People gather on and around a statue in the center of Place de la République at the end of a demonstration on a day of nationwide protests organized by high-school students and joined by unions and teachers, who for days have been demanding better learning conditions, in Paris, on October 6, 2026.
French high-school and university students attend a demonstration on a nationwide day of protests and blockades, in Nantes on October 6, 2026. Demonstrators are voicing their anger over overcrowded classrooms, teacher shortages, underinvestment, dilapidated school buildings, recent police actions, and more.
Riot police watch a fire at a makeshift barricade set up by protesters during a demonstration organized by high-school students in Lyon on October 6, 2026.
Riot police charge protesters at the end of a student demonstration in Bordeaux on October 6, 2026.
Riot police face protesting students who carry out a blockade outside Lycée Le Corbusier, in Aubervilliers, Paris, on October 1, 2026.
A youth is detained by a riot police officer in Nancy on October 5, 2026.
FreshRSS 1.30.1 - October 5, 2026
This is a security-oriented release with several security patches and bug fixes in the continuation of 1.30.0.
Note that our rolling-release channel (edge) is recommended for faster security patches.
Bug fixes highlights 🐛:
- Some security attack scenarios patched
- Fix domain-wide
Retry-After - Fix muting of feeds gone with HTTP 410
Feature highlights✨:
- CLI: Add optional feed argument to
actualize-user.php
This release has been made by @Alkarex, @andris155, @fzlzjerry, @Inverle, @jamalkamaladdin, @jtracey, @Otolock and newcomers @akine, @colons, @ethanstoner, @gigioneggiando, @Juice-de-Orange, @pavel-miniutka, @qwist1233-cpu, @Sharawey74, @shcheglovnd,
ALTEX. 2026 Sep 25. doi: 10.14573/altex.2608201. Online ahead of print.
ABSTRACT
Read-across is the most widely used adaptation to standard information requirements under REACH and is central to efforts to reduce unnecessary animal testing. However, its regulatory acceptance in European Chemicals Agency (ECHA) compliance check (CCH) decisions remains limited. This study systematically examined common deficiencies and trends in reasons that read-across adaptations fail based on publicly available CCH decisions. We reviewed ECHA CCH decisions published from 2010 through 2025, extracted information on read-across type, adaptation study type proposed, source and target substances, and reasons for rejection. The latter were coded using 17 assessment elements related to structural similarity, toxicokinetics, toxicodynamics, substance identity, and supporting data. Among 2,722 analyzed CCH decisions, nearly half contained at least one read-across adaptation, but only 85 read-across hypotheses were deemed acceptable. In contrast, 1,526 rejected read-across hypotheses were identified, most of which used analogue rather than group type of reasoning. Rejections were especially common for higher-tier repeated dose studies. The most frequent deficiencies in proposed adaptations involved unresolved uncertainty in toxicokinetic and toxicodynamic similarity, including limited evidence on bioavailability, metabolite formation, non-common compounds, and endpoint-relevant bridging data. Structural similarity was nearly always part of read-across but was rarely sufficient on its own. These findings show that successful read-across requires more than a plausible similarity argument; it must provide endpoint-specific evidence that residual uncertainty is low enough for regulatory use. Our results identify recurring pitfalls in submissions and support a path toward uncertainty-characterized, NAM-supported read-across that can improve regulatory confidence while reducing potentially unnecessary testing in animals.
PMID:42828518 | DOI:10.14573/altex.2608201
NAM J. 2026 Sep 18;2:100133. doi: 10.1016/j.namjnl.2026.100133. eCollection 2026.
NO ABSTRACT
PMID:42819917 | PMC:PMC13625428 | DOI:10.1016/j.namjnl.2026.100133
Front Cell Dev Biol. 2026 Aug 26;14:1887853. doi: 10.3389/fcell.2026.1887853. eCollection 2026.
ABSTRACT
Early embryogenesis is governed by precisely timed gene regulatory programs that coordinate cell fate specification, tissue patterning, and morphogenesis. The maternal-to-zygotic transition (MZT) represents a pivotal developmental milestone during which regulatory control shifts from maternally deposited transcripts to activation of the zygotic genome. Disruption of this transition has the potential to alter developmental trajectories with lasting consequences. Per- and polyfluoroalkyl substances (PFAS), environmentally persistent contaminants, have been linked to developmental abnormalities, yet their impact on core embryonic gene regulatory networks especially with exposure during MZT is not well understood. Using zebrafish (Danio rerio), a tractable vertebrate model and New Approach Methodology (NAM), we investigated how PFAS exposure during the MZT alters early developmental programming. Embryos were exposed starting at different times before and within the MZT time window and collected at 24 h post-fertilization (hpf) for transcriptomic analysis. Targeted qRT-PCR revealed dysregulation of genes controlling transcriptional activation, lineage specification, proliferation, and differentiation. Whole-transcriptome RNA sequencing (RNA-seq) further identified widespread perturbations in gene networks governing transcriptional regulation, cell signaling, and embryonic morphogenesis. Temporal analysis revealed that exposure beginning at 3.5 hpf, followed by 8 hpf, corresponding to early zygotic genome activation and near completion of zygotic activation, respectively, resulted in the greatest differential gene expression changes at 24 hpf. Consistent with these early gene regulatory perturbations, larvae exposed starting at 8 hpf also exhibited altered behavior at 5 days post-fertilization. Together, these findings demonstrate that PFAS exposure during MZT disrupts the establishment of embryonic gene regulatory networks, linking environmental toxicant exposure to altered developmental patterning and organismal outcomes. This work underscores the vulnerability of early developmental transitions to environmental perturbation and positions MZT as a critical window of susceptibility during development.
PMID:42719050 | PMC:PMC13553801 | DOI:10.3389/fcell.2026.1887853
The final wind-down of the National Asset Management Agency (NAMA) left a bill of almost €8m in termination payments for staff this year.
Environ Toxicol Chem. 2026 Sep 7:vgag244. doi: 10.1093/etojnl/vgag244. Online ahead of print.
ABSTRACT
High throughput (HTP) assays using aquatic species are being developed in response to the large number of chemicals in or entering commerce with little aquatic toxicological data. Transcriptomic points of departure (tPODs) coupled to HTP assays have shown promise in efficiently assessing possible toxicity of chemicals. With thousands of identified per- and polyfluoroalkyl substances (PFAS) such strategies are required to assess their potential hazard to aquatic species. This study investigated the utility of a HTP transcriptomic assay with an aquatic insect (Chironomus dilutus) to assess the toxicity of 22 PFAS. Larval C. dilutus were exposed for 24-hr in 96-well microplates to a concentration series of each PFAS. Following exposure, tPODs were calculated from the transcriptomic data. The tPODs ranged from 3 µg/L for 6:2 fluorotelomer sulfonic acid to 1602 µg/L for perfluoropentanoic acid. These values were compared to tPODs previously derived for fathead minnow (Pimephales promelas), Daphnia magna, a microalga (Raphidocelis subcapitata) and from mammalian cell culture HTP assays. In addition, C. dilutus tPODs were compared to published surface water concentrations which were typically orders of magnitude lower than the tPOD. The C. dilutus HTP assay showed promise as a New Approach Methodology (NAM) to assess the toxicity of chemicals, such as PFAS, as part of a tiered hazard evaluation strategy.
PMID:42707005 | DOI:10.1093/etojnl/vgag244
Environ Sci Technol. 2026 Sep 8;60(35):24617-24629. doi: 10.1021/acs.est.6c06087.
ABSTRACT
High-throughput in vitro cell assays are promising tools for predicting chemical-induced health effects in humans. Quantifying freely dissolved medium (Cfree,medium) and cellular concentrations is essential for robust quantitative in vitro-in vivo extrapolation (QIVIVE), but the miniaturized format of 384- and 1536-well plates makes these metrics challenging to measure directly. We developed DYNAMEX (dynamic NAM exposure), a time-resolved kinetic model simulating chemical fate in cell assays, accounting for volatilization, medium binding, well-plate sorption, and cellular uptake, including growth dilution. The model accurately captured uptake kinetics for neutral compounds and newly measured PFAS cellular uptake kinetics, reproduced empirical thresholds for volatilization losses, and predicted free fractions in medium across 51 compounds (RMSE = 0.49 log10 units) and cellular-to-nominal concentration ratios across 17 compounds (RMSE = 0.56 log10 units) under different bioassay conditions. Simulations across 113 chemicals and varying assay setups showed that, under standard assay conditions using 10% FBS, equilibrium mass balance modeling predicted Cfree,medium within 10% for 83 of 113 compounds and is sufficient for most applications. Kinetic modeling is required when volatilization or well-plate sorption causes substantial mass losses, particularly under serum-free conditions and in miniaturized formats, or when low membrane permeability limits cellular uptake within the assay duration, as observed for several hydrophobic ionizable organic chemicals. The model provides a mechanistic framework to improve in vitro dosimetry, guide assay design, and support integration of time-resolved exposure metrics into QIVIVE and in vivo modeling workflows.
PMID:42708955 | PMC:PMC13564414 | DOI:10.1021/acs.est.6c06087
PLoS One. 2026 Sep 8;21(9):e0337025. doi: 10.1371/journal.pone.0337025. eCollection 2026.
ABSTRACT
The transition toward a circular economy (CE) in agriculture relies not only on technological progress but also on the behavioural readiness of millers to embrace sustainable practices. This study employs the Norm Activation Model (NAM) to examine how psychological and structural factors shape CE practices adoption among olive oil mill business owners in Sicily. Drawing on survey data, we conducted a Partial Least Squares Structural Equation Modeling (PLS-SEM) analysis using actual behaviour as dependent variable. The results indicate that Awareness of Consequences and Ascription of Responsibility significantly strengthen Personal Norms, emphasizing their key role in fostering moral engagement with environmental sustainability. Yet, Personal Norms alone do not directly lead to CE practices adoption, highlighting a persistent attitude-behaviour gap typical of traditional farming contexts. Notably, Awareness of Consequences exerts a direct effect on observed behaviour while Personal Norms do not, suggesting that NAM may require adaptation when applied to small, family-run agri-food firms in which the owner-manager translates the cognitive recognition of environmental impacts directly into firm-level decisions. Conversely, education, experience, enterprise size, and milling type are found to be significant drivers of CE participation, indicating that moral motivation must be complemented by suitable organizational and contextual support. The findings provide novel empirical evidence that the CE transition in agri-food systems results from the relation between individual moral activation and organizational capacity. Policy measures should therefore combine behavioural and structural approaches, through education, technical assistance, and targeted incentives, to encourage CE innovation and the possible valorization of olive oil by-products.
