Toxicology letters最新文献

{"title":"S04-04 In Silico Decision Support Systems Enabling Next Generation Risk Assessments for Carcinogenicity","authors":"S. Stalford","doi":"10.1016/j.toxlet.2025.07.057","DOIUrl":"10.1016/j.toxlet.2025.07.057","url":null,"abstract":"<div><div>The ICH S1B(R1) addendum represents a significant milestone in improving human-relevant carcinogenicity testing. Utilizing relevant data and knowledge in a weight-of-evidence (WoE) assessment can now be used to determine if a two-year rat study would add value to a pharmaceutical safety package. Recent publications describing experiences in the practical implementation of the amended guidance have highlighted both opportunities and challenges from the initial application of this approach such as data gaps, documentation and interpretation. These reflections highlight the importance of developing best practice and having frameworks in place to ensure that the new regulation can be applied consistently and transparently with scientific rigour to support chemical safety decisions.</div><div><em>In silico</em> decision support systems provide a means of achieving this, through organising evidence, encoding guidance, and enabling best practices. A case study was performed using such a decision support system to enable an ICH S1B(R1) addendum decision. The system was able to capture the requirements from the ICH guidance and emerging best practice. In addition, relevant data and knowledge was organised around an AOP network, thus contextualising the evidence and bringing transparency and consistency. With this in place, guided expert review can then focus a user on where additional information or review is needed to reduce uncertainty. Overall, the decision support system enables systematic, transparent and robust outcomes for complex WoE assessments and thus supports greater consensus between organisations in the decisions reached.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Page S18"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145011197","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":"S13-03 NAMs and immunosafety assessment of biotherapeutics","authors":"H. Lebrec","doi":"10.1016/j.toxlet.2025.07.085","DOIUrl":"10.1016/j.toxlet.2025.07.085","url":null,"abstract":"<div><div>Biotherapeutics, including various immunotherapy modalities (monoand bi-specific antibodies, proteins and fusion proteins, cellular therapies), are now very well established or highly pursued approaches for the treatment of a variety of diseases, including many cancers and auto-immune / inflammatory diseases. A particularity of some biotherapeutics is the lack of pharmacologically relevant animal model for nonclinical safety assessment. In addition, it is generally accepted that animal models are not appropriate to assess immunogenicity of biotherapeutics. In that context, <em>in silico</em> and <em>in vitro</em> approaches have been and are being developed to mitigate for the lack of proper animal model and it can be envisioned that, when appropriate, nonclinical safety assessment relies solely on such approaches. This presentation will address how immune-related putative liabilities (immunogenicity, cytokine release, immunosuppression, off-target activity, on-target on-disease and/or on-target-off disease acitivty) of biologics and cell therapies (engineered effector and regulatory T cells) can be assessed using <em>in silico</em> and <em>in vitro</em> tools.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Page S28"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145011017","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":"Title Page","authors":"","doi":"10.1016/j.toxlet.2025.07.1357","DOIUrl":"10.1016/j.toxlet.2025.07.1357","url":null,"abstract":"","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Page III"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145010844","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":"S11-01 Assessing the potential toxicity of chemicals using human respiratory cell-based in vitro systems","authors":"N. Roldan ,&nbsp;A.O. Stucki ,&nbsp;M. Sharma ,&nbsp;S. Verstraelen ,&nbsp;A. Jacobs ,&nbsp;K. Hollanders ,&nbsp;J. Van Laer ,&nbsp;S. Remy ,&nbsp;E. Frijns ,&nbsp;A.J. Clippinger","doi":"10.1016/j.toxlet.2025.07.075","DOIUrl":"10.1016/j.toxlet.2025.07.075","url":null,"abstract":"<div><div>Surfactants are essential ingredients for household products, personal care items, and medicines. As widely used chemicals, understanding potential toxicity of these chemicals is a key focus for regulatory agencies. To evaluate potential respiratory toxicity of these chemicals, a normal human bronchial epithelial cell line (BEAS-2B) and a reconstructed human respiratory epithelial tissue model (RHRE; MucilAir™, Epithelix, Switzerland) were exposed to two surfactants: Triton X-100 (non-ionic surfactant; CAS Number: 9036-19-5) and oleoyl sarcosine (anionic surfactant; CAS Number: 110-25-8).