Archives of Toxicology最新文献

{"title":"Correction: Mitigation of depleted uranium-induced mitochondrial damage by ethylmalonic encephalopathy 1 protein via modulation of hydrogen sulfide and glutathione pathways.","authors":"Juan Li, Yong Li, Yazhen Zhao, Suiyi Liu, Wenrun Li, Huanhuan Tan, Li Shen, Yonghong Ran, Yuhui Hao","doi":"10.1007/s00204-025-04040-0","DOIUrl":"https://doi.org/10.1007/s00204-025-04040-0","url":null,"abstract":"","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172453","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":"Neurodevelopmental toxicity and mechanism of chlorinated polyfluoroalkyl ether sulfonate alternative F-53B in pubertal male rats.","authors":"Lu Sun, Yao Chen, Junyan Chen, Guanghua Mao, Weiwei Feng, Xiangyang Wu","doi":"10.1007/s00204-025-04093-1","DOIUrl":"https://doi.org/10.1007/s00204-025-04093-1","url":null,"abstract":"<p><p>F-53B, a substitute for perfluorooctane sulfonate (PFOS), has attracted considerable concerns due to its frequent detection in environment matrices. However, the potential health risks to mammals, especially neurodevelopmental toxicity, remain unclear. In this study, 3-week-old pubertal male rats were exposed to F-53B at concentrations of 0, 0.15, 1.5, and 15 μg/kg for 3 weeks continuously. Diminished cognitive abilities were observed by morris water maze (MWM) test, F-53B exposure increased the escape latency and decreased the time spent in the target quadrant of rats. Furthermore, F-53B significantly altered neurotransmitter levels in the hippocampus. Molecular docking studies indicated that F-53B might bind to metabotropic glutamate receptor 5 (mGluR5), potentially entering neurons and causing further neurotoxicity. qRT-PCR and western blot analyses were used to assess the expression of genes and proteins related to calcium pathways. Results revealed that F-53B exposure downregulated mRNA expression of ryanodine receptors (RyRs) and the phosphorylation of inositol trisphosphate receptors (IP3Rs), while upregulating sarco/endoplasmic reticulum Ca²⁺-ATPase2 (SERCA2) levels. F-53B inhibits the IP3/Ca²⁺ signaling pathway in the rat hippocampus, which may affect ER Ca²⁺ storage and release functions. Additionally, F-53B reduced the phosphorylation of IP3R, Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), extracellular signal-regulated kinase 1 and 2 (ERK1/2), and cAMP response element binding protein (CREB), potentially impairing synaptic plasticity and long-term potentiation (LTP), leading to learning and memory deficits. This study reveals that F-53B induced neurodevelopmental toxicity linked to calcium pathway disruption and provides new insight into the potential long-term hazards of F-53B.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144156044","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":"Toxicological concerns regarding glyphosate, its formulations, and co-formulants as environmental pollutants: a review of published studies from 2010 to 2025.","authors":"Szandra Klátyik, Gergely Simon, Eszter Takács, Marianna Oláh, Johann G Zaller, Michael N Antoniou, Charles Benbrook, Robin Mesnage, András Székács","doi":"10.1007/s00204-025-04076-2","DOIUrl":"https://doi.org/10.1007/s00204-025-04076-2","url":null,"abstract":"<p><p>Over the last decade and worldwide, an enormous investment in research and data collection has been made in the hope of better understanding the possible ecological and toxicological impacts triggered by glyphosate (GLY). This broad-spectrum, systemic herbicide became the most heavily applied pesticide ever in the 2000s. It is sprayed in many different ways in both agricultural and non-agricultural settings, resulting in multiple routes of exposure to organisms up and down the tree of life. Yet, relatively little is known about the environmental fate of GLY-based herbicide (GBH) formulations, and even less on how GBH co-formulants alter the absorption, distribution, metabolism, excretion, and toxicity of GLY. The environmental fate of GLY depends on several abiotic and biotic factors. As a result of heavy annual GBH use over several decades, GLY residues are ubiquitous, and sometimes adversely affect non-target terrestrial and aquatic organisms. GLY has become a frequent contaminant in drinking