Óscar, Siddique Ayesha, Liess Matthias, Braun Georg, Srebny Vanessa, Žegura Bojana, Hinfray Nathalie, Brion François, Knapen Dries, Vandeputte Ellen, Stinckens Evelyn, Vergauwen Lucia, Behrendt Lars, Silva Maria João, Blaha Ludek
Journal
Environment International
Vol. 189
108728
Keywords
BPA alternatives, Biological activity, In silico, Invertebrates, Vertebrates
Date of publication
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Bisphenol A alternatives are manufactured as potentially less harmful substitutes of bisphenol A (BPA) that offer similar functionality. These alternatives are already in the market, entering the environment and thus raising ecological concerns. However, it can be expected that levels of BPA alternatives will dominate in the future, they are limited information on their environmental safety. The EU PARC project highlights BPA alternatives as priority chemicals and consolidates information on BPA alternatives, with a focus on environmental relevance and on the identification of the research gaps. The review highlighted aspects and future perspectives. In brief, an extension of environmental monitoring is crucial, extending it to cover BPA alternatives to track their levels and facilitate the timely implementation of mitigation measures. The biological activity has been studied for BPA alternatives, but in a non-systematic way and prioritized a limited number of chemicals. For several BPA alternatives, the data has already provided substantial evidence regarding their potential harm to the environment. We stress the importance of conducting more comprehensive assessments that go beyond the traditional reproductive studies and focus on overlooked relevant endpoints. Future research should also consider mixture effects, realistic environmental concentrations, and the long-term consequences on biota and ecosystems.

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Regulatory and practical considerations on the implementation of a mixture allocation factor in REACH
Authors
Hassold Enken, Schulze Jona , Galert Wiebke, Treu Gabriele
Journal
Environmental Sciences Europe
Vol. 36
101
Keywords
Co-exposure, Mixture risk assessment, Risk management measures, Unintentional mixtures, MAF
Date of publication
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There is indisputable evidence that the environment, humans and wildlife are continuously exposed not to single but to multiple chemicals from diferent sources. Exposure to these mixtures can lead to combined risks not yet suffciently addressed in any of the European chemical legislations. Under the REACH regulation for industrial chemicals, specifc environmental mixture assessments are challenged by a lack of data on toxicity, use and exposures and the communication of data along the supply chain. Within the Chemicals Strategy for Sustainability the European Commission proposed to introduce (a) mixture allocation factor(s) (MAF) as regulatory management tool to reduce exposures, efects and potential risks of unintentional mixtures. The MAF is proposed to be applied as default value within the chemical safety assessments undertaken by companies under REACH. Here, we critically review the relevant literature discussing the conceptual background of the MAF and approaches to derive its magnitude.
The analysis focuses on the environment and key issues for an implementation in regulatory practise together with remaining uncertainties and needs for possible ways forward. At this stage introducing a MAF in REACH Annex I appears the most pragmatic and immediately implementable measure to address risks from unintentional mixtures in the environment. A so-called MAFceiling appears as the preferred option of policy makers, since it would only afect relevant substances close to their respective risk threshold. While the magnitude of a MAF will be decided politically, the choice of methods and assumptions to derive its size should be clear and transparent, build on the available scientifc evidence and take account for uncertainties. A MAF will be most efective reducing environmental releases and exposure levels if risk mitigation measures are implemented in practise. Its socioeconomic impacts and costs need to be assessed in a balanced way together with the benefts for the environment, society, and for companies — also in comparison to the eforts needed for specifc mixture risk assessments. In the future and with the experiences gathered in practise, a discussion is needed on how to assess and regulate unintentional mixtures across diferent pieces of chemicals legislation to consider the true exposure situation and ensure harmonisation.

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Protocol: Testing the performance of INVITES-IN, A tool for assessing the internal validity of in vitro studies
Authors
Mathisen Gro Haarklou, Vist Gunn E, Whaley Paul, White Richard A, Husøy Trine, Ames Heather M, Beronius Anna, Di Consiglio Emma, Druwe Ingrid, Hartung Thomas, Hoffmann Sebastian, Hooijmans Carlijn R., Machera Kyriaki, Prieto Pilar, Robin Joshua F, Roggen Erwin, Rooney Andrew A, Roth Nicolas, Spilioti Eliana, Spyropoulou Anastasia, Tcheremenskaia Olga, Testai Emanuela, Vinken Mathieu, Svendsen Camilla
Journal
Evidence-Based Toxicology
Vol. 1
No. 1
2293289
Keywords
Cell culture, Evidence-based toxicology, Risk of bias, User testing
Date of publication
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A tool for evaluation of internal validity of in vitro studies called INVITES-IN is currently under development. The tool is designed specifically for cell culture studies.