</div><div>The test systems were exposed to the two surfactants as a single or repeated exposure (only in MucilAir™). For single exposures, the test chemicals were pipetted (30 μL each) on the apical side and cellular effects were assessed ~24 hours (BEAS-2B and MucilAir™) and seven days (to assess recovery; MucilAir™) after exposure. These included cytotoxicity (lactate dehydrogenase (LDH) release), cell viability (resazurin-based PrestoBlue® assay), secretion of interleukins-6 and -8 (CXCL-8; MSD V-Plex Assay), and additionally for MucilAir™, transepithelial electrical resistance (TEER), cilia beat frequency (CBF), average active area (AAA), and histology. For repeated liquid exposures, Mucil-Air™ tissues were exposed (30 μL, apically) to the two surfactants for 4 hours daily, consecutively for 4 days, with a 7-day recovery period. Cellular effects were assessed each day and after recovery.</div><div>Concentration-dependent effects in cell viability and inflammatory markers were observed after single exposure of BEAS-2B cells and MucilAir™ tissues to the two surfactants for 24 hours. In MucilAir™ tissues there was a significant decrease in cell viability (&lt;25%) and TEER values, and an increase in cytotoxicity (&gt;70%) at the two highest concentrations (40 and 80 μg/cm²) for both surfactants. This observation aligned with histology showing partial or full cell layer destruction. No change in cell viability was observed at 5, 10, and 20 μg/cm². However, tissues exposed to 20 μg/cm² showed increased cytotoxicity and a marked decrease in TEER for both chemicals. TEER values were restored after 7 days, but cell viability remained slightly decreased for oleoyl sarcosine. Preliminary repeat exposure results may indicate an additive effect in oleoyl sarcosine (only at the highest concentration tested, 20 μg/cm²) that was not observed after exposure to Triton X-100.</div><div>This study builds upon the INSPIRE (<em>In vitro</em> System to PredIct REspiratory toxicity) initiative to help increase scientific confidence in human cell-based methods to assess respiratory tissue irritation. The results from this study were used to inform a multi-laboratory study testing approximately 20 chemicals in the MucilAir™ cell system. The aim is to establish a standardized method that will serve as the first of several approach","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Pages S24-S25"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145010729","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":"From data silos to virtual humans: guardrails for a new era in safety prediction","authors":"S.M. Levine","doi":"10.1016/j.toxlet.2025.07.009","DOIUrl":"10.1016/j.toxlet.2025.07.009","url":null,"abstract":"<div><div>No abstract has been submitted.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Page S3"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145010845","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":"Multicellular liver systems and how to deconvolute toxicity in a complex system?","authors":"L. Suter-Dick","doi":"10.1016/j.toxlet.2025.07.006","DOIUrl":"10.1016/j.toxlet.2025.07.006","url":null,"abstract":"<div><div>The liver is a major site for xenobiotic-induced toxicity and in vitro systems often focus on the hepatocyte. However, multicellular 3D-systems are better suited to reflect some types of toxicities such as immune-mediated responses and liver fibrosis. Immune-mediated liver toxicity may involve Kupffer cells or Hepatic sinusoidal cells (LSECs). Liver fibrosis involves a series of key events described in the adverse outcome pathway (AOP) #38, based on the interaction of at least three cellular players: hepatocytes, Kupffer cells, and hepatic stellate cells. Hence, complex in vitro systems are required to assess these effects. For example, 3D-co-culture spheroid models can reproduce a fibrotic phenotype and mimic the key events characteristic of the liver fibrosis AOP (hepatocellular damage, activation of Kupffer cells, activation of stellate cells and deposition of extracellular matrix). However, in these complex systems it is difficult to understand the contribution of each cell type to the observed response. Studies implementing co-cultures, monocultures, and cell-type specific endpoints such as cellular respiration and release of miRNAs can help better discern the specific involvement of target cells. As specific examples, we evaluated the effects of methotrexate and the response to adeno-associated viruses (AAVs) of several liver cell types.