PMID:42709695 | PMC:PMC13552747 | DOI:10.1371/journal.pone.0337025
Arch Toxicol. 2026 Aug 25. doi: 10.1007/s00204-026-04523-8. Online ahead of print.
ABSTRACT
To review recent advances in research on per- and polyfluoroalkyl substances (PFAS) and outline priority steps for risk assessment in consumer health protection, the German Federal Institute for Risk Assessment (BfR) organized the 'International PFAS Conference' in Berlin in October 2025. Building on the European Food Safety Authority's (EFSA) opinion in 2020, global research activities on PFAS have intensified. The conference was attended by 200 participants from 18 countries and covered topics such as analytical methods, human exposure, toxicokinetics, toxicity, and future perspectives. Given that there are more than 21,000 different PFAS in use, discussions highlighted the need for further data collection and a basis for prioritizing substances. Robust exposure assessment requires improved analytical methods combined with newly developed predictive tools to quantify, identify, and make better use of non-target data. Hazard characterization may benefit from the combined use of classic experimental data sets, epidemiological data, and new approach methodologies (NAMs) data. The participants emphasized the continuous need for refined data and proposed a systematic consolidation of global data on shared data platforms, accompanied by corresponding guidelines for data usage. In the final panel discussion, effective risk communication was identified as a critical challenge, necessitating clear and consistent messaging for the public and policymakers. The conference concluded with five key recommendations for future health risk assessments: prioritizing PFAS; improving analytical methods; promoting generation of robust data and data gap filling; promoting open science, including the development of shared data infrastructure and cross-institutional knowledge exchange; and strengthening risk communication. These recommendations aim to support transparent, evidence-based and effective PFAS consumer health risk management in the decades ahead.
PMID:42637957 | DOI:10.1007/s00204-026-04523-8
Arch Toxicol. 2026 Aug 25. doi: 10.1007/s00204-026-04525-6. Online ahead of print.
ABSTRACT
Immunotoxicity has emerged as a key health concern for per- and polyfluoroalkyl substances (PFAS), with animal studies showing reduced T-dependent antibody responses (TDAR) and epidemiological studies reporting decreased vaccine antibody titres. Notably, immunotoxicity is considered one of the most sensitive endpoints for PFAS exposure and has been used to inform regulatory guidance and health-based values. Given that more than 14,000 PFAS exist and are highly environmentally persistent, evaluating the immunotoxicity of individual compounds is critical but impractical, highlighting the need for efficient, human-relevant test systems that provide mechanistically informative, immune-relevant endpoints. Here, we assessed immunomodulatory effects of six PFAS analogues using an in vitro human peripheral blood mononuclear cell (PBMC) model. Two immune stimuli were applied, including lipopolysaccharide (LPS) to trigger innate responses and phytohemagglutinin (PHA) to simulate T-cell-mediated adaptive immune activation. Critically, several PFAS analogues enhanced T-cell proliferation following PHA activation, while a non-inclusive but overlapping subset of analogues suppressed cytokine secretion in response to PHA and LPS. Transcriptomic analyses indicate reduced B-cell identity and immunoglobulin gene expression alongside increased expression of genes associated with T-cell activation and proliferation. These findings implicate a dysregulated coordination between T- and B-cell responses as a potential mechanism underlying PFAS-associated immunotoxicity. Overall, the human PBMC model demonstrated that it is a cost-effective and ethical method for identifying and characterizing key events (KEs) in the adverse outcome pathway (AOP) for PFAS-induced immunotoxicity and has the potential to be refined and incorporated into a robust new approach method (NAM) to assess the next generation of commercial PFAS.
PMID:42637958 | DOI:10.1007/s00204-026-04525-6
Environ Int. 2026 Aug 7;215:110451. doi: 10.1016/j.envint.2026.110451. Online ahead of print.
ABSTRACT
Thyroid hormones (THs) are essential for growth, development, and metabolism across vertebrates. Thyroid hormone system disruption (THSD), as one of the mechanisms of endocrine disruption (ED), is widely recognised as a critical concern for both human and environmental health. Important challenges remain in the availability and regulatory application of methods for THSD assessment. Here we discuss recent methodological advances in the area of THSD, including validation efforts for in vitro assays and THSD-sensitive endpoints as additions to existing Organisation for Economic Co-operation and Development (OECD) Test Guidelines using fish early-life stages. We propose a modular adverse outcome pathway (AOP) network-based framework integrating mechanistic and effect-level information to support regulatory hazard assessment for both human and environmental health under a One Health paradigm. The framework summarises essential elements of the THSD AOP network relevant to human and environmental health and methods were mapped to these mechanism and effect components. In a case study on resorcinol, a chemical of regulatory interest relevant for both human and environmental health, we demonstrate how emerging methods, including in vitro and fish eleutheroembryo (developmental stage between hatching and the onset of independent feeding) assays as new approach methods (NAMs), complement traditional data to strengthen weight-of-evidence for ED classification. By mapping gaps and priorities, this work advances the integration of NAMs into chemical safety assessment, supporting a future update of OECD Guidance Document 150. These efforts align with European Union initiatives to gradually phase out animal testing for chemical hazard assessment and implement Next Generation Risk Assessment.
PMID:42585726 | DOI:10.1016/j.envint.2026.110451
J Appl Toxicol. 2026 Aug 10. doi: 10.1002/jat.70394. Online ahead of print.
ABSTRACT
The accelerating global diversification of food chemicals-encompassing mycotoxins, heavy metals, organophosphate pesticide residues and the increasingly prevalent burden of microplastics and nanoplastics (MNPs)-creates an urgent demand for rapid, human-relevant and ethically acceptable toxicity testing platforms. Conventional animal-based bioassays are insufficient to characterise the thousands of substances awaiting safety evaluation, a deficit particularly acute in tropical food-producing regions including Indonesia where environmental contamination profiles and regulatory infrastructure differ markedly from high-income countries. New approach methodologies (NAMs), comprising validated in vitro cell and organoid systems, high-throughput screening (HTS), multiomics toxicogenomics, in silico modelling and adverse outcome pathway (AOP) frameworks, represent a paradigm shift in food safety toxicology. This review critically appraises current evidence on in vitro NAMs for emerging food contaminants, with emphasis on (i) 2D cell line and 3D organoid/organ-on-chip models for hepatotoxicity, enterotoxicity and nephrotoxicity; (ii) mechanistic pathways-oxidative stress, mitochondrial dysfunction, genotoxicity and intestinal barrier disruption-as interrogated through standardised in vitro endpoints; (iii) AOP frameworks as regulatory bridges between molecular initiating events and adverse outcomes; (iv) high-throughput transcriptomics (HTTr) and Cell Painting integration for mechanism-informed hazard prioritisation; and (v) in vitro-to-in vivo extrapolation (IVIVE) via physiologically based toxicokinetic (PBTK) modelling. Critical gaps in chronic-exposure data, mixture toxicity assessment and BPOM regulatory acceptance are discussed. A novel evidence-based NAM validation roadmap tailored to the Southeast Asian regulatory context is proposed.
PMID:42575853 | DOI:10.1002/jat.70394
Across the faded blue covers of the exam books in my attic, I can trace the arc of my academic career. I can still see the grades I received on tests in “The Meaning of Abstraction in Modern Art” (A) and in Neurobiology (B–). Just the sight of the booklets is enough for me to feel the pressure to perform, to sculpt the contents of a semester’s worth of knowledge into some fresh shape. But by the time I became a college professor myself, in 2013, the blue book had begun to disappear. Why struggle to discern student penmanship, or risk misplacing a final exam in the trunk of one’s Subaru (to cite a completely hypothetical example), when tests, like everything else, can be administered on a laptop?
The coronavirus made every aspect of education virtual, but even after it abated, in-person final exams remained out of favor for many classes. Part of the reason was simply administrative—the challenge of finding faculty or graduate students to watch over the test-takers. But there was also a shift in how teachers appraised student learning. The blue book meant timed essays and handwritten work, modes of assessment that felt regressive, cruel. It recalled an age of higher education—punitive and bleak, the domain of Dickens’s stern Mr. Gradgrind—that the modern university was eager to outgrow. Not entirely, of course; some faculty still lugged boxes of blue books home in the snow and scribbled grades in red on the covers. But alternatives to the in-person exam proliferated: the capstone project, the take-home essay, the portfolio of selected work from the semester.
The blue book seemed destined to become a relic, as obsolete as cursive. But it had one virtue that hasn’t been easy to replicate: Cheating on a blue-book exam is difficult. When faculty moved away from in-person pen-and-paper exams, they assumed that cheating would be kept in check by honor codes, or by “locked” browsers, which would prevent students from accessing sites that would jog their memory or simply give them the answers. But these measures were never wholly effective. In a survey of undergraduates published in 2020, 62 percent admitted to cheating in some manner.
The advent of AI has only exacerbated the problem. In a matter of seconds, students can create an entire essay with the help of a chatbot. If they’re savvy, they can spend a bit more time to make it sound authentically human enough to evade detection by their professor. As my colleague Rose Horowitch has reported, such cheating has become so prevalent that Princeton recently gave up on its venerable honor code. For 133 years, students had signed a pledge not to cheat, and professors had trusted them to do the right thing. In May, in the face of rampant AI-enabled cheating, the university’s faculty voted to begin proctoring exams for the first time since the Gilded Age.
[Rose Horowitch: How AI killed a 133-year-old Princeton tradition]
Universities find themselves in a surprising position. The only reliable way to evaluate what students have learned may be to bring back pen and paper. Faculty are reverting to in-person, handwritten assignments and timed essays—anything that keeps assessments offline. The unlikely hero of the day is the blue book, sales of which are up by as much as 80 percent for some universities since 2023.