This protocol describes the testing of the performance of INVITES-IN. By performance, we mean the extent to which results of using INVITES-IN are the same for different users (consistency), the amount of time and cognitive effort it takes to apply INVITES-IN (assessor workload), the precision and potential for systematic error in results of applying INVITES-IN (accuracy), and how easy it is to use INVITES-IN (user experience).

The participants in the user testing will be representative for the expected end-users of INVITES-IN which are persons preparing literature reviews including in vitro studies (e.g. in the context of chemical hazard and risk assessments or drug development). All end-users are expected to have experience with in vitro methods.

Data collected from the performance testing will be used for further refinement and development of the release version of INVITES-IN.

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Estimating the dynamic early life exposure to PFOA and PFOS of the HELIX children: Emerging profiles via prenatal exposure, breastfeeding, and diet
Authors
Ratier Aude, Casas Maribel, Grazuleviciene Regina, Slama Rémy, Haug Line Småstuen, Thomsen Cathrine, Vafeiadi Marina, Wright John, Zeman Florence A, Vrijheid Martine, Brochot Céline
Journal
Environment International
Vol. 186
108621
Keywords
PBPK model, Reverse dosimetry, Longitudinal cohorts, Children, Human biomonitoring
Date of publication
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In utero and children’s exposure to per- and polyfluoroalkyl substances (PFAS) is a major concern in health risk assessment as early life exposures are suspected to induce adverse health effects. Our work aims to estimate children’s exposure (from birth to 12 years old) to PFOA and PFOS, using a Physiologically-Based Pharmacokinetic (PBPK) modelling approach. A model for PFAS was updated to simulate the internal PFAS exposures during the in utero life and childhood, and including individual characteristics and exposure scenarios (e.g., duration of breastfeeding, weight at birth, etc.). Our approach was applied to the HELIX cohort, involving 1,239 mother–child pairs with measured PFOA and PFOS plasma concentrations at two sampling times: maternal and child plasma concentrations (6 to 12 y.o). Our model predicted an increase in plasma concentrations during fetal development and childhood until 2 y.o when the maximum concentrations were reached. Higher plasma concentrations of PFOA than PFOS were predicted until 2 y.o, and then PFOS concentrations gradually became higher than PFOA concentrations. From 2 to 8 y.o, mean concentrations decreased from 3.1 to 1.88 µg/L or ng/mL (PFOA) and from 4.77 to 3.56 µg/L (PFOS). The concentration–time profiles vary with the age and were mostly influenced by in utero exposure (on the first 4 months after birth), breastfeeding (from 5 months to 2 (PFOA) or 5 (PFOS) y.o of the children), and food intake (after 3 (PFOA) or 6 (PFOS) y.o of the children). Similar measured biomarker levels can correspond to large differences in the simulated internal exposures, highlighting the importance to investigate the children’s exposure over the early life to improve exposure classification. Our approach demonstrates the possibility to simulate individual internal exposures using PBPK models when measured biomarkers are scarce, helping risk assessors in gaining insight into internal exposure during critical windows, such as early life.

