Archives of Toxicology最新文献

{"title":"Copper oxide nanoparticles: from EU-regulatory landscape and mechanistic toxicity towards a cuproptosis-linked adverse outcome pathway","authors":"Sophie Scholz,&nbsp;Julia Prinz,&nbsp;Linde Sevenants,&nbsp;Andrea Holzwarth,&nbsp;Birgit Mertens,&nbsp;Robert Pieper,&nbsp;Vera Ritz,&nbsp;Kirsten Schulz,&nbsp;Holger Sieg,&nbsp;Aswin Mangerich,&nbsp;Linda Böhmert","doi":"10.1007/s00204-026-04465-1","DOIUrl":"10.1007/s00204-026-04465-1","url":null,"abstract":"<div><p>Copper is an essential trace element, yet concerns regarding its toxic potential have gained increasing attention, particularly with regard to nanoparticulate forms of copper oxides. Both CuO and Cu₂O are currently authorised in the EU for use in agriculture, biocides, and animal nutrition, but regulatory clarity regarding their nanoforms remains limited. This comprehensive review—combining narrative, bibliometric, and systematic approaches—addressed three key questions: (i) whether CuO and Cu₂O nanoparticles are sufficiently considered within EU regulations to prevent unintentional oral exposure via the food and feed chain, (ii) whether these nanoparticles can cross the intestinal barrier as intact particles and accumulate in tissues, and (iii) whether they elicit distinct biological responses, including regulated cell death pathways such as cuproptosis. With respect to question (i), a detailed analysis of EU legal frameworks revealed a heterogeneous regulatory landscape and a lack of binding provisions that would preclude unintended presence of copper oxide nanoforms in regulated materials. Although some nano-specific data requirements exist, empirical information on nanoparticulate fractions in commercial products is still lacking. With respect to questions (ii) and (iii), our systematic literature analysis supports consistent intracellular uptake of CuO and Cu₂O nanoparticles, yet direct evidence for transport of intact particles across the intestinal barrier is scarce. Mechanistic evidence supports cuproptosis as a key pathway for CuO nanoparticle toxicity, while the extent to which these effects differ quantitatively from ionic copper remains unclear due to insufficient data using appropriate experimental controls. Notably, a pronounced data gap was identified for Cu₂O nanoparticles across all evaluated domains. Finally, to organise and integrate the mechanistic evidence presented, we developed an adverse outcome pathway (AOP), registered as AOP 590 in the AOP Wiki, describing how increased intracellular copper can induce cuproptosis via disruption of energy metabolism. Collectively, these findings highlight the need for coordinated analytical, mechanistic, and regulatory research to support evidence-based risk assessment of CuO and Cu₂O nanoparticles in the food and feed context.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"100 11","pages":"4855 - 4906"},"PeriodicalIF":10.9,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-026-04465-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemical components of tattoo inks and their potential role in carcinogenesis and their side effects","authors":"Luiza Czaczkowska,&nbsp;Ewa Jabłońska,&nbsp;Julia Bury,&nbsp;Natalia Szurant,&nbsp;Wioletta Ratajczak-Wrona","doi":"10.1007/s00204-026-04484-y","DOIUrl":"10.1007/s00204-026-04484-y","url":null,"abstract":"<p>Tattooing is an invasive procedure that has gained popularity, particularly among individuals. Growing attention has been directed toward the safety of tattoo ink ingredients, which are complex mixtures of synthesis precursors and byproducts. These inks may contain classified carcinogens, heavy metals, polycyclic aromatic hydrocarbons (PAHs), and phthalates, often at concentrations exceeding permissible limits. Tattooing involves the insertion of needles 1–3 mm into the dermis. While part of the pigment is eliminated with epidermal turnover, approximately 25% is transported to lymph nodes and subsequently into the bloodstream. The remaining pigment is engulfed by phagocytic cells involved in innate immunity. Repeated needle punctures trigger local inflammation, recruitment of immune cells, and release of inflammatory mediators, followed by tissue regeneration and remodelling driven by keratinocytes, fibroblasts, and endothelial cells. Cases of malignant melanoma, squamous cell carcinoma, keratoacanthoma, and lymphoma have been reported in individuals with tattoos. However, the relationship between tattooing and cancer is not fully understood. It is suspected that the cause may be the transfer of toxic substances to lymph nodes and then to organs. The possible carcinogenic effects of tattoo ink ingredients will be discussed based on available scientific reports.