Yet the blue book is more than a last redoubt against cheating. Despite its antiquated appearance, the blue book encourages experimentation, even virtuosity. It deserves to live on not because of what it rejects but because of what it makes possible: thinking on the page, a hallmark of the humanities that is indispensable to their value—and essential to the kinds of human beings that a liberal-arts institution hopes to send out into the world.
The blue book hasn’t changed much for a hundred years or more, with its sky-blue tint and pale-red margin lines, its two neat staples and wide-open spacing, and its austere list of requirements on the cover (NAME, SUBJECT, CLASS, SECTION). The prec
Integr Environ Assess Manag. 2026 Jul 25:vjag121. doi: 10.1093/inteam/vjag121. Online ahead of print. ABSTRACT Transitioning to Safe and Sustainable by Design (SSbD) in cosmetics requires reliable non-animal methods for early ingredient selection. This study proposes an approach that integrates New Approach Methodologies (NAMs) to screen for persistence, bioaccumulation, and toxicity (PBT), endocrine active substance (EAS), and environmental risk (predicted environmental concentration-to-predicted no-effect concentration (PEC/PNEC) ratio) to support the selection of less toxic ingredients for product formulation. A case study of nine organic ultraviolet (UV) filters commonly used in cosmetics, with exposure scenarios adapted to the Brazilian context, was used to demonstrate the applicability of the proposed approach. The selected UV filters were: bis-ethylhexyloxyphenol methoxyphenyl triazine (BEMT), butyl methoxydibenzoylmethane (BMD), diethylamino hydroxybenzoyl hexyl benzoate (DHHB), ethylhexyl methoxycinnamate (EMC), ethylhexyl salicylate (ES), ethylhexyl triazone (ET), octocrylene (OC), phenylbenzimidazole sulfonic acid (PSA), and tris- biphenyl triazine (TBT). For hazard predictions, PBT and endocrine activity were predicted using the freely available in silico tools QSAR Toolbox, VEGA, JANUS, Danish QSAR, T.E.S.T., and Endocrine Disruptome. In vitro data from the EPA ToxCast were included in the EAS evaluation. Using a majority consensus approach for integrating the in silico tools, ER activity was predicted only for ES. ToxCast data showed EAS potential for three of the four UV filters: OC and BMD (ER and AR antagonists), and ES as an ER agonist. Although results indicated some ingredients were toxic to aquatic life, under a conservative exposure scenario, PEC/PNEC ratios for water and sediment indicated acceptable environmental margins of exposure for PSA, BEMT, DHHB and TBT. In conclusion, hazard and risk assessments using NAMs data can be employed to identify UV filters of lower concern for aquatic environments and support the implementation of SSbD within the cosmetic industry. PMID:42503170 | DOI:10.1093/inteam/vjag121 Many promising New Approach Methodologies (NAMs) emerged in the last decades but only some are taken up as OECD Test Guidelines (TGs). For regulatory decision‐making data from non‐guideline studies is primarily considered as mechanistic support rather than direct evidence. The nanotechnology sector is particularly promising for the implementation of NAMs in risk assessment. The EFSA Guidance on risk assessment of nanomaterials (NMs) in the food and feed sector recommends using NAMs in the first steps to generate new information (EFSA Scientific Committee, 2021a). Front Immunol. 2026 Jul 9;17:1741650. doi: 10.3389/fimmu.2026.1741650. eCollection 2026. ABSTRACT Human immune system development is established through a sequence of tightly regulated processes occurring across multiple embryonic and fetal organs. Despite extensive research, our mechanistic understanding still relies largely on animal models, which often lack translational precision for human biology. This gap is particularly relevant for developmental immunotoxicity (DIT), where early-life exposure to environmental contaminants such as dioxins, PCBs, and PFAS has been associated with long-term immune dysfunction, including reduced vaccine responsiveness in children. To address this need, we created the Human Immune System Development Map (HIDmap), a curated, findability, accessibility, interoperability, and reusability (FAIR)-compliant digital resource that systematically captures prenatal immune ontogeny. The HIDmap integrates literature-derived data into a modular, three-layered structure linking anatomical niches, cell migration, and differentiation trajectories across 24 organs. Implemented in the MINERVA (Molecular Interaction NEtwoRks VisuAlization) platform, the HIDmap allows interactive exploration of developmental processes and molecular markers relevant to immune function. By embedding the HIDmap within the Adverse Outcome Pathway (AOP) framework, we constructed a putative AOP to demonstrate how the map can help to connect molecular initiating events related to environmental exposures - such as Aryl hydrocarbon receptor (AhR) activation - to downstream immunological key events and adverse outcomes. This resource offers a human-centered foundation for curating and visualizing human developmental immunobiology and may support the future development of predictive in vitro New Approach Methodologies (NAMs). In the future, the HIDmap may contribute to the identification of critical windows of susceptibility and support the advancement of mechanism-based, animal-free approaches in developmental immunotoxicology. PMID:42495614 | PMC:PMC13392540 | DOI:10.3389/fimmu.2026.1741650 Front Toxicol. 2026 Jul 9;8:1815869. doi: 10.3389/ftox.2026.1815869. eCollection 2026. ABSTRACT Bisphenol A (BPA) alternatives are increasingly used in the manufacture of industrial and consumer products, following regulatory restrictions on BPA. However, insufficient safety data on these substitutes raise concern as regards potential regrettable substitutions. Under the EU Partnership for the Assessment of Risks from Chemicals (PARC), Work Package 5 (WP5) addresses this challenge by applying a human-relevant tiered hazard assessment strategy grounded on OECD test guidelines as first tier and expanding the battery to include NAMs (New Approach Methodologies). Eight BPA alternatives were prioritized for studies addressing key toxicological endpoints, namely, endocrine disruption (ED), developmental neurotoxicity (DNT), immunotoxicity, genotoxicity and carcinogenicity and metabolic fate examination (detoxification vs. potential bioactivation), to enable early identification of biological activity and support cross-endpoint prioritization. This manuscript describes the structure and implementation of the testing framework. This integrated testing strategy proposes a structured approach to identify substances of potential concern, guide targeted higher-tier studies, and support regulatory prioritization. PARC WP5 framework is testing whether coordinated NAM-based methods may contribute to next-generation risk assessment and help prevent regrettable substitutions among BPA alternatives for rapid regulatory adoption. Detailed experimental results will be reported separately upon completion of the project. PMID:42488797 | PMC:PMC13391043 | DOI:10.3389/ftox.2026.1815869 Research (Wash D C). 2026 Jul 14;9:1360. doi: 10.34133/research.1360. eCollection 2026. ABSTRACT The perithyroidal adipose tissue (PAT), given its direct anatomical proximity to the thyroid gland, has long been postulated as a modulator of the thyroid tumor microenvironment. However, its cellular composition, functional heterogeneity, and specific roles in thyroid cancer progression remain unknown. To address these knowledge gap, we performed single-nucleus RNA sequencing of PAT from patients with papillary thyroid carcinoma (PTC) and multinodular goiter (MNG), combined with machine learning, proteomics, immunofluorescence, ex vivo assays, and human serum analysis. We constructed the first high-resolution atlas of human PAT, revealing an immune-rich niche and previously unrecognized adipocyte heterogeneity, including thermogenic subpopulations (BL-Ad1, BL-Ad2, OXPHOS-Ad) from distinct progenitors. Functionally, the PAT secretome from PTC substantially enhanced thyroid cancer cell proliferation compared to MNG. Integrated analyses identified a pathogenic adipokine triad characterized by loss of ADIPOQ and gain of NAMPT and IGF1. Restoring ADIPOQ signaling or inhibiting NAMPT/IGF1 suppressed tumor growth in vitro and in vivo. Additionally, we identified CCL14, down-regulated in PTC-derived OXPHOS-Ad, as a key immune regulator. Reduced CCL14-CCR1 signaling impaired CD80 expression in M1-like macrophages, disrupting CD80-CD28 costimulation and consequently diminishing T cell proliferation and recruitment. Consistently, circulating CCL14 levels were reduced in PTC patients. In conclusion, PAT acts as a dynamic endocrine and immunomodulatory component of the tumor microenvironment that promotes thyroid tumor growth through adipokine-mediated and immune-dependent mechanisms. PMID:42453940 | PMC:PMC13365586 | DOI:10.34133/research.1360 NAM J. 2025 Aug 7;1:100041. doi: 10.1016/j.namjnl.2025.100041. eCollection 2025. ABSTRACT OBJECTIVE: This study aims to investigate the potential mechanisms by which EDCs, recognized as emerging pollutants, induce metabolic disorders leading to metabolic diseases in humans. METHODS: Network toxicology and molecular docking techniques were employed to elucidate the molecular mechanisms underlying EDCs-induced pathogenesis of the six diseases. Potential targets associated with EDCs and these diseases were identified using databases such as PubChem, ChEMBL, Super-PRED, GeneCards, OMIM, and TTD. STRING analysis and Cytoscape software were further utilized to determine core targets most significantly linked to these metabolic disorders. GO and KEGG pathway enrichment analyses were performed on the core targets using the DAVID database. Finally, molecular docking was conducted to validate the binding affinities between EDCs and core target proteins. RESULTS: EDCs may potentially induce metabolic disorders by modulating cellular expression, influencing apoptosis and proliferation, and regulating related signaling pathways. Notably, a close interrelationship was observed among lipid metabolism disorders and atherosclerosis, Alzheimer's disease, type 2 diabetes mellitus, osteoporosis, hyperuricemia, and non-alcoholic fatty liver disease. CONCLUSION: This study provides novel insights into the mechanisms through which EDCs induce metabolic diseases in humans and highlights correlations among distinct disorders, thereby establishing a theoretical foundation for disease prevention and therapeutic strategies. PMID:42369416 | PMC:PMC13289039 | DOI:10.1016/j.namjnl.2025.100041 NAM J. 2025 Sep 13;1:100052. doi: 10.1016/j.namjnl.2025.100052. eCollection 2025. ABSTRACT In recent years, there has been a significant push towards the development of animal-free methods in toxicology. Despite this progress, the adoption of such methods in safety assessment practices remains limited, particularly in the context of gonadal and placental toxicity. This paper reviews current in vitro models relevant to gonadal (gametogenesis and steroidogenesis) and placental biology, and potentially applicable in developmental and reproductive toxicology (DART). Additionally, we present the results of a survey conducted among DART experts (n = 16), examining current practices and perceptions in industry regarding these in vitro methodologies. The findings indicate a predominant reliance on animal models, largely driven by regulatory requirements, despite concerns about their ability to reliably predict human outcomes. Respondents reported limited familiarity with and confidence in available in vitro models for gonadal and placental toxicity, yet expressed optimism about their future integration. These findings underscore the need for increased awareness of gonadal and placental in vitro models, particularly among DART risk assessors, to facilitate a shift toward more reliable and human relevant risk assessments. PMID:42369432 | PMC:PMC13289032 | DOI:10.1016/j.namjnl.2025.100052 Neurotoxicology. 