Toxicology letters最新文献

{"title":"S14-04 Integrate NAM data into bottom-up PBK modelling approaches","authors":"M. Spänig","doi":"10.1016/j.toxlet.2025.07.090","DOIUrl":"10.1016/j.toxlet.2025.07.090","url":null,"abstract":"<div><div>Next generation risk assessment aims to reduce and ultimately replace animal testing while ensuring confidence in the approach. Recent results from ongoing projects such as ADME4NGRA and PARC will be shared to illustrate how <em>in silico</em> and <em>in vitro</em> NAM-based data can be implemented in PBK modelling. This integration is essential for the development of more reliable and ethical frameworks for chemical safety assessment.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Page S29"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145011059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S15-01 Building a virtual human for chemical risk assessment from software and data; integrating reproducible research and predictive modelling","authors":"M. Teunis ,&nbsp;E. Willighagen ,&nbsp;O. Cinar ,&nbsp;M. Martens ,&nbsp;M. Klaassen ,&nbsp;M. Liem ,&nbsp;F. Hepkema ,&nbsp;I. Djidrovski ,&nbsp;A. Kienhuis ,&nbsp;C. Evelo","doi":"10.1016/j.toxlet.2025.07.091","DOIUrl":"10.1016/j.toxlet.2025.07.091","url":null,"abstract":"<div><div>The ever-increasing scientific body of knowledge on health and disease, together with the ongoing development of innovative <em>in vitro</em> and <em>in silico</em> Non-Animal Methods (NAM), offer opportunities for animal-free safety assessment. To fully leverage the promise of NAMs and at the same time ensure safety, intersectoral and -disciplinary collaborations are necessary. This is explored in the Virtual Human Platform for Safety Assessment project (VHP4Safety). VHP4Safety is a Dutch funded research project that runs from 2021 to 2026 and brings together international partners from 32 organisations representing scientists, industry, regulators, policy makers, clinicians and Non-Animal Methods.</div><div>During the projects’ Designathons and Hackathons, data scientists, toxicologists and social scholars collaborate: (1) to build a data infrastructure to integrate existing and newly developed data and services at the Virtual Human Platform (VHP), (2) to feed the VHP with toxicological knowledge and NAM data and (3) to implement the VHP taking into account stakeholder perspectives <span><span>^[1]</span></span>.</div><div>Here, we will demonstrate how principles of reproducible science are applied throughout the development of the VHP. We will address the most crucial technical solutions to build, test and host the VHP platform, using open science community standards. To build the VHP, an interdiciplinary development team with mixed expertise in bioinformatics, cheminformatics, molecular biology, artificial intelligence, toxicology, statistics and cloud development, work together in short sprints to deliver tangible minimal-viable products. The team has recently adopted an Agile way of working and we will share some insights on the benefits of using such an approach above the more classical ‘waterfall’ project stucture.</div><div>The VHP consists of artifacts being: software, models, documentation, standard operating procedures, workflows and data. In this presentation we will dive into how we are structuring these artifacts to form a coherent and user-friendly platform that can be used to address chemical risk-assessment questions. The VHP design and implementation is revolving around three specific case-studies: thyroid toxicity, kidney toxicity and neuro-toxicity. These case studies guide the direction of the platform development and are aimed at showcasing its capabilities. We will focus on how we are generating a sustainable platform in terms of reuse and the ability to further the develop the VHP after project end. We will showcase specific technologies that are geared towards sharing all the artifacts in the platform in a reproducible and consistent manner.</div><div><em>The VHP4Safety project is funded by the Netherlands Research Council (NWO) Netherlands Research Agenda: Research on Routes by Consortia (NWA-ORC 1292.19.272).</em></div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Pages S29-S30"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145011060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CEC03-04 PBPK and QST for safety assessments","authors":"M. Siccardi","doi":"10.1016/j.toxlet.2025.07.023","DOIUrl":"10.1016/j.toxlet.2025.07.023","url":null,"abstract":"<div><div>The integration of physiologically based pharmacokinetic (PBPK) modeling with quantitative systems toxicology (QST) represents a mechanistic framework to support modern safety assessments. While PBPK models can support the simulation of concentrations across tissues and species, QST adds a dynamic layer that captures biological processes underlying toxicity at the organ and systems level.