Archives of Toxicology最新文献

{"title":"Ranking rather than predicting: what optimised T-cell assays can tell us about the immunogenicity of biologics.","authors":"Yueming Luo","doi":"10.1007/s00204-026-04636-0","DOIUrl":"https://doi.org/10.1007/s00204-026-04636-0","url":null,"abstract":"","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149376980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CYP450 quantification and metabolic activation capacity of rat and hamster liver S9 fractions: implications for nitrosamine mutagenicity testing.","authors":"Jessica Dieckhoff, Frank Bringezu, Jasjot Singh, Sébastien Moniot, Stephanie Simon","doi":"10.1007/s00204-026-04623-5","DOIUrl":"https://doi.org/10.1007/s00204-026-04623-5","url":null,"abstract":"<p><p>N-nitrosamine impurities are a major concern in the pharmaceutical industry and public safety. The assessment of this chemically diverse group using conventional regulatory test batteries, including the Ames test (OECD TG 471), remains challenging. Consequently, refined strategies such as the Enhanced Ames Test (EAT) have been developed and recommended by regulatory authorities, requiring 30% induced rat and hamster S9. Recently, we showed that hamster S9 metabolizes short-chain N-nitrosamines more efficiently than rat S9, likely due to differences in the induction pattern of metabolizing enzymes. Metabolic activation by cytochrome P450 isoenzymes (CYP) is a critical step in the bioactivation of N-nitrosamines. Building on our previous publication, the present work focusses on key CYPs and sets the proteome data into perspective with in vitro mutagenicity data for selected N-nitrosamines. Targeted proteomics quantified CYP1A2, 2A6, 2C8/9/19, 2D6, 2E1, and 3A4 of rat and hamster orthologs in uninduced, Aroclor 1254-, and PB/NF-induced rat and hamster liver S9. In rat S9, induction markedly increased CYP1A2 and CYP3A1 (> 40-fold). For the selected set of CYPs, most protein levels in hamster S9 decreased or increased only slightly (< 6-fold) following induction, although baseline levels were higher than those in uninduced rat S9. Nevertheless, induced hamster S9 generated the strongest Ames responses for NDBA and 1-CPNP, indicating that induction enhances CYP activity beyond protein quantity alone. N-nitroso-atenolol was negative under all rat S9 conditions but positive in TA1535 only with induced hamster S9, indicating that larger NDSRIs require elevated metabolic activity for detection. These findings provide a mechanistic basis for species- and induction-specific differences in mutagenicity detection and contribute to a better understanding of the metabolic activation capacity of S9.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149376979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myelin in a dish? Proving it's myelin.","authors":"Massimo Frangiamone, Katharina Koch, Ellen Fritsche, Fanny Langlet, Moritz Rossner, Oddvar Myhre, Marie-Gabrielle Zurich","doi":"10.1007/s00204-026-04619-1","DOIUrl":"https://doi.org/10.1007/s00204-026-04619-1","url":null,"abstract":"","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149340463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stress granule assembly drives an adaptive survival response in keratinocytes under TiO₂ nanoparticles and UV irradiation.","authors":"Hyeon-Ji Jo, In Young Kim, Ik Hwan Kwon, Suho Kim, Sang-Won Lee, Tae Geol Lee, Se-Hwa Kim","doi":"10.1007/s00204-026-04611-9","DOIUrl":"https://doi.org/10.1007/s00204-026-04611-9","url":null,"abstract":"<p><p>Nanoscale processing enhances the photocatalytic reactivity of titanium dioxide nanoparticles (TiO₂ NPs) under UV exposure. While these nanoparticles are widely utilized in cosmetics and industrial formulations, the molecular decision-making processes that dictate keratinocyte survival following UV exposure remain poorly understood. Here, we demonstrate that concurrent exposure to TiO₂ NPs and UVA radiation induces substantial synergistic phototoxicity, which does not occur under individual exposure at the same respective doses. Under phototoxic conditions, keratinocytes were found to engage an adaptive response characterized by G3BP1-dependent stress granule (SG) assembly to mitigate cellular stress. Mechanistically, this cytoprotective response was driven by PERK/eIF2α signaling and coordinated by endoplasmic reticulum-mediated calcium flux. Pharmacological inhibition of SG assembly or genetic knockdown of G3BP1 exacerbated cell death, indicating that SG formation serves as a cytoprotective mechanism that relieves proteotoxic burden. Collectively, these findings delineate a proteostatic defense mechanism against TiO₂-mediated phototoxicity, providing fundamental insights for the safe-by-design evaluation of advanced dermatological materials.