2026 Jul;115:103501. doi: 10.1016/j.neuro.2026.103501. Epub 2026 Jun 27. ABSTRACT BACKGROUND: Developmental neurotoxicity (DNT) arises from disruption of key neurodevelopmental processes-including neural stem cell proliferation, neuronal and glial differentiation, radial migration, and synaptogenesis-that collectively shape corticogenesis. Traditional in vivo guideline studies are costly, low-throughput, and provide limited mechanistic insight, prompting OECD and EFSA to promote new approach methodologies (NAMs) such as the neurosphere assay (NSA). METHODS: We refined and characterized a mouse cortical NSA over a three-week differentiation period using a multiparametric endpoint battery encompassing proliferation, neuronal and astrocytic differentiation, radial migration, synaptogenesis, and astrocytic maturation. Baseline differentiation was defined by flow cytometry, confocal immunofluorescence, and qPCR. Two chronic exposure scenarios were implemented: (i) during the 7-day proliferation phase, and (ii) from the onset of differentiation and migration throughout the three-week maturation period. Chlorpyrifos (CPF) was used as a DNT-positive reference compound, and a biomonitoring-informed PFAS mixture of PFOS, PFOA and PFUnDA was designed using French Esteban data to reflect low-nM, environmentally relevant exposure levels; due to availability constraints, PFHxS was not included and 4:2 fluorotelomer sulfonic acid (4:2 FTSA) was used as the short-chain sulfonate component. RESULTS: Baseline analyses showed progressive acquisition of neuronal (TUBB3, MAP2, SATB2) and astrocytic (GFAP) phenotypes, emergence of SYP⁺/PSD95⁺ synaptic structures, and dependence on mitogenic signaling, consistent with key features of mid-gestational corticogenesis. CPF exerted biphasic effects, with early neurosphere enlargement followed by growth arrest and impaired radial migration; at 250 µM, CPF induced overt cytotoxicity and was associated with reduced GFAP expression. In contrast, PFAS mixture produced only modest effects on bulk viability yet consistently reduced radial migration and significantly downregulated Gfap and Syp at low-nM concentrations, in line with epidemiological and experimental evidence implicating PFAS in neurodevelopmental disorders. Within this proof-of-concept dataset, radial migration emerged as a more sensitive endpoint than bulk viability, revealing functional impairments below overt toxicity thresholds. CONCLUSIONS: The cortical NSA captures key cellular and functional features of mid-gestational corticogenesis and discriminates compound-specific DNT liabilities, with CPF linked to reduced Gfap expression under overtly toxic conditions and PFAS mixture disrupting astrocytic and synaptic programs at biomonitoring-relevant levels. By integrating complementary endpoints under chronic, developmentally targeted exposures, this work advances the NSA as a mechanistic, regulatory-relevant NAM and a strong candidate for inclusion in the OECD DNT in vitro battery. PMID:42364883 | DOI:10.1016/j.neuro.2026.103501 Front Toxicol. 2026 Jun 9;8:1751726. doi: 10.3389/ftox.2026.1751726. eCollection 2026. ABSTRACT The increasing global production of plastics has raised concerns about additive chemicals that can leach from polymer matrices and lead to widespread human and environmental exposure. While regulatory attention to endocrine-disrupting chemicals (EDCs) and their association with plastic additives has increased in recent years, hazard information for numerous plastic additives remains limited. Here, we applied an integrated new approach methodologies (NAMs)-based framework combining in silico molecular docking and in vivo Caenorhabditis elegans assays to efficiently screen the endocrine-disrupting potential of plastic additives. Molecular docking of 162 EU REACH-registered additives was performed against human estrogen and androgen receptors (ERα and AR), followed by cross-species docking using AlphaFold-predicted homology models of the C. elegans nuclear receptors (NHR-14 and NHR-69). Chemicals showing strong binding interactions across species were further examined through a systematic literature review focused on ER- and AR-mediated effects. By integrating evidence, 1,3-diphenylpropane-1,3-dione (DBM) and 2-(benzotriazol-2-yl)-4-methylphenol (UV-P) were identified as potential ER and AR disruptors and were subsequently validated through reproductive toxicity assays using C. elegans wild-type N2 and loss-of-function mutant strains (nhr-14 and nhr-69). This integrated approach provides a practical NAMs-based prioritization strategy by linking molecular interactions to phenotypic outcomes. By positioning C. elegans as a biological bridge between human toxicology and ecotoxicology, the framework supports cross-species hazard characterization within a One Health perspective. PMID:42338659 | PMC:PMC13286444 | DOI:10.3389/ftox.2026.1751726 Front Toxicol. 2026 Jun 3;8:1764276. doi: 10.3389/ftox.2026.1764276. eCollection 2026. ABSTRACT Inhalation is a major route of chemical exposure for both consumers and workers. Physiologically-based kinetic (PBK) modeling is a promising tool to understand the absorption, distribution, metabolism, and excretion (ADME) of inhaled chemicals and to predict systemic concentrations of chemicals in humans. New Approach Methodologies (NAMs) can help generate essential input parameters for PBK models. However, validated NAM-based test methods to assess uptake of inhaled chemicals are currently lacking. Reliable information on respiratory uptake is required to determine relevant exposure concentrations for evaluation of systemic effects using NAMs. This manuscript describes a project that aims to apply robust and reliable in vitro models to study cellular uptake, intracellular accumulation, absorption and systemic exposure of chemicals following inhalation. To evaluate the robustness and predictivity of different NAM-based barrier models, to examine appropriate in vitro to in vivo scaling strategies, and to assess sensitivity and uncertainty in the resulting PBK models, the project will focus on relatively data-rich chemicals, specifically per- and polyfluoroalkyl substances (PFAS). While some have been widely explored and others remain data-poor, the entire chemical family is of interest due to its health hazards. Therefore, the work combines experimental and modeling approaches by generating in vitro data on the respiratory uptake and benchmark this to existing human in vivo data, developing biokinetic models to better understand chemical fate within the test systems, and refining inhalation PBK models to improve estimates of systemic uptake. Read-Across (RAx) will be employed as data gap filling technique to infer on the apparent permeability of non-tested PFAS. Together, the in vitro and in silico results will inform and parameterize PBK models, ultimately enabling more reliable predictions of systemic availability. The project will deliver a workflow to combine in vitro and in silico methods to assess the uptake of inhaled substances, that could be modified and applied to other inhaled substances. Standardized in vitro models for respiratory uptake will improve the evaluation of inhalation as a route of exposure contributing to systemic effects, which is a key requirement for quantitative in vitro to in vivo extrapolation (qIVIVE) and supports the implementation of next-generation risk assessment (NGRA). PMID:42338660 | PMC:PMC13286702 | DOI:10.3389/ftox.2026.1764276 Front Toxicol. 2026 May 29;8:1757928. doi: 10.3389/ftox.2026.1757928. eCollection 2026. ABSTRACT Chemical exposure in real-world settings occurs predominantly as mixtures, whereas toxicological assessment has long been shaped by single-substance paradigms. As interest in more human-relevant and mechanistically informative testing strategies has grown, new approach methodologies (NAMs) have been increasingly incorporated into mixture toxicity research. However, the role of advanced in vitro NAMs in chemical mixture toxicity assessment has not yet been examined in a structured manner. This review therefore evaluated how advanced in vitro NAMs are currently being applied in mixture toxicity assessment and considered their potential value for regulatory translation. A PubMed-based literature search covering studies published between 2021 and 2025 identified 353 in vitro NAM-based studies related to chemical mixture toxicity, of which 70 were classified as advanced in vitro NAM-based studies and included for in-depth analysis. Among the advanced in vitro NAM categories, route-of-exposure-relevant models were the most frequently applied, followed by Omics, 3D models, stem cell-based models, and HTS/HCI approaches. The reviewed studies addressed diverse mixtures, including air pollutants, PFAS, phthalates, pesticides/herbicides, consumer product-related mixtures, and other environmentally relevant chemical combinations. Across these studies, advanced in vitro NAMs were used not only to assess overall mixture effects, but also to compare observed and predicted responses, distinguish mixture effects from those of individual chemicals, identify effect-driving components, and interpret non-additive responses under biologically relevant conditions. The reviewed evidence indicates that advanced in vitro NAMs are being used not simply as alternative test systems, but as tools to address key challenges intrinsic to mixture toxicity assessment, including defining relevant mixture entities, identifying toxicity drivers, interpreting non-additivity, and supporting prioritization under combinatorial complexity. These findings suggest that the future value of advanced in vitro NAMs in mixture assessment will depend not only on continued technological development, but also on their integration into question-driven and fit-for-purpose testing strategies. From this perspective, advanced in vitro NAMs may contribute most effectively when used to generate decision-relevant evidence aligned with specific mixture assessment needs and regulatory contexts. PMID:42293281 | PMC:PMC13258531 | DOI:10.3389/ftox.2026.1757928 Nanomaterials (Basel). 2026 May 26;16(11):668. doi: 10.3390/nano16110668. ABSTRACT The widespread presence of micro- and nanoplastics (MNPs) in the environment represents an emerging risk for human and environment health. New Approach Methodologies (NAMs) offer valuable tools to improve the mechanistic understanding of nanoscale processes and support hazard identification without animal testing. This study investigated the biological effects of exposure to 0-100 µg/mL 100 and 20 nm polystyrene (PS-NPs) and 100 nm polycaprolactone nanoplastics (PCL-NPs) using advanced in vitro intestinal models and the 3R-compliant in vivo Caenorhabditis elegans model. In vitro endpoints included cytotoxicity, oxidative stress, DNA damage, cellular internalization, and barrier integrity, while in vivo analyses focused on oxidative stress and locomotor behavior across multiple exposed generations. PS-NPs induced significant DNA damage in vitro, particularly at ≥50 µg/mL after 24-48 h exposure, and were rapidly internalized by cells, with 20 nm particles also detected in the nucleus. In contrast, 100 nm PCL-NPs elicited weaker biological responses. In vivo, PS-NPs caused an increase in oxidative stress response and locomotor behavior across exposed generations, whereas PCL-NPs produced milder effects, consistent with in vitro findings. These results support the potential of integrated NAMs for assessing human health risks associated with MNP exposure within a One Health framework. PMID:42274675 | PMC:PMC13258071 | DOI:10.3390/nano16110668 Aquat Toxicol. 