</div><div>Together, these approaches enable a more comprehensive understanding of dose–response relationships by linking predicted exposure to biologically relevant modes of action. This is particularly valuable when translating <em>in vitro</em> or nonclinical data into quantitative human-relevant outcomes. By coupling kinetic and dynamic models, it becomes possible to identify points of departure based on mechanistic approaches and supported by predicted concentrations, rather than relying on empirical thresholds or safety factors.</div><div>In this session, we will explore how PBPK-QST integration enhances the relevance and reproducibility of safety evaluations, supports the reduction of animal use, and aligns with current trends in regulatory science. The presentation will also reflect on how modular, open-source modeling ecosystems contribute to greater transparency and flexibility in model development, qualification, and application across sectors.</div><div>Overall, PBPK-QST frameworks represent a strategic step forward in next-generation risk assessment by providing a quantitative and mechanistic basis for predicting toxicity, refining uncertainty, and supporting evidence-based decisions in both pharmaceutical and non-pharmaceutical contexts.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Page S8"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145010751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CEC04-05 Feasability of quality criteria and tentative assessment tools to align with artificial intelligence","authors":"A. Sonnenburg","doi":"10.1016/j.toxlet.2025.07.029","DOIUrl":"10.1016/j.toxlet.2025.07.029","url":null,"abstract":"<div><div>Artificial Intelligence (AI) tools are <em>the</em> emerging technology that is on everyone's lips nowadays – AI chat bots manage customer support, ChatGPT summarises long texts, Copilot assists with programming … But are these tools also capable enough to be of use in science in general and regulatory toxicology in particular? Could AI also help with the critical appraisal of toxicokinetic studies?</div><div>The session will provide an overview on AI in the broader sense, on possible applications, and related challenges. It will also critically address concerns that arise from the use of this technology in scientific settings, such as ethical considerations, financial and ecologic costs, transparency and data protection as well as inherent biases.</div><div>The participants of the CEC will have the opportunity to test the (non-AI) tool developed by our group to assess the reliability of kinetic studies on two example publications during the practical exercise. After this session's talk, we will take an interactive look at one available AI tool to see how the tool performs with this same task on one of the example publications. Thus, participants will be able to directly compare their results with results generated by the AI tool and to gain first-hand experience of the advantages and disadvantages of using AI in the systematic evaluation of kinetic studies.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Page S10"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145010754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S12-04 Developments and potential applications of epigenetic tools for chemical hazard assessment","authors":"M. Jacobs","doi":"10.1016/j.toxlet.2025.07.082","DOIUrl":"10.1016/j.toxlet.2025.07.082","url":null,"abstract":"<div><div>Epigenetic modulations underlie critical developmental processes that contribute to determining adult phenotypes (physiological outcomes). They involve a series of mechanisms that entail histone and DNA covalent modifications and non-coding RNAs, which collectively contribute to programming cell functions and differentiation. Epigenetic anomalies and DNA mutations are co-drivers of cellular dysfunction pathways, from endocrine disruption (Greally and Jacobs 2013, Jacobs <em>et al.</em> 2017), to metabolic and immune disruption and ultimately carcinogenesis (Jacobs <em>et al.</em> 2020, Desaulniers <em>et al.</em> 2021, Louekari and Jacobs 2024). Test methods that can be adapted to measure and monitor key epigenetic marks in response to toxicant exposure could already be providing a valuable tool for predicting adverse health outcomes. However the evidence basis for regulatory purposes needs to be translated from <em>in vivo</em> to <em>in vitro</em> and strengthened experimentally. Furthermore, how such tests could be combined into and be interpreted by integrated approaches for testing and assessment of chemicals needs to be clearly described to assist test method developers, regulators and policy makers. These considerations will be discussed, with examples, in my presentation.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Page S27"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145011013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S15-02 New Approaches to Data and Model Integration of Adverse Outcome Pathway information in the EPA AOP-DB","authors":"H.M. Mortensen","doi":"10.1016/j.toxlet.2025.07.092","DOIUrl":"10.1016/j.toxlet.2025.07.092","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Adverse Outcome Pathways (AOPs) is a conceptual framework that describes the mechanistic progression of key biological events that result in an adverse response. How we catalog these entities and interactions enhances our ability to understand mechanistic effects and subsequently toxicological outcomes relevant to human health. Structured implementation of AOP knowledge contributes to New Approach Methodologies (NAMs) and further development of machine learning and artificial intelligence (AI) utilization for regulatory objectives.