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Page S2"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145010848","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":"CEC01-05 An integrated human-in vitroapproach to explore the role of miRNAs in occupational asthma","authors":"V. Galbiati","doi":"10.1016/j.toxlet.2025.07.1362","DOIUrl":"10.1016/j.toxlet.2025.07.1362","url":null,"abstract":"<div><div>Asthma resulting from sensitization of the respiratory tract to chemicals and defined allergic asthma, is associated with significant morbidity, and is clearly an important health concern with serious clinical consequences. Occupational allergic asthma resulting from sensitization of the respiratory tract to chemicals is clearly an important health concern with serious clinical consequences. The main pathological feature of allergic asthma is due to the complex interactions between immune cells and immunological mediators. Basically, Th1/Th2 ratio imbalance is one of the essential immunological mechanisms of asthma but also Th17/Tregs imbalance form an extreme complex interactive network. Recent evidences reported alterations in miRNA expression in a variety of lung diseases, including allergic asthma. Several miRNAs have been associated with asthma and airways inflammation but target identification remain not yet determined for the majority of the studies. Despite research for more than three decades, there are still no validated methods for the assessment of respiratory sensitizing potential of LMW compounds. The main idea of this project is based on the assessment of a new in vitro approach to better study and investigate the allergic asthma pathology. The central hypothesis of this project is that miRNAs play a key role in the activation and maintenance of the allergic asthma through the active involvement of the immune system. The specific aim of this project, that is entirely based on human cells, is to identify miRNA patterns and consequently which specific targets are involved in the interaction between the respiratory system and the immune system in the allergic asthma disease. The project could be ideally divided in two parts: the in vitro part (Part I) and the human part (Part II). Part I – For the in vitro approach the human lung epithelial cells, namely Calu-3, will be exposed to 5 respiratory sensitizers (hexamethylen, methylene diphenyl, and toluene diisocyanate; ammonium hexachloroplatinate; trimellitic anhydride), 1 skin sensitizer (2,4-dinitrochlorobenzene) and 1 irritant (sodium dodecyl sulphate) through a liquid aerosols system (Cloud Alpha System – VITROCELL ® Systems). A microRNA panels will be performed in control conditions and exposed conditions. A bibliographic research will be made to investigate miRNAs possibly involved in allergic asthma and/or immune system activation/de-regulation. Part II – in collaboration with Dott. Liviero (Occupational Unit of Padova University) a broad miRNA evaluation in asthmatic patients will be conducted, through the analysis of miRNA expression in blood microvesicles and in exhaled breath condensate obtained from healthy and asthmatic patients. The translational potential of the project is due to the use of a primary cell culture model as well as human samples. Furthermore, implementation of miRNA patterns could be useful as prevention tool (biomarkers for diagnosis) of allergic","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Page S6"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145010833","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":"Establishing scientific confidence in a two-chamber co-culture system to evaluate androgenic response in the presence of hepatic metabolism","authors":"Tessa C.A. van Tongeren ,&nbsp;Susan J. Hall ,&nbsp;Samantha J. Madnick ,&nbsp;Blanche C. Ip ,&nbsp;Paul L. Carmichael ,&nbsp;Hequn Li ,&nbsp;Wei Chen ,&nbsp;Lori A. Breitweiser ,&nbsp;Heather E. Pence ,&nbsp;David M. Ames ,&nbsp;Andrew J. Bowling ,&nbsp;Kamin J. Johnson ,&nbsp;Richard Cubberley ,&nbsp;Bruce Sherf ,&nbsp;Jeffrey R. Morgan ,&nbsp;Kim Boekelheide","doi":"10.1016/j.toxlet.2025.08.014","DOIUrl":"10.1016/j.toxlet.2025.08.014","url":null,"abstract":"<div><div>For the <em>in vitro</em> determination of toxicity on target organs in the presence of physiologically relevant human metabolism, we recently developed a two-chamber liver-target organ co-culture system in a medium-throughput 96-well format. Our proof-of-concept study using human HepaRG microtissues cultured in three-dimension (3D) and AR-CALUX reporter cells demonstrated the significantly reduced testosterone (T)-mediated androgen receptor (AR) responses in the presence of human liver metabolism. The present study further increased the scientific confidence in this two-chamber co-culture system as a flexible and robust tool to capture androgen-mediated responses by incorporating alternate AR reporter cell systems as the target and examining additional androgenic compounds. The system generated concordant metabolism-dependent changes in T- and 5α-dihydrotestosterone (DHT)-mediated AR responses using two different AR reporter cell systems (AR-CALUX, AR-INDIGO). The AR reporters had different sensitivity ranges and required media optimization. We demonstrated that this two-chamber co-culture system with integrated hepatic biotransformation can be used to evaluate endocrine activity with potential metabolism modulation of parent compounds.