2026 Jun 2;298:107883. doi: 10.1016/j.aquatox.2026.107883. Online ahead of print. ABSTRACT Endocrine-disrupting chemicals (EDCs), including some bisphenols, are of increasing concern. Aligned with the 3Rs (Reduction, Replacement, Refinement of animal experiments) and the EU's roadmap to phase out animal testing, zebrafish eleutheroembryos are key in developing New Approach Methodologies (NAMs) as they are non-protected until five days post-fertilization. While bisphenol A is restricted in the EU, the effects of bisphenol E (BPE) on thyroid hormone system (THS) sensitive endpoints and developmental neurotoxicity (DNT) remain unclear. We investigated whether BPE disrupts THS-sensitive endpoints and induces DNT in zebrafish eleutheroembryos. Based on adverse outcome pathways (AOPs): AOP 364 and AOP 157, we assessed eye morphology, inner plexiform layer (IPL), retinal pigmentary layer (RPE), posterior swim bladder inflation and swimming performance, and transcriptional analysis of THS- and DNT-related genes. We hypothesized that BPE would affect THS-sensitive endpoints, such as RPE and posterior swim bladder inflation, impairing swimming performance, and exert DNT effects through THS-mediated mechanisms. BPE impairs RPE without affecting overall eye development. However, transcriptional analysis of THS-related genes did not support a THS-mediated mechanism. BPE exposure also impaired posterior swim bladder inflation, which was identified as the primary contributor to impaired swimming performance. No effects were seen on quantitative brain measurements, leaving the sensitivity of zebrafish eleutheroembryos for brain morphological assessment unclear. Nevertheless, molecular DNT markers were detected, which could indirectly contribute to impaired swimming performance. Overall, our results demonstrate that the zebrafish eleutheroembryo is a valuable NAM model for assessing THS effects and DNT, and that BPE induces DNT and THS effects. PMID:42269479 | DOI:10.1016/j.aquatox.2026.107883 Clin Epigenetics. 2026 Jun 6. doi: 10.1186/s13148-026-02158-1. Online ahead of print. ABSTRACT This narrative mini-review examines how endocrine-disrupting chemicals (EDCs) induce persistent epigenetic alterations that shape endocrine, metabolic, and developmental trajectories across the lifespan. It addresses the emerging gap in integrating mechanistic epigenetic evidence with population-level vulnerability, particularly in underrepresented regions such as Latin America. These effects are especially critical during sensitive windows-including fetal development, childhood, and puberty-when DNA methylation, histone modifications, and non-coding RNA networks establish long-term molecular programming. While animal models have provided key mechanistic insights, their translational limitations highlight the need for human-relevant systems capable of capturing endocrine-specific and epigenetic endpoints under environmentally realistic conditions. We propose that epigenetic programming represents a central biological interface linking EDC exposure to context-dependent vulnerability. New Approach Methodologies (NAMs)-including organoids, micro-physiological systems, and computational models-offer a translational bridge aligned with Adverse Outcome Pathway frameworks. Importantly, susceptibility to endocrine disruption is shaped not only by biological factors but also by environmental, nutritional, and socioeconomic determinants. Evidence from Latin American populations-including altitude gradients, nutritional transitions, and structural inequalities-illustrates how these contextual factors interact with epigenetic mechanisms to influence metabolic and endocrine outcomes. This integrative perspective supports the development of more equitable and context-sensitive approaches to endocrine toxicology. PMID:42251462 | DOI:10.1186/s13148-026-02158-1 bioRxiv [Preprint]. 2026 May 26:2026.05.21.726952. doi: 10.64898/2026.05.21.726952. ABSTRACT Early embryogenesis is governed by precisely timed gene regulatory programs that coordinate cell fate specification, tissue patterning, and morphogenesis. The maternal-to-zygotic transition (MZT) represents a pivotal developmental milestone during which regulatory control shifts from maternally deposited transcripts to activation of the zygotic genome. Disruption of this transition has the potential to alter developmental trajectories with lasting consequences. Per- and polyfluoroalkyl substances (PFAS), environmentally persistent contaminants, have been linked to developmental abnormalities, yet their impact on core embryonic gene regulatory networks especially during MZT is not well understood. Using zebrafish (Danio rerio), a tractable vertebrate model and New Approach Methodology (NAM), we investigated how PFAS exposure during the MZT alters early developmental programming. Embryos were exposed starting at different times within the 8-hour MZT window and collected at 24 hours post-fertilization (hpf) for transcriptomic analysis. Targeted qRT-PCR revealed dysregulation of genes controlling transcriptional activation, lineage specification, proliferation, and differentiation. Whole-transcriptome RNA sequencing (RNA-seq) further identified widespread perturbations in gene networks governing transcriptional regulation, cell signaling, and embryonic morphogenesis. Temporal analysis revealed that exposure beginning at 3.5 hpf, followed by 8 hpf, corresponding to early zygotic genome activation and near completion of zygotic activation, respectively, resulted in the greatest differential gene expression changes. Consistent with these early gene regulatory perturbations, larvae exposed at 8 hpf also exhibited altered behavior at 5 days post-fertilization. Together, these findings demonstrate that PFAS exposure during MZT disrupts the establishment of embryonic gene regulatory networks, linking environmental toxicant exposure to altered developmental patterning and organismal outcomes. This work underscores the vulnerability of early developmental transitions to environmental perturbation and positions MZT as a critical window of susceptibility during development. PMID:42244528 | PMC:PMC13232098 | DOI:10.64898/2026.05.21.726952 Neurotoxicology. 2026 Jun 3;115:103485. doi: 10.1016/j.neuro.2026.103485. Online ahead of print. ABSTRACT Thousands of chemicals have not been assessed for developmental neurotoxicity (DNT) despite potential human exposure, prompting efforts to screen chemicals for possible DNT hazard using in vitro approaches. Ninety-five chemicals were screened in in a battery including in vitro assays covering the key neurodevelopmental processes (KNDPs) of proliferation, apoptosis, cell migration, neuronal differentiation, neurite outgrowth, neuronal maturation and synaptogenesis, oligodendrocyte differentiation, and network formation using human and rat (primary cortical) cells. An in vivo assay of zebrafish neurobehavior was also included. This assay battery was sensitive enough to detect effects in the neurodevelopmental processes modeled. The chemicals comprised negative controls and several use classes: drugs, flame retardants, fungicides, herbicides, industrial chemicals (including PFAS), and insecticides. A data analysis pipeline was developed using a benchmark concentration approach and included multi-objective optimization (Pareto) and ToxPi analysis to integrate data from the individual assays to evaluate DNT hazard and prioritize chemicals, ranking them for further evaluation. Although the zebrafish assay was the most sensitive for detecting potency, selectivity varies significantly by assay and chemical class with neurite outgrowth assays and fungicides exhibiting the highest percentage of selective hits. Chemicals from the fungicide, drug, and insecticide use classes had higher priority in the Pareto and ToxPi analysis based on having the most potent and selective activity in the assays. These prioritization methods represent a novel and useful approach for comparative evaluation of potential developmental neurotoxicity hazard in large groups of chemicals. PMID:42242322 | DOI:10.1016/j.neuro.2026.103485 Regul Toxicol Pharmacol. 2026 May 26;170:106142. doi: 10.1016/j.yrtph.2026.106142. Online ahead of print. ABSTRACT Obesity prevalence has more than doubled globally over the last 30 years. Exposure to certain chemicals, obesogens, may promote obesity by disrupting lipid metabolism and adipogenesis. There is an urgent need to better identify obesogens using robust and human-specific new approach methodologies (NAMs), as well as to interpret the outcomes of combinations of NAMs in regulatory decision making. The goal of this study is to assess whether an in vitro-based testing strategy based on the combined application of human-specific NAMs, a PPARγ transactivation assay and a human mesenchymal stem cell (hMSC)-based adipogenesis assay, supports in vitro identification of obesogens. To this end, a case study was performed with 21 PFAS. Seven PFAS (HFPO-DA, FBSA, PFHpA, PFBS, PFPrS, PFPrA, and PBSF) showed both PPARγ transactivation and increased lipid content. Three PFAS increased cellular lipid content without measurable PPARγ activation (3:3 FTCA, MeFBSA, EtFOSA), implying alternative mechanisms of adipogenesis. Notably, seven PFAS decreased lipid content; five of these (PFOS, PFDA, PFNA, PFBA, PFEtS) were PPARγ agonists, whereas two (TFA and TFMS) did not transactivate PPARγ. Our findings underscore the need for an integrated testing strategy that incorporates multiple mechanisms and downstream phenotypic endpoints to identify substances with obesogenic properties. PMID:42202891 | DOI:10.1016/j.yrtph.2026.106142 Regul Toxicol Pharmacol. 