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"100 11","pages":"5293 - 5303"},"PeriodicalIF":10.9,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-026-04484-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thyroxin displacement from single and combined thyroid hormone binding proteins by various test substances","authors":"J. Brandt,&nbsp;E. Fabian,&nbsp;A. Aktalay-Hippchen,&nbsp;L. Jedermann,&nbsp;R. Landsiedel","doi":"10.1007/s00204-026-04400-4","DOIUrl":"10.1007/s00204-026-04400-4","url":null,"abstract":"&lt;div&gt;&lt;p&gt;The thyroid hormone system regulates physiological processes that are crucial for growth and metabolism. The homeostasis of thyroid hormones can be affected by test substances via multiple molecular interactions, one of them being the displacement of thyroid hormones from their binding proteins. The main thyroid hormone in the human bloodstream is L-thyroxine (T4), ≥ 99.5% of which is transported bound to three proteins: thyroxine binding globulin (TBG), transthyretin (TTR) and human serum albumin (HSA). To investigate the interactions of xenobiotics with the binding of T4 to these proteins, an in vitro thyroid hormone protein binding assay (THPB-assay) was developed. Samples containing 100 nM T4 were incubated with a T4-binding protein and increasing concentrations of a test compound, followed by removal of the unbound T4 via size exclusion chromatography and analysis of protein-bound T4. This assay allows for multiple adjustable parameters, including the choice of binding protein and the detection method for protein-bound T4, which can be extracted and measured via LC-MS or, when using &lt;sup&gt;125&lt;/sup&gt;I-T4, by a gamma counting. Eight test substances were tested for the displacement of T4 from TTR and TBG respectively. For interference with T4-TTR binding, Tetrabromobisphenol A was established as a positive control with an average measured IC&lt;sub&gt;50&lt;/sub&gt; of 287 nM. Displacement of T4 was observed for five more test substances, which displaced T4 from TTR with IC&lt;sub&gt;50&lt;/sub&gt; ranging from 101 nM for Tetrac and 121 nM for 2,4,6-tribromophenol (TBP) to 1056 nM for Genistein. 6-propylthiouracil and L-DOPA did not displace T4 from TTR. LC-MS analysis and gamma counting of &lt;sup&gt;125&lt;/sup&gt;I-T4 yielded similar results for each test substance. The five test substances which displaced T4 from TTR were additionally tested for displacement of T4 from TBG. Tetrac and Benziodarone displaced T4 with IC&lt;sub&gt;50&lt;/sub&gt; values of 3 µM and 22 µM, respectively, whereas the remaining compounds did not. Finally, a mix of TTR, TBG and HSA, in concentrations of 536 nM, 26.5 nM and 65.35 µM respectively, was tested with the potent T4 displacer Tetrac. Tetrac displaced T4 from this protein mix with an IC&lt;sub&gt;50&lt;/sub&gt; of 154 µM. Using the radioligand detection method, the T4 displacement of compounds from human and rat serum was tested to elucidate their effect in a physiological environment and identify potential species differences. Tetrac displaced T4 from human and rat serum at 10% serum concentration in samples, with IC&lt;sub&gt;50&lt;/sub&gt; values of 38 µM and 242 µM respectively. TBP displaced T4 from 10% rat serum with an IC&lt;sub&gt;50&lt;/sub&gt; of 1.3 mM. No displacement was observed in 10% human serum. At higher serum concentrations, no test substance was measured to displace T4 regardless of the species. While further research is essential, the insights regarding the absence of displacement at physiological serum concentrations challenge current risk assessment frameworks, ","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"100 11","pages":"5123 - 5133"},"PeriodicalIF":10.9,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-026-04400-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Species, cell proliferation state and oxygen partial pressure are major factors in the in vitro toxicity of repurposed potential ADPKD drugs in human and murine renal proximal tubule cells","authors":"Paraskevi Sotiropoulou,&nbsp;Andrea Gerdemann,&nbsp;Stefan Jovanovic,&nbsp;Hans-Ulrich Humpf,&nbsp;Alexander Bürkle,&nbsp;Daniel R. Dietrich","doi":"10.1007/s00204-026-04472-2","DOIUrl":"10.1007/s00204-026-04472-2","url":null,"abstract":"<div><p>Unexpected nephrotoxicity during clinical