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"412 ","pages":"Pages 202-211"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144988596","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":"S05-01 Mechanical cues shaping tumor progression and their relevance for pathways of chemical carcinogenesis","authors":"G. Del Favero","doi":"10.1016/j.toxlet.2025.07.058","DOIUrl":"10.1016/j.toxlet.2025.07.058","url":null,"abstract":"<div><div>Mechanical cues can be seen as an essential part of the tumor microenvironment: these include changes in tissue architecture upon tumor growth, shear stress experienced by the metastatic cells in the bloodstream or the interaction with the extracellular matrix (ECM) and its physiological stiffness. To support the necessary plasticity, cells can efficiently convert physical stimuli into biochemical signals via mechanotransduction. On these premises, the integration of physical cues into cell culture models (e.g. for the development of organ-on-chip platforms or microfluidic devices) not only contributes to the recreation of <em>in vitro</em> models that more faithfully reproduce cellular environment, but also opens up the possibility of novel signaling crossroads. Hypothesizing that physical forces could lever the same molecular targets as those modulated by the xenobiotics, it is possible to postulate that the final cellular response could reflect both contributions, similarly to chemical-mixture toxicology. Pursuing these ambitious questions, ovarian cancer cell models were chosen here to explore these delicate interactions. In addition to being prone to chemoresistance and sensitive to the activity of endocrine disrupting chemicals (EDCs), ovarian cancer cells are exposed to a complex biophysical microenvironment in the abdominal cavity <span><span>^[1–3]</span></span>. Retracing molecular events that accompany cancer development and spread, cells were exposed to fluid shear stress, or cultivated on modified ECM stiffness. Exploring signaling pathways inwards and outwards, targeted (microscopy-based) and untargeted (omics-based) analyses were harmonized to investigate whether chemical-driven cascades can affect cell capacity to withstand mechanical stimulation and, in turn, how physical preconditioning can possibly tune cellular response to xenobiotics. Considering molecular effectors that play an acknowledged role in carcinogenesis and might sustain pathway interaction with xenobiotics, a special focus was given to mechanosensitive transcription factors (TFs), including Krüppel-like factors (KLFs), the Nuclear factor erythroid 2-related factor 2 (Nrf2), Sterol regulatory element-binding proteins (SREBPs) or the Yes1 associated transcriptional regulator (YAP1) <span><span>4</span></span>, <span><span>5</span></span>, <span><span>6</span></span>, <span><span>7</span></span>. Tailored physical and chemical manipulation of the TFs translocation patterns enabled the definition of cell-line specific functional performances, such as the regulation of cancer cell proliferation and metabolism, ROS management or the response to cytotoxic insults. Taken together, these data contribute to elucidating molecular mechanisms of toxicity that can be tuned by chemical and physical cues. These promise to be of relevance when extending the use and application of organ-on-chip platforms and support the identification of synergistic or antagonis","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Pages S18-S19"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145011199","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":"S07-02 Results from a new in vivo DNT study on glyphosate alone and in mixtures with other herbicides","authors":"A.O. Docea","doi":"10.1016/j.toxlet.2025.07.065","DOIUrl":"10.1016/j.toxlet.2025.07.065","url":null,"abstract":"<div><div>The potential neurodevelopmental toxicity of glyphosate remains a subject of debate within the research community. A recent study was conducted with the objective of investigating the impact of long-term effects of exposure to environmentally relevant levels of glyphosate and to its mixture with 2,4-D and dicamba during the intrauterine life (from gestational day 6) followed by the lactation period and 3 months after lactation, in a murine model. The results of the study indicated that exposure to glyphosate at very low doses led to a decline in research activity and an increase in anxiety, which was associated with an increase in degenerating cells and vacuolization in the hippocampus and cerebral cortex. In the mixture group, the effects were analogous, demonstrating an additive effect of the herbicides. It is important to note that chemical interactions, which often deviate from simple dose addition, have a major impact on neurotoxicity.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Page S21"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145011205","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}