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149332173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Concurrent low-dose-rate gamma irradiation and inorganic arsenite: genotoxicity and transcriptional responses in liver and testis in CBA and C57BL/6 mice.","authors":"Dag M Eide, Anne Graupner, Birgitte Lindeman, Hildegunn Dahl, Dag A Brede, Nur Duale, Ann Karin Olsen","doi":"10.1007/s00204-026-04626-2","DOIUrl":"https://doi.org/10.1007/s00204-026-04626-2","url":null,"abstract":"<p><p>Humans in arsenic-endemic and radiologically exposed settings may be co-exposed to inorganic arsenic and ionizing radiation, yet the combined effects of chronic low-dose-rate irradiation and environmentally relevant arsenic are poorly defined. In a single factorial experiment, male CBA and C57BL/6N mice were exposed to sodium arsenite in drinking water (0, 0.3 or 3 mg/L) and chronic γ irradiation (2.5 mGy/h, total 3 Gy), alone and combined. We measured blood genotoxicity (comet and micronucleus assays), characterised 21 circulating miRNAs, global DNA methylation and sequenced liver and testis transcriptomes to identify significant pathways. Arsenite exposure was accompanied by an increase in FPG-sensitive DNA lesions in white blood cells alongside a slight reduction in single strand breaks. Micronucleus frequency in reticulocytes and erythrocytes was not affected by arsenite. Arsenite was identified as an oxidative rather than a chromosomal genotoxicant. Only one miRNA (miR-133a-5p) responded clearly to arsenite. Global DNA methylation was only affected by irradiation. The liver and testis transcriptomes shared common DNA-repair and oxidative-stress pathways, but the organs diverged in response. Irradiation was the dominant stressor while the effect of the concurrent arsenite exposure was additive, antagonistic or synergistic. Baseline strain differences were large but additive, with negligible strain × treatment interaction in the transcriptome, whereas strain × arsenite interactions were found for the FPG-comet signal and hepatic arsenic. Our study contributes new data, experimental design and analysis methods about the genotoxic and transcriptional landscape of multiple stressor exposure.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149332170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modern targeted nerve agent incidents: toxicokinetic complexity, biomarker interpretation and forensic uncertainty.","authors":"Kamil Kuca, Eugenie Nepovimova","doi":"10.1007/s00204-026-04629-z","DOIUrl":"https://doi.org/10.1007/s00204-026-04629-z","url":null,"abstract":"<p><p>Nerve agent poisoning is often linked with mass-casualty events. Typical examples are battlefield use or large terrorist attacks. However, documented incidents from the last decades show a broader and more complex picture. The perspective follows a line of documented cases. It starts with the 1978 ricin \"umbrella\" murder of Georgi Markov in London (non-nerve agent attack, but historically important). It then moves to the sarin attacks in Matsumoto (1994) and the Tokyo subway (1995), the VX assassinations by the Aum Shinrikyo cult (1994-1995), the 2013 sarin attack in Ghouta and the recent targeted poisonings of Kim Jong-nam (2017), Sergei and Yulia Skripal (2018), Dawn Sturgess and Charlie Rowley (2018) and Alexei Navalny (2020). We use these cases to show how route of exposure, dose, formulation and environmental persistence shape toxicokinetics, clinical presentation, biomarker formation and forensic interpretation. For each case we give the circumstances, the agent, the route, the clinical course, the treatment and the forensic confirmation in detail. We focus on acetylcholinesterase and butyrylcholinesterase inhibition, aging, protein adduct formation, dermal absorption and environmental persistence. We describe a recurring \"toxicological paradox\": greater control over exposure can reduce immediate lethality, but at the same time it increases diagnostic uncertainty and forensic complexity. The cases also show that mass and targeted use are not two separate historical stages. They coexist within the same period, sometimes even within one perpetrator organisation. This perspective has direct implications for emergency preparedness, biomarker development, antidotal treatment windows and international chemical incident response.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149332172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Concentration categories do not represent equivalent exposure intensity in comparative PFAS transcriptomics.","authors":"Luis F O Silva","doi":"10.1007/s00204-026-04628-0","DOIUrl":"https://doi.org/10.1007/s00204-026-04628-0","url":null,"abstract":"<p><p>Sprenger et al. (2026) provide an extensive transcriptomic dataset covering 33 PFAS congeners in differentiated HepaRG cells and report broadly comparable molecular responses across structurally diverse substances. The dataset is valuable, but the cross-PFAS comparison requires a clearer distinction between relative concentration categories, numerical exposure concentrations and toxicological potency. For each PFAS, three non-cytotoxic concentrations were selected individually. The resulting numerical concentrations ranged from 5 to 250 µM. All 33 congeners were tested at 25 µM, 25 of 33 at 100 µM and 22 of 33 at 250 µM. Nevertheless, the subsequent comparative IPA analyses were based on the labels \"low\", \"medium\" and \"high\", rather than numerical concentrations. These labels therefore do not represent equivalent exposure intensities across PFAS. The distinction becomes consequential because the authors report concentration-dependent increases in differentially expressed genes for most compounds and because several additional pathways emerged predominantly at the high concentration, which was close to the cytotoxicity threshold for some PFAS but substantially below it for others. Thus, the high category can simultaneously encode chemical identity, nominal dose and position relative to cytotoxicity. This does not mean that category-based comparisons are invalid. Rather, they answer a narrower question: whether compounds perturb common pathways at their individually selected exposure levels. Concentration-resolved or potency-based analyses would complement this approach and help distinguish shared molecular response from comparable potency and from effects emerging only at different positions on the concentration-response continuum.