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Inconsistencies in the EU regulatory risk assessment of PFAS call for readjustment
Authors
Reinikainen Jussi, Bouhoulle Elodie, Sorvari Jaana
Journal
Environment International
Vol. 186
108614
Keywords
PFAS, Risk assessment, Health protection, Contamination, Quality standard, Policy
Date of publication
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Recognition of per- and polyfluoroalkyl substances (PFAS) as widespread environmental pollutants and a consequent risk to human health, has recently made the European Union (EU) adopt several regulatory measures for their management. The coherence of these measures is challenged by the diversity and the ubiquitous occurrence of PFAS, which also complicates the EU’s endeavor to advance justified, harmonized, and transparent approaches in the regulatory assessment of chemical risks. Our study critically reviews the European approach for the risk assessment of PFAS, by applying a comparative analysis of the current and pending regulatory thresholds issued for these chemicals in water bodies, drinking water, and certain foodstuffs. Our study shows that the level of health protection embedded in the studied thresholds may differ by three orders of magnitude, even in similar exposure settings. This is likely to confuse the common understanding of the toxicity and health risks of PFAS and undermine reasonable decision-making and the equal treatment of different stakeholders. Wealso indicate that currently, no consensus exists on the appropriate level of required health protection regarding PFAS and that the recently adopted tolerable intake value in the EU is too cautious. Based on our analysis, we propose some simple solutions on how the studied regulations and their implicit PFAS thresholds or their application could be improved. We further conclude that instead of setting EU-wide PFAS thresholds for all the environmental compartments, providing the member states with the flexibility to consider case-specific factors such as regional background concentrations or food consumption rates, in their national regulatory procedures would likely result in more sustainable management of environmental PFAS without compromising the scientific foundation of risk assessment, the legitimacy of the EU policy framework and public health.

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Exposure to benzotriazoles and benzothiazoles in Czech male population and its associations with biomarkers of liver function, serum lipids and oxidative stress
Authors
Pálešová Nina, Bláhová Lucie, Janoš Tomáš, Řiháčková Katarína, Pindur Aleš, Šebejová Ludmila, Čupr Pavel
Journal
International Archives of Occupational and Environmental Health
Vol. 97
523–536
Keywords
Benzotriazole, Human biomonitoring, Liver Function, Serum lipids, Oxidative stress
Date of publication
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Introduction: Benzotriazoles and benzothiazoles (BTs) are high-production volume chemicals as well as widely distributed
emerging pollutants with potential health risk. However, information about human exposure to BTs and associated health
outcomes is limited.
Objective: We aimed to characterise exposure to BTs among Czech men, including possible occupational exposure among
firefighters, its predictors, and its associations with liver function, serum lipids and oxidative stress.
Methods: 165 participants (including 110 firefighters) provided urine and blood samples that were used to quantify the urinary
levels of 8 BTs (high-performance liquid chromatography-tandem mass spectrometry), and 4 liver enzymes, cholesterol,
low-density lipoprotein, and 8-hydroxy-2’-deoxyguanosine. Linear regression was used to assess associations with population
characteristics and biomarkers of liver function, serum lipids and oxidative stress. Regression models were adjusted for
potential confounding variables and false discovery rate procedure was applied to account for multiplicity.
Results: The BTs ranged from undetected up to 46.8 ng/mL. 2-hydroxy-benzothiazole was the most predominant compound
(detection frequency 83%; median 1.95 ng/mL). 1-methyl-benzotriazole (1M-BTR) was measured in human samples for
the first time, with a detection frequency 77% and median 1.75 ng/mL. Professional firefighters had lower urinary 1M-BTR
compared to non-firefighters. Urinary 1M-BTR was associated with levels of γ-glutamyl transferase (β = − 17.54%; 95%
CI: − 26.127, − 7.962).
Conclusion: This is the first study to investigate BT exposure in Central Europe, including potentially exposed firefighters.
The findings showed a high prevalence of BTs in the study population, the relevance of 1M-BTR as a new biomarker of
exposure, and an urgent need for further research into associated adverse health outcomes.

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AOPWIKI-EXPLORER: An interactive graph-based query engine leveraging large language models
Authors
Kumar Saurav, Deepika Deepika, Slater Karin, Kumar Vikas
Journal
Computational Toxicology
Vol. 30
100308
Keywords
Adverse outcome pathway, Large language model, Graph database, Risk assessment, Artificial intelligence, Data integration, Information retrieval, Information extraction
Date of publication
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Adverse Outcome Pathways (AOPs) provide a basis for non-animal testing, by outlining the cascade of molecular and cellular events initiated upon stressor exposure, leading to adverse effects. In recent years, the scientific community has shown interest in developing AOPs through crowdsourcing, with the results archived in the AOP-Wiki: a centralized repository coordinated by the OECD, hosting nearly 512 AOPs (April, 2023). However, the AOP-Wiki platform currently lacks a versatile querying system, which hinders developers’ exploration of the AOP network and impedes its practical use in risk assessment. This work proposes to unleash the full potential of the AOP-Wiki archive by adapting its data into a Labelled Property Graph (LPG) schema. Additionally, the tool offers a visual network query interface for both database-specific and natural language queries, facilitating the retrieval and analysis of graph data. The multi-query interface allows non-technical users to construct flexible queries, thereby enhancing the potential for AOP exploration. By reducing the time and technical requirements, the present query engine enhances the practical utilization of the valuable data within AOP-Wiki. To evaluate the platform, a case study is presented with three levels of use-case scenarios (simple, moderate, and complex queries). AOPWIKI- EXPLORER is freely available on GitHub (https://github.com/Crispae/AOPWiki_Explorer) for wider community reach and further enhancement.