&lt;/div&gt;&lt;div&gt;The longevity and success of database/knowledgebase and infrastructure projects have typically been hampered by inconsistent and limited funding. This has clear effects on data sustainability practices, quality of data, and data reuse policies. For AOPs, improving consistent mapping to other types of biological and toxicological data will increase utility, reuse, and interoperability. For example, integrating FAIR (findable, accessible, interoperable, and re-usable) data standards is a good approach, but is reliant on 3&lt;sup&gt;rd&lt;/sup&gt; party tools. One such tool, the EPA Adverse Outcome Pathway Database (AOP-DB), integrates multiple publicly available resources, extending ontology mapping of AOPs to the mapping of molecular and mechanistic componentsincluding biomedical entities &lt;em&gt;(e.g.,gene, protein, biological pathway, disease, tissue, assay, etc&lt;/em&gt;)&lt;em&gt;.&lt;/em&gt;Since the AOP-DB was created, additional tools have been initiated to improve automatic and systematic parsing, machine-actionability of AOP data to elucidate biological mechanism, and mapping to (meta)data. These tools are necessarybecause the AOP-Wiki, the primary repository of AOP information, does not programmatically map to this type of information. As a result, there is no consistency across AOPs in FAIR reporting standards related to biomedical entity mapping or the human/machine readability within a given AOP. Currently, no 3&lt;sup&gt;rd&lt;/sup&gt; party mapping of biomedical information pertaining to an AOP feeds into the AOP-Wiki repository. Standardization/harmonization of AOP (meta)data and defining AOP biomedical data lifecycles will facilitate the machine-actionability of AOPs and improve trust, transparency and accessibility.&lt;/div&gt;&lt;div&gt;Four independent, expert workgroups have been formed to address FAIR AOP data standards: &lt;em&gt;the FAIR AOP Cluster Workgroup; the Elixer Toxicology Community; the Environmental Health Language Collaborative AOP Standards Workgroup;&lt;/em&gt; and &lt;em&gt;the AOP Ontology Workgroup&lt;/em&gt;. These workgroups are currently interacting todevelop a &lt;em&gt;FAIR AOP Roadmap&lt;/em&gt; to ensure that AOP data and related biomedical information are easily accessible and interoperable for researchers across different disciplines (e.g., AOP, toxicology, biomedical, regulatory). Here we report on the current direction of the OECD, WPHA, SAAOP, and expert workgroups to improve standards for AOP biomedical entity mapping and coordinate this ","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Page S30"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145011239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S09-01 Roundtable Discussion","authors":"J.-L. Dorne ,&nbsp;D. Strauss ,&nbsp;R. Roberts","doi":"10.1016/j.toxlet.2025.07.070","DOIUrl":"10.1016/j.toxlet.2025.07.070","url":null,"abstract":"<div><div>No abstract has been submitted.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Page S22"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145011125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S10-01 From AOPs to IOPs: Bridging Human and Environmental Impact Assessment in Safe and Sustainable by Design Through Mechanistic Integration","authors":"A. Schaffert ,&nbsp;M. Paparella ,&nbsp;I. Virmani ,&nbsp;A. Serra ,&nbsp;D. Greco","doi":"10.1016/j.toxlet.2025.07.071","DOIUrl":"10.1016/j.toxlet.2025.07.071","url":null,"abstract":"<div><div>Safe and Sustainable by Design (SSbD) is a framework that aims to ensure the safety and sustainability of chemicals and materials across their life cycle. However, current SSbD approaches evaluate human health and environmental impacts separately, limiting their ability to capture cross-domain interactions and cumulative risks. Additionally, SSbD as defined by the Joint Research Centre (JRC) still relies on traditional hazard classifications, which hampers the direct use of non-animal methods (NAMs) in regulatory and industrial decision-making.</div><div>To address these limitations, we reviewed Next Generation Risk Assessment (NGRA) concepts and their potential to better integrate risk assessment and life cycle assessment (LCA) within SSbD. We found NAMs to be particularly key for SSbD, as their mechanistic insights foster the integration of human health and environmental assessments, addressing one of the most important limitations of current SSbD frameworks. Additionally, NAMs enable rapid, early-stage, predictive assessments of safety and sustainability, supporting proactive design choices and reducing the need for costly redesigns.