stages of drug development, due to undetected toxicity in in vitro and in vivo settings, can lead to drug attrition and jeopardize drug development. The latter highlights the importance of in vitro renal toxicity testing that can safely be translated to humans. Two factors commonly overlooked in the latter are the continuous cell proliferation that occurs in regeneration processes after renal insult and the physiological O₂ tension in the kidney. Autosomal Dominant Polycystic Kidney Disease is a genetic disorder characterized by the development of renal cysts and cellular changes, i.e. abnormal proliferation in conjunction with the Warburg effect. There is only one drug approved for the disease, tolvaptan, which, however, presents with liver toxicity and polyuria. In a quest for potential alternatives to tolvaptan, we compared the nephrotoxic and metabolic effects of four repurposed drugs, salicylic acid (up to 10 mM), birinapant (up to 100 µM), bardoxolone methyl (up to 1000 nM), and rapamycin (up to 160 nM) to tolvaptan (up to 100 µM) on human differentiated and proliferating (RPTEC/TERT1) and mouse proliferating (mProx24) renal proximal tubular epithelial cells at atmospheric (21%) and physiological (10%) O₂ tensions. The focus was on improved interpretation of in vitro test results for the detection of potential adverse effects. We found that cell proliferation and O₂ tension are major factors that determine the susceptibility of cells to compounds, while the drug effects on the metabolism and mitochondrial function provided further insight into the mechanisms underlying the observed in vitro toxicity.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"100 11","pages":"5225 - 5245"},"PeriodicalIF":10.9,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-026-04472-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deficient arsenic methylation and global proteomic reprogramming in human keratinocytes during arsenic-induced skin carcinogenesis","authors":"Alexandra N. Nail,&nbsp;Mayukh Banerjee,&nbsp;Manting Xu,&nbsp;Caitlin H. Reynolds,&nbsp;Miroslav Stýblo,&nbsp;Peter H. Cable,&nbsp;Daniel W. Wilkey,&nbsp;Michael L. Merchant,&nbsp;Ana P. Ferragut Cardoso,&nbsp;Shelia D. Thomas,&nbsp;J. Christopher States","doi":"10.1007/s00204-026-04478-w","DOIUrl":"10.1007/s00204-026-04478-w","url":null,"abstract":"<div><p>Chronic inorganic arsenic (iAs) exposure affects &gt; 220 million people worldwide and skin cancer is a hallmark of long-term iAs exposure. Limited information exists regarding arsenic methylation by human keratinocytes and how methylation influences skin carcinogenesis. Inorganic arsenite (iAs^III) and its methylated metabolites disrupt diverse zinc finger proteins, leading to differential toxicity patterns. We examined arsenic methylation capacity in non-malignant human keratinocytes and interrogated proteomic remodeling across three stages of iAs^III induced malignant transformation using the well-established preclinical HaCaT model. Arsenic methylation was assessed by hydride generation cryotrapping inductively coupled-mass spectrometry and global proteomic changes were analyzed by tandem-mass tagging liquid chromatography-tandem mass spectrometry. Primary, hTERT-immortalized and HaCaT human keratinocytes exhibited negligible arsenic methylation, with iAs^III comprising at least 98.5% of total intracellular arsenic, attributable to minimal expression of arsenite methyltransferase. Proteomic profiling identified over 275 differentially expressed proteins at each stage of transformation, including multiple zinc finger proteins implicated in cell cycle control, RNA metabolism, and genome stability. Ingenuity® Pathway Analysis revealed progressive, coordinated disruption of cancer-associated pathways and regulatory networks over the transformation timeline, including zinc-coordinating upstream regulators that may explain widespread pathway dysregulation. Collectively, our findings suggest that iAs^III promotes skin carcinogenesis by disrupting C3H1- and C4-type zinc finger protein-centered regulatory networks that coordinate cancer-associated signaling and metabolic pathways in human keratinocytes, highlighting key candidates for future mechanistic studies.