2026 Sep;170:106142. doi: 10.1016/j.yrtph.2026.106142. Epub 2026 May 26. ABSTRACT Obesity prevalence has more than doubled globally over the last 30 years. Exposure to certain chemicals, obesogens, may promote obesity by disrupting lipid metabolism and adipogenesis. There is an urgent need to better identify obesogens using robust and human-specific new approach methodologies (NAMs), as well as to interpret the outcomes of combinations of NAMs in regulatory decision making. The goal of this study is to assess whether an in vitro-based testing strategy based on the combined application of human-specific NAMs, a PPARγ transactivation assay and a human mesenchymal stem cell (hMSC)-based adipogenesis assay, supports in vitro identification of obesogens. To this end, a case study was performed with 21 PFAS. Seven PFAS (HFPO-DA, FBSA, PFHpA, PFBS, PFPrS, PFPrA, and PBSF) showed both PPARγ transactivation and increased lipid content. Three PFAS increased cellular lipid content without measurable PPARγ activation (3:3 FTCA, MeFBSA, EtFOSA), implying alternative mechanisms of adipogenesis. Notably, seven PFAS decreased lipid content; five of these (PFOS, PFDA, PFNA, PFBA, PFEtS) were PPARγ agonists, whereas two (TFA and TFMS) did not transactivate PPARγ. Our findings underscore the need for an integrated testing strategy that incorporates multiple mechanisms and downstream phenotypic endpoints to identify substances with obesogenic properties. PMID:42202891 | DOI:10.1016/j.yrtph.2026.106142 Birth Defects Res. 2026 May;118(5):e70048. doi: 10.1002/bdr2.70048. ABSTRACT BACKGROUND: Psilocybe mushrooms (psilocybin/psilocin [PSI/PSC]) and ayahuasca (N,N-dimethyltryptamine [DMT]) are hallucinogenic serotonergic agonists. Pregnant and lactating women are frequently omitted from clinical studies; hence minimal developmental/reproductive/neurotoxicity (DART/DNT) and endocrine disruption (ED) data in humans are available. Hallucinogens contaminated with pesticides may have overlapping metabolic pathways affecting toxicity. An examination of potential adverse effects on pregnancy and development from exposure to hallucinogenic plants, hypothetically contaminated with organophosphates (OP) or organochlorines (OC), was performed using new approach methodologies (NAMs) and open access tools. METHODS: Cheminformatics Modules, Predicting Developmental Toxicity Potential Project, Toxicity Estimation Software Tool (TEST) using quantitative structure-activity relationships, Endocrine Disruptor Screening Program, California's Proposition 65 list, and ToxCast assays were investigated for DART/DNT and ED reported effects and/or predictions related to PSI/PSC, DMT, and sentinel pesticides (chlorpyrifos/chlorpyrifos-oxon and endosulfan). ToxCast data were inputs for Integrated Chemical Environment (ICE) PBTK adult and fetal models to generate adjusted human Administered Equivalent Doses (AdjAEDs) that were compared to regulatory dose ranges for hallucinogens and pesticides to assess model predictions. RESULTS: Cheminformatics Modules, PregPred, and TEST-QSAR predicted that hallucinogens and pesticides have DART, DNT, and ED effects. No ToxCast data were reported for DMT and PSI was ToxCast inactive. PSC/pesticide overlapping metabolic pathways were CYP2C9 modulated by serotonin, thyroid hormones and sonic hedgehog, each associated with development. Clinical PSC and regulatory pesticide points of departure were generally within range of predicted fetal AdjAEDs. CONCLUSIONS: Open access NAMs tools identified risks to fetal development from exposure to hallucinogens and pesticides. PMID:42163018 | DOI:10.1002/bdr2.70048 The North American Modern Building Alliance (NAMBA) of the American Chemistry Council is excited to host its third annual Building Fire Safety Symposium on Sept. 9-10, 2026, at the Hyatt Regency O’Hare Chicago. Environ Sci Technol. 2026 May 5. doi: 10.1021/acs.est.5c18135. Online ahead of print. ABSTRACT Endocrine disrupting chemicals (EDCs) are associated with various adverse health outcomes, thus necessitating high-throughput screening. However, current EDC screening models struggle to achieve high predictive performance and biological interpretability. Considering the predominant contribution of molecular interactions between EDCs and nuclear receptors (NRs) to molecular initiating events associated with adverse health outcomes, it is essential to integrate chemical-NRs interactions profiles into EDCs screening. Herein, we develop mechanism-driven models by integrating chemical-NRs interactions features of 372 434 chemicals with 16 NRs from large-scale molecular docking and chemical structural features, enabling comprehensive molecular representation of binding potential and physicochemical properties. Multiple models are constructed using diverse algorithms (XGBoost, NGBoost, Random Forest, TabPFN, and graph convolutional network), with SHAP analysis identifying key features of endocrine disruption to link predictions to chemical-NRs interactions. The optimal models achieved impressive performance (AUC: 0.815-0.995) and wide applicability with external validation against published EDCs inventory. The models are implemented in an open-access web server named EDC Profiler (http://www.edcprofiler.cn/service/edcprofiler), featuring interactive input interfaces, batch processing capabilities, and intuitive result visualization. The platform facilitates efficient EDCs screening and promotes new approach methods (NAMs) development for EDCs health risk assessment. PMID:42084471 | DOI:10.1021/acs.est.5c18135 The Joint Research Centre (JRC) Nanomaterials Repository hosts a representative selection of industrially relevant nanomaterials (NMs), including those investigated in large-scale international research initiatives. Each NM is produced as a single large batch and sub-sampled into individual vials, ensuring the availability of well-characterized and consistent representative materials for scientific activities. Its value is demonstrated in more than 386 scientific publications (2011–2024) that have made use of materials from the JRC Repository. At present, the Repository provides essential support to the European Food Safety Authority (EFSA) funded NAMs4NANO project, supplying characterized, pristine, real-world materials to the consortium under the framework of the JRC–EFSA collaboration agreement on food and feed safety. The results of NAMs4NANO will contribute to the ongoing update of the EFSA Guidance on the Risk Assessment of Nanomaterials and Small Particles in the Food and Feed Chain. The updated guidance extends the scope of risk assessment beyond the conventional nanoscale (1–100 nm) to include particles up to 250 nm, recognizing their potential to traverse gastrointestinal barriers and trigger additional testing requirements. The characterization of pristine nanomaterial powders provides a physical-chemical baseline for subsequent biological testing. In the NAMs4NANO project, these materials are assessed under simulated gastrointestinal conditions to study dissolution, and degradation processes relevant to determining the need for nanospecific risk assessments. A key objective of the updated EFSA guidance is to further integrate New Approach Methodologies (NAMs) into hazard assessment frameworks for nanomaterials. The variability of real-world NMs, such as differences in size, shape, impurities, as well as unintentional surface coatings might challenge the performance of NAMs. The NAMs4NANO project is conducting case studies to evaluate the reliability and applicability of NAMs when tested with real world materials. The inclusion of real-world materials, e.g., pesticides and food additives, in the JRC Nanomaterials Repository provides an additional set of representative materials that strengthen the scientific foundation for food safety policy implementation. This resource will enhance regulatory science capacity by supporting the standardization of testing methods and promoting the harmonization of risk assessment approaches for nanomaterials and small particles. By fostering consistency and comparability across studies, it will improve the reliability of safety evaluations, reinforce consumer protection, and facilitate the effective implementation of European and international food safety policies. Environ Sci Technol. 2026 Apr 21;60(15):11243-11252. doi: 10.1021/acs.est.6c00444. Epub 2026 Apr 8. ABSTRACT Chemical persistence has long been recognized as a critical determinant of ecosystem and human exposure, exemplified by legacy pollutants such as DDT, PCBs, and, more recently, PFAS. Despite decades of regulation and research, robust experimental half-life data are available for only a fraction of chemicals in use, hampering their persistence assessment. Current testing frameworks, while refined, lack the efficacy to address these large data gaps, underscoring the need for innovative approaches. We argue that new approach methodologies for persistence assessment (P-NAMs)─including high-throughput (HT) experimental systems and advanced in silico models─are needed. HT-testing can bridge the gap between biodegradability screening tests and resource-intensive simulation studies. Simultaneously, HT-testing can generate large, consistent data sets needed to improve the mechanistic understanding of biotransformation and train more accurate predictive models. Integration of transformation product analysis and FAIR (findable, accessible, interoperable, and reusable) data repositories will further enhance mechanistic understanding and model reliability. We call for coordinated efforts across academia, industry, and regulatory bodies to establish standardized reporting, expand accessible data sets, and validate predictive tools. By advancing P-NAMs, the scientific community can ensure that persistence assessment evolves from a regulatory bottleneck into a driver of innovation, safeguarding human and ecosystem health and promoting safe chemical design. PMID:41950227 | DOI:10.1021/acs.est.6c00444 Online
2026-02-25
to 2026-02-25 The EFSA Stakeholder Workshop on Genotoxicity Guidance Revision was held on 3‐4 November 2025 in Brussels, Belgium. The event aimed to inform stakeholders about the ongoing revision of EFSA's genotoxicity guidance framework and gather input on key scientific aspects, including the testing strategy, integration of new approach methodologies (NAMs), quantitative genotoxicity assessment and genotoxicity assessment of mixtures. The Workshop featured presentations from EFSA, sister agencies (ECHA, EMA), the European Commission (EC), OECD, as well as stakeholders from industry and academia. Arch Toxicol. 2026 May;100(5):1877-1901. doi: 10.1007/s00204-025-04268-w. Epub 2026 Feb 17. ABSTRACT Bottom-up in vitro ADME parameterized PBK models play a vital role in Next Generation Risk Assessment (NGRA), which evaluates the toxicological hazards of compounds through New Approach Methods (NAMs). The ZeroPM project, funded by the EU under Horizon 2020, develops strategies to prioritize persistent (P) and mobile (M) compounds for regulatory measures based on exposure levels and toxicological properties. This study developed a quantitative in vitro to in vivo extrapolation (QIVIVE) approach for two classes of PM compounds - 9 triazines and 16 triazoles. The virtual in vitro distribution model (VIVD) derived free medium benchmark concentration values (EC20 and IR1.5 (mol/L)) from a previously published NAMs testing battery. The VIVD model accounted for partitioning and ionization of PM compounds, while a bottom-up PBK model using in vitro ADME data accurately predicted rat plasma concentrations for tebuconazole and cyromazine. The same assumptions were translated to a human oral-route PBK model. Most triazines/triazoles had in vitro ADME data, where the data gaps were filled using read-across approach. The human PBK model employed forward dosimetry to estimate plasma concentrations from preclinical lowest observed adverse effect levels (LOAELs) or hypothetical exposure data, using surface- and groundwater concentrations as worst-case scenarios. Comparison to QIVIVE data indicates that NAMs-derived values are protective and can serve as basis for human risk assessment or risk-based prioritization. PMID:41699307 | PMC:PMC13086896 | DOI:10.1007/s00204-025-04268-w bioRxiv [Preprint]. 