</div><div>A key tool for integrating NAMs within NGRA is the Adverse Outcome Pathway (AOP) framework. Because many toxicity mechanisms are evolutionarily conserved, AOPs enable cross-species and ecosystem-wide assessments, providing a mechanistic understanding of chemical hazards in environmental health and improving predictions. Building upon the mechanistic and multi-scale characteristics of AOPs, we introduce Impact Outcome Pathways (IOPs) as an extended framework that integrates human and environmental health assessments with LCA in SSbD. IOPs describe sector-specific causeeffect chains that link chemical impacts to outcomes across environmental, health, social, and economic domains. Interconnected Key Event Relationships (KERs) bridge these domains, ensuring that mechanistic insights are transferred between different dimensions, while Modulating Factors (MFs) capture context-dependent variables reflecting indirect effects across biological, ecological, and socio-economic scales. Using case studies on per- and polyfluoroalkyl substances (PFAS) and graphene-based advanced materials, we exemplify how the IOP framework may achieve a more holistic and mechanistic assessment of the chemical or material and improve decision-making in SSbD.</div><div>By integrating (eco)toxicological pathways with broader sustainability mechanisms, IOPs enable a unified, cross-domain assessment of chemical risks. Their multiscale nature allows incorporation of diverse NAM-based mechanistic data and computational models, making IOPs a flexible and evolving tool for implementing a One Health approach within SSbD.</div><div><em>This research has been funded by the European Union Project INSIGHT (Integrated Models for the Development and Assessment of High Impact Chemicals and Materials) SSbD (GA101137742). Views andopinions ex","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Page S23"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145011126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S03-02 Taking Chemical Risk Assessment to Heart: Cardiotoxicity Evaluation of Complex Botanical Mixtures","authors":"M. Gossmann","doi":"10.1016/j.toxlet.2025.07.051","DOIUrl":"10.1016/j.toxlet.2025.07.051","url":null,"abstract":"<div><div>No abstract has been submitted.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Page S17"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145011130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S12-03 Occupational Exposure to Benzene and Epigenetic Biomarkers of Effect: From Early Discoveries to Emerging Insights","authors":"L. Ferrari","doi":"10.1016/j.toxlet.2025.07.081","DOIUrl":"10.1016/j.toxlet.2025.07.081","url":null,"abstract":"<div><div>Benzene is a well-established occupational and environmental carcinogen, classified by IARC as Group 1 with sufficient evidence for acute myeloid leukemia (AML) and limited evidence for other hematologic malignancies. While its leukemogenic potential at high doses is undisputed, increasing attention is now focused on the biological effects of long-term exposure to low concentrations, still frequent in various occupational and environmental settings.</div><div>Over the past two decades, epigenetic alterations have emerged as early and sensitive markers of toxicant exposure. In both experimental and epidemiological studies, benzene has been shown to induce DNA methylation changes affecting key biological pathways, including inflammation, oxidative stress, apoptosis, and immune and hematopoietic regulation. These epigenetic disruptions may serve as mechanistic intermediates between exposure and disease and are also implicated in the development of age-related conditions. As a result, growing emphasis is being placed on epigenetic biomarkers not only as indicators of early toxicity but also as tools to estimate biological age and capture the broader impacts of environmental exposures on health.</div><div>In our research group, we have been studying the impact of airborne benzene exposure on epigenetic biomarkers in peripheral blood mononuclear cells (PBMCs) from occupationally exposed individuals. Exposure levels were quantified using personal air monitoring across a wide concentration range, including levels well below current regulatory thresholds. Genome-wide DNA methylation profiling identified exposure-associated alterations at CpG sites involved in critical regulatory networks. Additionally, estimates of biological age and telomere length measured by qPCR showed consistent associations with benzene exposure, even at low concentrations (&lt;0.1 ppm).</div><div>These findings underscore the role of epigenetic mechanisms in mediating early effects of benzene exposure and support their utility as biomarkers of effect in occupational and environmental health. Integrating quantitative exposure metrics with molecular endpoints may improve early detection of biological responses and inform future risk evaluation and prevention strategies.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Page S27"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145011015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}