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Innovative analytical methodologies for characterizing chemical exposure with a view to next-generation risk assessment
Authors
Tkalec Žiga, Antignac Jean-Philippe, Bandow Nicole, Béen Frederic M., Belova Lidia, Bessems Jos, Le Bizec Bruno, Brack Werner, Cano-Sancho German, Chaker Jade, Covaci Adrian, Creusot Nicolas, David Arthur, Debrauwer Laurent, Dervilly Gaud, Duca Radu - Corneliu, Fessard Valerie, Grimalt Joan, Guerin Thierry, Habchi Baninia, Hecht Helge, Hollender Juliane, Jamin Emilien L., Klanova Jana, Kosjek Tina, Krauss Martin, Lamoree Marja, Lavison-Bompard Gwenaelle, Meijer Jeroen, Moeller Ruth, Mol Hans, Mompelat Sophie, Van Nieuwenhuyse An, Oberacher Herbert, Parinet Julien, Van Poucke Christof, Roškar Robert, Togola Anne, Trontelj Jurij, Price Elliott
Journal
Environment International
Vol. 186
108585
Keywords
High-resolution mass spectrometry, Effect-based methods, Sampling strategies, Chemical exposure, Chemical risk assessment , Effect-directed analysis
Date of publication
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The chemical burden on the environment and human population is increasing. Consequently, regulatory risk assessment must keep pace to manage, reduce, and prevent adverse impacts on human and environmental health associated with hazardous chemicals. Surveillance of chemicals of known, emerging, or potential future concern, entering the environment-food-human continuum is needed to document the reality of risks posed by chemicals on ecosystem and human health from a one health perspective, feed into early warning systems and support public policies for exposure mitigation provisions and safe and sustainable by design strategies. The use of less-conventional sampling strategies and integration of full-scan, high-resolution mass spectrometry and effect-directed analysis in environmental and human monitoring programmes have the potential to enhance the screening and identification of a wider range of chemicals of known, emerging or potential future concern. Here, we outline the key needs and recommendations identified within the European Partnership for Assessment of Risks from Chemicals (PARC) project for leveraging these innovative methodologies to support the development of next-generation chemical risk assessment.

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Intuitive toxicology in the 21st century - Bridging the perspectives of the public and risk assessors in Europe
Journal
Risk Analysis
Vol. 44
No. 10
2348-2359
Keywords
Chemical risk assessment, intuitive toxicology, New approach methodologies, next-generation riskassessment, risk perception
Date of publication
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Three decades ago, several articles on the subjectivity in chemical risk judgments (i.e., labeled “intuitive toxicology”) measured the divide between the public and toxicologists with different backgrounds regarding the validity of predicting health effects based on in vivo studies. Similar divides with impacts on societal discourse and chemical risk assessment practices might exist concerning alternative toxicity testing methods (i.e., in vitro and in silico). However, studies to date have focused either on the public's views of in vivo or stem cell testing or on experts’ views of in vivo testing and potential alternatives (i.e., toxicologists and medical students), which do not allow for a direct investigation of potential divides. To fill this knowledge gap, we conducted two online surveys, involving members of the German-speaking public in Switzerland and European human health risk assessors, respectively. This article presents the results of these two surveys regarding the divide in the public's and risk assessors’ perspectives on risk assessment based on in vivo, in vitro, and in silico testing. Particularly, the survey with the risk assessors highlights that, beyond scientific and regulatory barriers, alternatives to in vivo testing may encounter individual hurdles, such as higher uncertainty associated with them. Understanding and addressing these hurdles will be crucial to facilitate the integration of new approach methodologies into chemical risk assessment practices as well as a successful transition toward next-generation risk assessment, bringing us closer to a fit-for-purpose and more efficient regulatory landscape.