water and food chains. Human exposures have been associated with numerous adverse health outcomes including carcinogenicity, metabolic syndrome, and reproductive and endocrine-system effects. Nonetheless, the existence and magnitude of GLY-induced effects on human health remain in dispute, especially in the case of heavily exposed applicators. A wide range of biochemical/physiological modes of action have been elucidated. Various GBH co-formulants have long been considered as inert ingredients relative to herbicidal activity but clearly contribute to GLY-induced hazards and risk gradients. In light of already-identified toxicological and ecosystem impacts, the intensive research focuses on GLY and GBHs should continue, coupled in the interim with commonsense, low-cost changes in use patterns and label requirements crafted to slow the spread of GLY-resistant weeds and reduce applicator and general-population exposures.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141185","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":"A framework for evaluating less-than-lifetime exposures: advancing toxicological risk assessment for drinking water quality.","authors":"Sanah Majid, Astrid Reus, Renske Hoondert, Mirjam Blokker, Amitosh Dash, Corine Houtman, Merijn Schriks, Milou M L Dingemans","doi":"10.1007/s00204-025-04061-9","DOIUrl":"https://doi.org/10.1007/s00204-025-04061-9","url":null,"abstract":"<p><p>The increasing production and use of chemicals leads to a higher number of contaminants in (drinking) water sources, which poses significant challenges to those responsible for water quality. An important task for water companies and regulators is to ensure that (drinking) water quality does not compromise public health and confidence in water safety. A key component of this effort is toxicological risk assessment, which evaluates the safety of chemicals that may be present in water systems. Although there has been considerable progress in risk assessment methods, there is currently a lack of a clear approach to the risk assessment of chemicals in (drinking) water for which concentrations vary over time. In the current study, methods for the assessment of less than lifetime exposure (LTL) are presented that are particularly applicable for substances with time-varying concentrations in (drinking) water. The presented framework is a decision tree that helps experts to decide whether a measured or predicted LTL exposure to a chemical can lead to adverse health effects. To develop these methods, we used existing knowledge and incorporated new developments in toxicological risk assessment. A case study illustrates the application of the proposed approaches in a realistic scenario. The method can be used by risk assessors as a tool to improve the understanding of human exposure to contaminants in (drinking) water and to inform risk-based monitoring. In addition, it enables customised investigations and responses that lead to a more nuanced view of water quality and its impact on public health.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141156","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":"Framework for classifying chemicals for repeat dose toxicity using NAMs.","authors":"J E Doe, P Botham, D Holland, M Fuart Gatnik, V Giri, H Kang, P Kalra, S León Pérez, S Marty, S Moors, R Raeburn, E Reale, R Settivari, M Sica, K Z Travis, S J Wijeyesakere","doi":"10.1007/s00204-025-04069-1","DOIUrl":"https://doi.org/10.1007/s00204-025-04069-1","url":null,"abstract":"<p><p>EPAA's 'NAM Designathon 2023' challenge for human toxicity sought to identify a classification system capable of categorising chemicals based on their bioactivity and bioavailability properties determined using non-animal methodologies (Worth et al. 2025). The proposal is made to classify chemicals into three levels of concern: low concern could be used without restriction, medium concern requiring assessment to establish safe use levels and high concern being candidates requiring risk management (Berggren and Worth in Regul Toxicol Pharmacol 142:105431, https://doi.org/10.1016/j.yrtph.2023.105431 , 2023). We developed a NAMs based classification system for \"human systemic toxicity\" mainly focussed on repeat dose toxicity, similar