2026 Jan 22:2026.01.19.700343. doi: 10.64898/2026.01.19.700343. ABSTRACT Development is a tightly regulated process that establishes body axes and orchestrates the spatial organization of tissues and organs. Although developmental programs contain inherent redundancies, they remain highly sensitive to environmental cues. Among environmental contaminants, per- and polyfluoroalkyl substances (PFAS), chemicals that resist degradation and bioaccumulate in the body, are of particular concern. These "forever chemicals" are widespread in our household products, including non-stick and waterproof materials, and drinking water remains a major source of exposure. PFAS accumulate in specific tissues and have been associated with developmental delays, childhood leukemia, and other adverse health outcomes, yet the cellular and molecular mechanisms by which they disrupt early development remain largely unknown. To address this, we employ zebrafish embryos as a New Approach Methodology (NAM) to investigate how perfluorooctanoic acid (PFOA), a prevalent environmental PFAS, alters early embryogenesis. Embryos were exposed to physiologically relevant low and high doses of PFOA and analyzed at 24 hours post-fertilization (hpf), a key stage of organogenesis. We also included a parental exposure group, in which adults were treated with PFOA and their offspring were collected to assess whether the effects of exposure were transmitted to the next generation. Developmental processes are inherently plastic, and we wanted to understand the extent to which PFOA impacts normal cellular processes as well as the redundancy in the system (different developmental signaling pathways) which ensures that an embryo develops properly. Towards this, we performed single-nucleus RNA sequencing at 24 hpf, and it revealed that neuronal and muscle tissue clusters are particularly sensitive to PFOA exposure. These molecular perturbations correspond with anxiety-like behavioral phenotypes we observed in the exposed larvae, linking early developmental disruptions to organism-level outcomes. Overall, our findings provide mechanistic insight into the way in which PFAS exposure alters development, disrupting gene expression patterns and chromatin organization in developing tissues, revealing how early molecular perturbations can give rise to long-term behavioral consequences. PMID:41648621 | PMC:PMC12871824 | DOI:10.64898/2026.01.19.700343 Front Toxicol. 2025 Dec 17;7:1690491. doi: 10.3389/ftox.2025.1690491. eCollection 2025. ABSTRACT Read-across has matured from an expert-driven extrapolation based largely on structural analogy into a rigorously documented, mechanistically informed cornerstone of next-generation risk assessment. Three pivotal frameworks are compared that now shape its regulatory use: the European Food Safety Authority's (EFSA) 2025 guidance for food and feed safety, the European Chemicals Agency's (ECHA) Read-Across Assessment Framework (RAAF) for industrial chemicals under REACH, and the community-driven Good Read-Across Practice (GRAP) principles. Using five analytical lenses-conceptual structure, scientific rigor, implementation tools, regulatory acceptance, and practical impact-we identified areas of complementarity and divergence. EFSA provides a seven-step, uncertainty-anchored workflow that actively embeds new approach methodologies (NAMs) and adverse outcome pathway reasoning, offering applicants a transparent "how-to" template. RAAF, in contrast, operates as an evaluator's rubric: six scenario types and associated assessment elements delineate what evidence must be delivered, thereby standardizing regulatory scrutiny but leaving dossier construction to the registrant. GRAP supplies the conceptual glue, emphasizing mechanistic plausibility, exhaustive analogue selection, explicit uncertainty characterization, and the strategic use of NAMs; its influence is evident in both EFSA's and ECHA's evolving expectations. (Terminology note: the acronym "NAM" was popularized at an ECHA workshop in 2016; earlier documents such as RAAF and initial GRAP papers therefore may not use the term explicitly). Regulatory experience under REACH demonstrates that dossier quality and acceptance rates rise markedly when RAAF criteria are met, while EFSA's new guidance is poised to catalyze similar gains in food and feed assessments. Globally, the convergence of these frameworks-reinforced by OECD initiatives and NAM-enhanced case studies-signals an emerging international consensus on what constitutes defensible read-across. In conclusion, harmonizing EFSA's procedural roadmap with RAAF's evaluative rigor and GRAP's best-practice ethos can mainstream reliable, animal-saving read-across across regulatory domains, paving the way for fully mechanistic, AI-enabled chemical safety assessment. PMID:41479674 | PMC:PMC12753468 | DOI:10.3389/ftox.2025.1690491 The project Computational characterisation of ecological hazard and risk of environmental mixtures focused on two key priorities in advancing a next‐generation risk assessment (NGRA) workflow: (i) transitioning to assessing mixtures and (ii) utilising mechanism‐based hazard assessment based on new approach methodology (NAM) data. New approach methodologies (NAMs) are gaining increasing attention within the scientific community as strategies to reduce the use of animal testing. Their integration into regulatory frameworks for chemical hazard and risk assessment in food and feed would directly support the goals of the European Food Safety Authority (EFSA). International Journal of Toxicology, Volume 45, Issue 2, Page 136-156, March/April 2026. International Journal of Toxicology, Ahead of Print. International Journal of Toxicology, Volume 44, Issue 6, Page 499-506, November/December 2025. International Journal of Toxicology, Ahead of Print. Regul Toxicol Pharmacol. 2025 Nov;162:105884. doi: 10.1016/j.yrtph.2025.105884. Epub 2025 Jun 6. ABSTRACT Read-across is a widely used adaptation to address information requirements under REACH. However, registrants submitting for the 2010 and 2013 deadline have often failed to satisfy regulatory requirements from ECHA's point of view. Due to their complex composition and unique physicochemical properties, surfactants are posing major challenges in this respect. With the aim to improve future submissions and prevent unnecessary animal testing, read-across-related discussions of 72 ECHA Final Decisions on Compliance Checks and Testing Proposal Evaluations of 24 major surfactant groups were analysed in-depth, and causes for acceptance or rejection were identified. Key drivers of regulatory acceptance/rejection were presence or absence of composition information, considerations on structural similarity as well as availability and nature of bridging studies. Several elements were identified that may be easily improved in future REACH dossiers without the need for additional animal testing. Other cases revealed uncertainty of expectations by ECHA, highlighting the need for improved communication during the dossier preparation. Notably, no example for acceptance of read-across based on non-animal New Approach Methodologies (NAMs) was identified in this analysis. Owing to the benefits that non-animal NAMs may present as supporting information, all stakeholders are encouraged to contribute to an increase of regulatory acceptance. PMID:40484111 | DOI:10.1016/j.yrtph.2025.105884 The American Chemistry Council’s Long-Range Research Initiative (LRI) is proud to announce its participation in the NIH Common Fund’s Complement Animal Research In Experimentation (Complement-ARIE) public-private partnership (PPP) to accelerate the scientific development and evaluation of New Approach Methodologies (NAMs). Neurotoxicology. 2025 Jul;109:11-26. doi: 10.1016/j.neuro.2025.05.006. Epub 2025 May 19. ABSTRACT With the societal interest to decrease experimental animal testing for regulatory purposes, the need for reliable new approach methods (NAMs) has become evident. To ensure the continued safe use of chemicals, NAMs should perform ideally at a comparable or better level of sensitivity and specificity as the in vivo modalities that they aim to replace, especially if they are to be used for hazard assessment. The use of relevant reference substances, selected with transparent criteria, forms a cornerstone of developing and validating (in silico and in vitro) NAMs. Claims on sensitivity and specificity should be based on results generated with reference chemicals that were previously scrutinised by independent expert panels on whether the substance has a hazardous property. CLP (Regulation (EC) No 1272/2008 on the classification, labelling and packaging of substances and mixtures) forms a key pillar in EU chemicals management. The evaluation of all available information by the Committee for Risk Assessment (RAC) and their comparison to CLP classification criteria creates the opportunity to objectively compile lists of positive reference substances. We collated a reference list of neurotoxic substances to aid in the development of neurotoxicity NAMs. We screened CLP Annex VI and reflected on existing reference lists and mode of action data. The identified substances included industrial chemicals and active substances in plant protection products and biocidal products. This list of neurotoxicants is not an exhaustive consensus list, which ideally would be the result of combining this list with those generated by other authorities or expert groups. PMID:40398565 | DOI:10.1016/j.neuro.2025.05.006 Deadline: 2025-06-03
Approximate launch date: 05/06/2025 In 2023 EFSA launched a project to promote the use of New Approach Methods (NAMs) into the risk assessment of pesticide residues metabolites (NAMs4PestRes) through the use of the OECD QSAR toolbox, a free available in silico tool managed by ECHA, to enhance connectivity of IUCLID and MetaPath and to implement embedded in silico models. The result will be an automated and standardized workflow for the assessment of mutagenicity (bacterial gene mutation) of pesticide residue metabolites to be implemented in a... The 2nd Commission Conference on the Roadmap towards Phasing out Animal Testing for Chemical Safety Assessments, held on 25 October 2024, brought together key stakeholders from regulatory bodies, industry, research organisations, and NGOs to discuss the future of chemical safety assessments done using non-animal methods (NAMs) in the EU. This second conference aimed to collect input from various stakeholders on how they address the transition from animal-based testing to innovative, reliable non-animal alternatives and to report progress with the development of the roadmap, which will set out actions and milestones to drive this transformation across chemical safety assessments. This editorial provides an update on research & innovation (R&I) needs that can support EFSA's regulatory science in the coming years. The paper presents research needs for EFSA's work in a number of domains: omics technologies; gut microbiome; new approach methodologies (NAMs); allergenicity risk assessment; aggregate exposure assessment and environmental risk assessment (ERA). In briefly describing R&I needs, the document also addresses emerging challenges and opportunities. Comput Toxicol. 