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Revealing the cascade of pesticide effects from gene to community
Authors
Siddique Ayesha, Shahid Naeem, Liess Matthias
Journal
Science of the Total Environment
Vol. 917
170472
Keywords
Adaptation, Neonicotinoids, Genetic diversity, AFLP, G. pulex
Date of publication
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Global pesticide exposure in agriculture leads to biodiversity loss, even at ultra-low concentrations below the legal limits. The mechanisms by which the effects of toxicants act at such low concentrations are still unclear, particularly in relation to their propagation across the different biological levels. In this study, we demonstrate, for the first time, a cascade of effects from the gene to the community level. At the gene level, agricultural pesticide exposure resulted in reduced genetic diversity of field-collected Gammarus pulex, a dominant freshwater crustacean in Europe. Additionally, we identified alleles associated with adaptations to pesticide contamination. At the individual level, this genetic adaptation to pesticides was linked to a lower fecundity, indicating related fitness costs. At the community level, the combined effect of pesticides and competitors caused a decline in the overall number and abundance of pesticides susceptible macroinvertebrate competing with gammarids. The resulting reduction in interspecific competition provided an advantage for pesticide-adapted G. pulex to dominate macroinvertebrate communities in contaminated areas, despite their reduced fitness due to adaptation. These processes demonstrate the complex cascade of effects, and also illustrate the resilience and adaptability of biological systems across organisational levels to meet the challenges of a changing environment. 

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Curated mode-of-action data and effect concentrations for chemicals relevant for the aquatic environment
Authors
Kramer Lena, Schulze Tobias , Klüver Nils, Altenburger Rolf, Hackermüller Jörg, Krauss Martin, Busch Wibke
Journal
Scientific Data
Vol. 11
60
Date of publication
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Chemicals in the aquatic environment can be harmful to organisms and ecosystems. Knowledge on efect concentrations as well as on mechanisms and modes of interaction with biological molecules and signaling pathways is necessary to perform chemical risk assessment and identify toxic compounds. To this end, we developed criteria and a pipeline for harvesting and summarizing efect concentrations from the US ECOTOX database for the three aquatic species groups algae, crustaceans, and fsh and researched the modes of action of more than 3,300 environmentally relevant chemicals in literature and databases. We provide a curated dataset ready to be used for risk assessment based on monitoring data and the frst comprehensive collection and categorization of modes of action of environmental chemicals. Authorities, regulators, and scientists can use this data for the grouping of chemicals, the establishment of meaningful assessment groups, and the development of in vitro and in silico approaches for chemical testing and assessment.

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Why adverse outcome pathways need to be FAIR
Authors
Wittwehr Clemens, Clerbaux Laure-Alix, Edwards Stephen, Angrish Michelle, Mortensen Holly, Carusi Annamaria, Gromelski Maciej , Lekka Eftychia, Virvilis Vassilis Virvilis, Martens Marvin, Bonino da Silva Santos Luiz Olavo, Nymark Penny
Journal
ALTEX
Vol. 41
No. 1
50-56
Keywords
Adverse outcome pathways, FAIR data, Machine-actionability, Trust, Visibility
Date of publication
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Adverse outcome pathways (AOPs) provide evidence for demonstrating and assessing causality between measurable toxicological mechanisms and human or environmental adverse effects. AOPs have gained increasing attention over the past decade and are believed to provide the necessary steppingstone for more effective risk assessment of chemicals and materials and moving beyond the need for animal testing. However, as with all types of data and knowledge today, AOPs need to be reusable by machines, i.e., machine-actionable, in order to reach their full impact potential. Machine-actionability is supported by the FAIR principles, which guide findability, accessibility, interoperability, and reusability of data and knowledge. Here, we describe why AOPs need to be FAIR and touch on aspects such as the improved visibility and the increased trust that FAIRification of AOPs provides.

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Applicability of food monitoring data for assessing relative exposure contributions of pyrethroids in retrospective human biomonitoring risk estimations
Journal
Toxics
Vol. 12
No. 1
24
Keywords
Pyrethroids, Urinary levels, DCCA, CFMP, 3PBA, DBCA, F3PBA, CLF3CA, Pesticide risk, HBM4EU
Date of publication
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