to the assessment carried out in classification for 'Specific Target Organ Toxicity-Repeated Exposure' (STOT-RE) based on ECETOC's Tiered Approach integrating three lines of evidence: In silico predictions, In vitro bioavailability and PBK modelling, In vitro bioactivity assays. The first stage employed an in silico approach, covering several toxicity endpoints across various (Q)SAR in silico models to identify indicators of toxicity. Bioavailability was categorised by simulating 14-day plasma C_max predictions for a standard dose level using three TK models (Firman et al. in Arch Toxicol 96:817-830, https://doi.org/10.1007/s00204-021-03205-x , 2022). Bioactivity was categorised using a matrix with potency and severity. In vitro data were obtained from ToxCast. Potency makes use of dose response AC50 values. Severity categorisation is based on consideration of the adverse effects associated with the assays. 12 chemicals have been assessed through the framework. Overall, we have demonstrated that the matrix suggested by the EPAA Designathon can be used to categorise chemicals into three different levels of concern but there are areas still to be explored especially for the range of assays used, the framework categorisation being defined, and how such a matrix would fit into a tiered approach, pragmatically, including targeted in vivo studies.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144135970","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":"Tail-less precursors in synthetic cannabinoid production: investigating a clandestine laboratory, seized samples, and CB₁ activity.","authors":"Manuela Carla Monti, Tobias Rautio, Marie H Deventer, Markus Schläpfer, Johannes Tveit, Alex J Krotulski, Victoria Marland, Robert Reid, Niamh Nic Daeid, Craig McKenzie, Christophe P Stove, Henrik Green, Caitlyn Norman","doi":"10.1007/s00204-025-04086-0","DOIUrl":"https://doi.org/10.1007/s00204-025-04086-0","url":null,"abstract":"<p><p>An emerging new trend reveals that potent synthetic cannabinoid receptor agonists (SCRAs) that were prevalent prior to the Chinese class-wide ban in July 2021 have remained on the market or re-emerged. This is likely because of a new production route where unscheduled tail-less precursors are converted into the desired controlled SCRA via a one-step synthesis. This study reports the discovery of a clandestine production site in Switzerland for this synthesis. Controlled recreations of the synthesis of ADB-BUTINACA (also known as ADB-BINACA or ADMB-BUTINACA) and MDMB-4en-PINACA based on a recipe recovered from the Swiss production site were undertaken. The recreations yielded oils or waxy products with chromatographic purities ranging from 39.3 to 93.4% with the precursors (ADB-INACA or MDMB-INACA) remaining in all products. Mixtures of a precursor (e.g., MDMB-INACA, ADB-INACA, AB-INACA, MDMB-ICA, ADB-IATA, MDMB-5'Me-INACA) with corresponding final SCRA(s) (e.g., MDMB-4en-PINACA, 4F-MDMB-BUTINACA, MDMB-BUTINACA, MDMB-FUBINACA, ADB-BUTINACA, ADB-4en-PINACA, AB-CHMINACA, 4F-MDMB-BUTICA, ADB-FUBIATA) were found in 28 forensic casework samples in the US received between February 2023 and February 2024 and 87 samples seized from the Scottish prisons between February 2023 and July 2024. In vitro CB₁ receptor activity of the precursors, synthesized products, and mixtures of precursors and final SCRAs were examined using β-arrestin 2 recruitment and intracellular calcium release assays. The precursors were much less potent than the final SCRAs and the concentration of the final SCRA dictated the activity of mixtures. This study raises awareness of the emergence of a new production method for SCRAs as observed in multiple countries.