2024 Jun;30:1-15. doi: 10.1016/j.comtox.2024.100304. ABSTRACT Read-across is a well-established data-gap filling technique used within analogue or category approaches. Acceptance remains an issue, mainly due to the difficulties of addressing residual uncertainties associated with a read-across prediction and because assessments are expert-driven. Frameworks to develop, assess and document read-across may help reduce variability in read-across results. Data-driven read-across approaches such as Generalised Read-Across (GenRA) include quantification of uncertainties and performance. GenRA also affords opportunities on how New Approach Method (NAM) data can be systematically incorporated to support the read-across hypothesis. Herein, a systematic investigation of differences in expert-driven read-across with data-driven approaches was pursued in terms of establishing scientific confidence in the use of read-across. A dataset of expert-driven read-across assessments that made use of registration data as disseminated in the public International Uniform Chemical Information Database (IUCLID) (version 6) of Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) Study Results were compiled. A dataset of ~5000 read-across cases pertaining to repeated dose and developmental toxicity was extracted and mapped to content within EPA's Distributed Structure Searchable Toxicity database (DSSTox) to retrieve chemical name and structural identification information. Content could be mapped to ~3600 cases which when filtered for unique cases with curated quantitative structure-activity relationship-ready SMILES resulted in 389 target-source analogue pairs. The similarity between target and the source analogues on the basis of different contexts - from structural similarity using chemical fingerprints to metabolic similarity using predicted metabolic information was evaluated. An attempt was also made to quantify the relative contribution each similarity context played relative to the target-source analogue pairs by deriving a model which predicted known analogue pairs. Finally, point of departure values (PODs) were predicted using the GenRA approach underpinned by data extracted from the EPA's Toxicity Values Database (ToxValDB). The GenRA predicted PODs were compared with those reported within the REACH dossiers themselves. This study offers generalisable insights on how read-across is already applied for regulatory submissions and expectations on the levels of similarity necessary to make decisions. PMID:38993812 | PMC:PMC11235147 | DOI:10.1016/j.comtox.2024.100304 Front Toxicol. 2024 Apr 26;6:1359507. doi: 10.3389/ftox.2024.1359507. eCollection 2024. ABSTRACT In the European regulatory context, rodent in vivo studies are the predominant source of neurotoxicity information. Although they form a cornerstone of neurotoxicological assessments, they are costly and the topic of ethical debate. While the public expects chemicals and products to be safe for the developing and mature nervous systems, considerable numbers of chemicals in commerce have not, or only to a limited extent, been assessed for their potential to cause neurotoxicity. As such, there is a societal push toward the replacement of animal models with in vitro or alternative methods. New approach methods (NAMs) can contribute to the regulatory knowledge base, increase chemical safety, and modernize chemical hazard and risk assessment. Provided they reach an acceptable level of regulatory relevance and reliability, NAMs may be considered as replacements for specific in vivo studies. The European Partnership for the Assessment of Risks from Chemicals (PARC) addresses challenges to the development and implementation of NAMs in chemical risk assessment. In collaboration with regulatory agencies, Project 5.2.1e (Neurotoxicity) aims to develop and evaluate NAMs for developmental neurotoxicity (DNT) and adult neurotoxicity (ANT) and to understand the applicability domain of specific NAMs for the detection of endocrine disruption and epigenetic perturbation. To speed up assay time and reduce costs, we identify early indicators of later-onset effects. Ultimately, we will assemble second-generation developmental neurotoxicity and first-generation adult neurotoxicity test batteries, both of which aim to provide regulatory hazard and risk assessors and industry stakeholders with robust, speedy, lower-cost, and informative next-generation hazard and risk assessment tools. PMID:38742231 | PMC:PMC11089904 | DOI:10.3389/ftox.2024.1359507 Sci Total Environ. 2024 Feb 20;912:168738. doi: 10.1016/j.scitotenv.2023.168738. Epub 2023 Nov 27. ABSTRACT Per- and polyfluoroalkyl substances (PFAS) are ubiquitously distributed in the aquatic environment. They include persistent, mobile, bioaccumulative, and toxic chemicals and it is therefore critical to increase our understanding on their adsorption, distribution, metabolism, excretion (ADME). The current study focused on uptake of seven emerging PFAS in zebrafish (Danio rerio) and their potential maternal transfer. In addition, we aimed at increasing our understanding on mixture effects on ADME by developing a physiologically based kinetic (PBK) model capable of handling co-exposure scenarios of any number of chemicals. All studied chemicals were taken up in the fish to varying degrees, whereas only perfluorononanoate (PFNA) and perfluorooctanoate (PFOA) were quantified in all analysed tissues. Perfluorooctane sulfonamide (FOSA) was measured at concerningly high concentrations in the brain (Cmax over 15 μg/g) but also in the liver and ovaries. All studied PFAS were maternally transferred to the eggs, with FOSA and 6:2 perfluorooctane sulfonate (6,2 FTSA) showing significant (p < 0.02) signs of elimination from the embryos during the first 6 days of development, while perfluorobutane sulfonate (PFBS), PFNA, and perfluorohexane sulfonate (PFHxS) were not eliminated in embryos during this time-frame. The mixture PBK model resulted in >85 % of predictions within a 10-fold error and 60 % of predictions within a 3-fold error. At studied levels of PFAS exposure, competitive binding was not a critical factor for PFAS kinetics. Gill surface pH influenced uptake for some carboxylates but not the sulfonates. The developed PBK model provides an important tool in understanding kinetics under complex mixture scenarios and this use of New Approach Methodologies (NAMs) is critical in future risk assessment of chemicals and early warning systems. PMID:38030006 | DOI:10.1016/j.scitotenv.2023.168738 Arch Toxicol. 2023 Dec;97(12):3075-3083. doi: 10.1007/s00204-023-03601-5. Epub 2023 Sep 27. ABSTRACT In Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) the criterion for deciding the studies that must be performed is the annual tonnage of the chemical manufactured or imported into the EU. The annual tonnage may be considered as a surrogate for levels of human exposure but this does not take into account the physico-chemical properties and use patterns that determine exposure. Chemicals are classified using data from REACH under areas of health concern covering effects on the skin and eye; sensitisation; acute, repeated and prolonged systemic exposure; effects on genetic material; carcinogenicity; and reproduction and development. We analysed the mandated study lists under REACH for each annual tonnage band in terms of the information they provide on each of the areas of health concern. Using the European Chemicals Agency (ECHA) REACH Registration data base of over 20,000 registered substances, we found that only 19% of registered substances have datasets on all areas of health concern. Information limited to acute exposure, sensitisation and genotoxicity was found for 62%. The analysis highlighted the shortfall of information mandated for substances in the lower tonnage bands. Deploying New Approach Methodologies (NAMs) at this lower tonnage band to assess health concerns which are currently not covered by REACH, such as repeat and extended exposure and carcinogenicity, would provide additional information and would be a way for registrants and regulators to gain experience in the use of NAMs. There are currently projects in Europe aiming to develop NAM-based assessment frameworks and they could find their first use in assessing low tonnage chemicals once confidence has been gained by their evaluation with data rich chemicals. PMID:37755502 | PMC:PMC10567824 | DOI:10.1007/s00204-023-03601-5 Regul Toxicol Pharmacol. 2022 Dec;136:105278. doi: 10.1016/j.yrtph.2022.105278. Epub 2022 Oct 21. ABSTRACT The Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) regulation was created to protect human health and the environment through the better and earlier identification of harmful intrinsic properties of chemical substances on the European market. One of its central aims was the promotion of alternatives to animal testing, yet it has instead become a long tick-box list of in vivo experiments questionable relevance to human health outcomes despite a global trend towards new approach methods (NAMs) in chemical safety assessment. The Chemicals Strategy for Sustainability (CSS), proposed by the European Commission in 2020, is a golden opportunity to revise REACH in a significant and impactful way, yet proposals presented so far have significant negative animal welfare consequences. There is still time to correct the course of the ongoing REACH revision - proposals made herein offer a path towards the promising future intended by the CSS. These proposals are anchored in three vectors of action, varying in level of complexity - from changes that ECHA can implement to improve existing processes, through technical changes aimed at minimizing animal testing and increasing NAM acceptance, to deeper structural changes to establish non-animal testing strategies as the basis for risk assessment. PMID:36280152 | DOI:10.1016/j.yrtph.2022.105278 Regul Toxicol Pharmacol. 2022 Nov;135:105261. doi: 10.1016/j.yrtph.2022.105261. Epub 2022 Sep 11. ABSTRACT New Approach Methodologies (NAMs) are considered to include any in vitro, in silico or chemistry-based method, as well as the strategies to implement them, that may provide information that could inform chemical safety assessment. Current chemical legislation in the European Union is limited in its acceptance of the widespread use of NAMs. The European Partnership for Alternative Approaches to Animal Testing (EPAA) therefore convened a 'Deep Dive Workshop' to explore the use of NAMs in chemical safety assessment, the aim of which was to support regulatory decisions, whilst intending to protect human health. The workshop recognised that NAMs are currently used in many industrial sectors, with some considered as fit for regulatory purpose. Moreover, the workshop identified key discussion points that can be addressed to increase the use and regulatory acceptance of NAMs. These are based on the changes needed in frameworks for regulatory requirements and the essential needs in education, training and greater stakeholder engagement as well the gaps in the scientific basis of NAMs. PMID:36103951 | DOI:10.1016/j.yrtph.2022.105261
The U.S. Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER), and Office of New Drugs (OND) has continuously encouraged the submission of nonclinical tests utilizing new approach methodologies (NAMs) and sponsor engagement ...
The U.S. Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER), and Office of New Drugs (OND) has continuously encouraged the submission of nonclinical tests utilizing new approach methodologies (NAMs) and sponsor engagement ...
Technological advances and the desire to reduce dependence on animal models have brought human-relevant models to the forefront of drug development. This paradigm shift is leveraging the advances inin vitrosystems and new approach methodologies (NAMs), ...
Technological advances and the desire to reduce dependence on animal models have brought human-relevant models to the forefront of drug development. This paradigm shift is leveraging the advances inin vitrosystems and new approach methodologies (NAMs), ...
Deadline to register interest: 03/06/2025