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149317376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Molecular basis of azole fungicide interactions with human estrogen receptor alpha (ERα): an integrated in silico and in vitro toxicological assessment.","authors":"Rajesh Kumar Pathak, Da-Hyun Jeong, Vikas Kumar, Hee-Seok Lee, Jun-Mo Kim","doi":"10.1007/s00204-026-04640-4","DOIUrl":"https://doi.org/10.1007/s00204-026-04640-4","url":null,"abstract":"","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149332171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interpreting liver volume changes after rifampicin in healthy volunteers.","authors":"Kaifeng Han, Ruiqin He","doi":"10.1007/s00204-026-04622-6","DOIUrl":"https://doi.org/10.1007/s00204-026-04622-6","url":null,"abstract":"<p><p>Rifampicin-associated liver volume changes in healthy volunteers provide an opportunity to examine the human relevance of xenobiotic-induced liver growth. This Comment considers three aspects of the clinical analysis relevant to interpreting the observed response. Clarification of whether the volumetric outcomes and choice of normalisation were prespecified, alongside paired treatment effects and confidence intervals, would help establish the basis for inference and assess the response's magnitude and precision. For a small volumetric response, blinded repeat segmentation of existing magnetic resonance images and details of scan timing and pre-scan intake would help assess reproducibility under comparable physiological conditions. Associations between 4β-hydroxycholesterol and liver volume could also be examined using within-participant rifampicin-minus-placebo differences, with appropriate attention to the crossover design and an exploratory interpretation. Most of these suggestions could be addressed through protocol information and existing imaging and crossover data, strengthening interpretation of the human findings and guiding further investigation of pregnane X receptor-mediated liver growth.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149317456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physiologically based pharmacokinetic modeling as a translational tool in forensic toxicology: from pig to human synthetic cannabinoid toxicokinetics using 5F-Cumyl-P7AICA and its major metabolite as a case study.","authors":"Omar Zaher, Dominik Selzer, Helena Loer, Felix Neuschwender, Frank Filip Steinbauer, Christiane Dings, Simeon Rüdesheim, Nicola Luigi Bragazzi, Nadja Walle, Adrian A Doerr, Benjamin Peters, Matthias Schwab, Matthias W Laschke, Michael D Menger, Peter H Schmidt, Markus R Meyer, Nadine Schaefer, Thorsten Lehr","doi":"10.1007/s00204-026-04613-7","DOIUrl":"https://doi.org/10.1007/s00204-026-04613-7","url":null,"abstract":"<p><p>Synthetic cannabinoids are increasingly associated with severe adverse events and fatalities. The SC 5F-Cumyl-P7AICA (5FC) is particularly concerning due to its high potency. Human studies of such compounds are ethically and practically constrained, highlighting the value of physiologically based pharmacokinetic/toxicokinetic (PBTK) modeling as a translational tool. Here, we developed a PBTK model for 5FC and its primary metabolite N-pentanoic acid (NPA) in pigs and translated it to humans for predicting systemic and tissue-specific exposure. Using the published toxicokinetic data in pigs receiving 200 µg/kg 5FC via intravenous (IV) and inhalation routes, a parent-metabolite PBTK model was built. Serum, whole blood, and fat tissue concentrations were used for calibration and evaluation. The model was used to predict various tissue concentrations in pigs as well as translated to humans using species-specific physiological parameters and in vitro-measured human plasma protein binding and subsequently compared with allometric scaling of a population TK model. The pig model accurately predicted mean concentration-time profiles (MRD: 1.49 and 2.19 for 5FC, 1.51 and 1.62 for NPA, IV and inhalation, respectively). Individual predictions fell within two-fold of observed values for all TK parameters. The human PBTK model predicted lower 5FC exposure compared to allometric scaling after both IV and inhalation dosing, while NPA exposure was comparable after IV and higher after inhalation dosing. Tissue-level simulations in humans showed organ-specific distribution patterns for both compounds. In conclusion, the PBTK model described 5FC and NPA disposition in pigs, including tissue concentrations and generated exploratory human systemic and tissue exposure predictions.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149317459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}