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126450","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":"Validation of new AI-based classification method for in silico cardiac safety assessment of drugs following the CiPA framework.","authors":"Ulfa Latifa Hanum, Ali Ikhsanul Qauli, Yunendah Nur Fuadah, Rahmafatin Nurul Izza, Ki Moo Lim","doi":"10.1007/s00204-025-04079-z","DOIUrl":"https://doi.org/10.1007/s00204-025-04079-z","url":null,"abstract":"<p><p>The comprehensive in vitro proarrhythmia assay (CiPA) has paved the way for integrating in silico trials into drug evaluation processes. In alignment, the International Council for Harmonization (ICH) has initiated efforts to update the ICH S7B and E14 guidelines through a structured Questions and Answers (Q&A) format. A significant challenge in this paradigm is ensuring consistent application and evaluation of diverse proarrhythmia risk prediction models across experimental systems. This study utilized the CiPAORdv1.0 model to predict cardiac toxicity, leveraging in vitro data from 28 drugs for training and validation. A modified O'Hara-Rudy model simulated a virtual population of human ventricular cell models. Seven critical features (qNet, APD50, APD90, Camax, Carest, CaTD50, CaTD90) were extracted as inputs for analysis. CiPAORdv1.0 demonstrated robust performance, achieving predictive accuracies with an area under the curve (AUC) of 1.0 for high risk and 0.95 for low-risk categories. The calibration process was enhanced using normalized Euclidean distances (R1 and R2), effectively distinguishing risk categories. Sensitivity analysis identified key drugs, ensuring a strong calibration drug set to anchor model predictions. The proposed ANN model validated the CiPAORdv1.0 framework as an effective TdP-risk prediction system, ensuring robust and lab-specific validation. This study presents a novel algorithm leveraging artificial neural networks to implement validated cardiac safety models, addressing a critical need for standardized proarrhythmia risk assessment in drug development.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126452","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":"In vitro toxicological assessment using NCI-H292 cells of the relationship between cytotoxic effects and chemical composition in flavored e-liquids.","authors":"Shuhong Zhang, Yumeng Zhang, Hongjuan Wang, Shulei Han, Huan Chen, Hongwei Hou","doi":"10.1007/s00204-025-04072-6","DOIUrl":"https://doi.org/10.1007/s00204-025-04072-6","url":null,"abstract":"<p><p>The range of e-cigarette flavors has driven consumer interest while raising concerns about potential health risks. However, the toxicological impact and chemical composition of flavored e-liquids remain poorly characterized. This study investigates cytotoxicity differences between tobacco- and non-tobacco-flavored e-liquids and identifies key compounds contributing to toxicity through chemical correlation analysis. We assessed the cytotoxicity of 100 e-liquids (50 tobacco-flavored, 50 non-tobacco-flavored) using IC₅₀ values in NCI-H292 cells and selected representative samples for genotoxicity evaluation. Three component categories-principal constituents, organic acids, and cooling agents-were analyzed, alongside correlations between specific compounds and cytotoxicity. Our findings revealed that non-tobacco-flavored e-liquids exhibited significantly higher cytotoxicity than tobacco-flavored variants, with considerable variation across different flavors and nicotine concentrations. Among non-tobacco flavors, tropical fruit and melon varieties induced the greatest cytotoxicity. Genotoxicity analysis showed that while tobacco-flavored e-liquids (0.2 × to 1 × IC₅₀) did not cause significant DNA damage, certain non-tobacco flavors (0.2 × to 1 × IC₅₀) triggered pronounced DNA damage. Correlation analysis identified N,2,3-trimethyl-2-isopropylbutamide (WS-23), benzoic acid, and nicotine as negatively correlated with IC₅₀ values, with WS-23 displaying the strongest association. Further in vitro validation confirmed that WS-23 (0-2.4 mg/mL) induces DNA damage and elevates reactive oxygen species (ROS) levels in a dose-dependent manner. These findings highlight the need for more rigorous investigation and regulatory oversight of flavored e-liquids to mitigate potential health risks.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118613","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":"Temporal analyses of germ cell mutations using the MutaMouse model support the recommended design in OECD test guideline 488.","authors":"Gu Zhou, Andrew Williams, Danielle P M LeBlanc, George R Douglas, Carole L Yauk, Francesco Marchetti","doi":"10.1007/s00204-025-04085-1","DOIUrl":"https://doi.org/10.1007/s00204-025-04085-1","url":null,"abstract":"<p><p>The Organisation for Economic Co-operation and Development test guideline (TG) 488 uses transgenic rodent models to assess in vivo mutagenesis. TG 488 recommends 28 consecutive days of exposure with sampling of germ cells from seminiferous tubules 28 days post-exposure (i.e., 28 + 28d). We analyzed mutant frequencies (MF) in male germ cells up to 70 days post-exposure to determine whether designs other than 28 + 28d are necessary for assessing germ cell mutagenicity. Adult MutaMouse males received various doses of benzo(a)pyrene (BaP), N-ethyl-N-nitrosourea (ENU), isopropyl methanesulfonate (iPMS), or procarbazine (PRC) alongside vehicle controls for 28 days orally. Germ cells were collected from seminiferous tubules at + 3d, + 28d, + 42d, or + 70d post-exposure and MF quantified using the lacZ assay. Significant increases in lacZ MF were observed for all four chemicals at 28 + 28d. No further increases occurred at later sampling times. There was no significant effect with BaP at 28 + 3d, and a significantly stronger response with ENU and BaP at 28 + 28d compared to 28 + 3d. PRC produced the strongest response at 28 + 3d, while there was no impact of different sampling times for iPMS. Both these chemicals significantly reduced testis weight at 28 + 3d and 28 + 28d. Finally, benchmark dose modeling generated overlapping confidence intervals among the four sampling times for ENU, iPMS, and PRC. However, for BaP, the confidence interval was significantly greater at 28 + 3d than at the other sampling times. These results support the use of the 28 + 28d design as the recommended experimental design for germ cells in TG 488 and that later sampling times are not necessary.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118616","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":"Molecular dosimetry of estragole and 1'-hydroxyestragole-induced DNA adduct formation, clastogenicity and cytotoxicity in human liver cell models.","authors":"G Ackermann, M Peil, C Quarz, A Schmidt, M Halaczkiewicz, A D Thomas, S Stegmüller, E Richling, G Manolikakes, M Christmann, J H Küpper, D Schrenk, J Fahrer","doi":"10.1007/s00204-025-04084-2","DOIUrl":"https://doi.org/10.1007/s00204-025-04084-2","url":null,"abstract":"<p><p>The phenylpropene estragole (ES) is found in essential oils of herbs and spices, such as bitter fennel and basil. Humans are exposed to ES through the diet and phytomedicines. After its absorption, ES undergoes metabolic activation by CYP1A2 and SULT1A1 in the liver, which can give rise to DNA adducts and hepatocarcinogenesis. Until now, quantitative genotoxicity data for ES in human liver cells are scarce, correlating DNA adduct levels with critical effects such as clastogenicity. Here, we used human HepG2 and HepG2-CYP1A2 cells as well as primary human hepatocytes (PHH) to study the genotoxic, clastogenic and cytotoxic potential of ES and its crucial metabolite 1'-hydroxyestragole (1'OH-ES). In addition, primary rat hepatocytes (PRH) were used for selected endpoints. Treatment of HepG2-CYP1A2 cells with ES (0-2 mM) led to the concentration-dependent formation of E3'-N²-dG adducts. Apart from a moderate γH2AX induction, neither p53 accumulation nor cytotoxicity was observed. However, clastogenicity was demonstrated at ES concentrations ≥ 1 mM. Incubation of HepG2 cells with 1'OH-ES (0-35 µM) led to 10-50-fold higher E3'-N²-dG adduct levels compared to equimolar ES concentrations. Furthermore, 1'OH-ES caused γH2AX formation, p53 accumulation and cytotoxicity, which was confirmed in PHH. In agreement, 1'OH-ES induced clastogenicity at concentrations ≥ 25 µM. Molecular dosimetry revealed that a certain E3'-N²-dG adduct level is required to trigger clastogenicity and cytotoxicity. This was confirmed by Benchmark Concentration (BMC) modelling, showing that the BMC for clastogenicity is 12-17-fold higher than the respective BMC for DNA adduct formation. Our data indicate that a threshold level of DNA adducts is required, both in rat and human liver cells, to trigger markers of clastogenicity. These levels are unlikely to be reached in humans following chronic ES exposure through phytomedicines or the diet.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109686","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}