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"100 11","pages":"5053 - 5070"},"PeriodicalIF":10.9,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13546112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PBK modelling of phthalates and their metabolites and the application in next generation risk assessment","authors":"Miaoying Shi,&nbsp;Ans Punt,&nbsp;Gopal Pawar,&nbsp;Shuo Yang,&nbsp;Hui Yang,&nbsp;Xudong Jia,&nbsp;Dawei Tang","doi":"10.1007/s00204-026-04487-9","DOIUrl":"10.1007/s00204-026-04487-9","url":null,"abstract":"<div><p>Next generation risk assessment (NGRA) has substantially contributed to development of animal-free chemical risk assessment by integrating new approach methodologies. The present study aimed to further expand the applicability of NGRA to compounds with bioactive metabolites, using dibutyl phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP) as case studies. Physiologically based kinetic (PBK) models were developed for DBP, DEHP and their primary metabolites mono-butyl phthalate and mono-(2-ethylhexyl) phthalate by using in silico and in vitro-derived parameters, including measured metabolic clearance obtained by performing in vitro liver microsomal incubations. Models were evaluated against observed kinetic data and used to predict plasma maximum concentrations (C_max) from external exposure scenarios, which were further compared with ToxCast-derived points of departure (PoDs) to calculate bioactivity-exposure ratios (BERs) for risk classification. Results showed that the in <i>silico</i>-in vitro based PBK models accurately predicted plasma kinetics for the metabolites within 2-fold difference. Predicted C_max values for parent compounds across all exposure scenarios were much lower than minimal PoDs, resulting in BERs higher than 20,000. When metabolites were considered, BERs decreased markedly with the lowest value of 8.1, highlighting the importance of accounting for metabolites for phthalates. Our study provides a proof-of-principle for incorporating metabolites into PBK modelling and corresponding NGRA, enhancing its applicability to chemicals with bioactive metabolites.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"100 11","pages":"5027 - 5041"},"PeriodicalIF":10.9,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-026-04487-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: The potent human CAR activator CITCO is a non-genotoxic hepatic tumour-promoting agent in humanised constitutive androstane receptor mice but not in wild-type animals","authors":"C. J. Henderson,&nbsp;A. W. McLaren,&nbsp;A. K. MacLeod,&nbsp;D. Lin,&nbsp;A. R. Cameron,&nbsp;L. R. Chatham,&nbsp;J. Moggs,&nbsp;F. Inesta‑Vaquera,&nbsp;John P. Thomson,&nbsp;Richard R. Meehan,&nbsp;P. Chakravarty,&nbsp;M. Schwarz,&nbsp;C. Roland Wolf","doi":"10.1007/s00204-026-04463-3","DOIUrl":"10.1007/s00204-026-04463-3","url":null,"abstract":"","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"100 11","pages":"5329 - 5330"},"PeriodicalIF":10.9,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-026-04463-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic responses to repeated exposure of human C3A liver spheroids to polystyrene nanoplastics","authors":"Kyriaki Xiftou,&nbsp;Jian Jiang,&nbsp;Florian Caiment,&nbsp;Theo M. de Kok,&nbsp;Mathieu Vinken,&nbsp;Julen Sanz-Serrano,&nbsp;Andres Tabernilla","doi":"10.1007/s00204-026-04473-1","DOIUrl":"10.1007/s00204-026-04473-1","url":null,"abstract":"<div><p>Increasing evidence of nanoplastics (NPs) accumulation in the human liver has raised concerns regarding their potential hepatotoxicity. However, current knowledge is largely derived from animal studies or simplistic in vitro models, often with unrealistic exposure scenarios, thereby constraining their relevance to human health. Human liver spheroids have emerged as relevant tools for long-term mechanistic toxicological studies, yet their application to the hepatotoxicity assessment of NPs remains limited. This study aimed to establish and characterize a human liver C3A spheroid model to explore the effects of repeated exposure to polystyrene (PS) NPs for up to 21 days at concentrations informed by real-life human intake and internal exposure estimates, namely 0.0068, 0.068, and 1.6 µg/mL. Throughout the 21-day culture period, the human liver spheroids preserved stable morphology, overall viability, low levels of cell death, and stable expression of hepatic-associated genes. PS NPs accumulated within the human liver spheroids in a concentration-dependent and spatially heterogeneous manner, but did not induce detectable changes in spheroid size, viability, or cell death across all concentrations and time points measured. Transcriptomic profiling revealed subtle, concentration-dependent gene expression changes, which were most pronounced at day 3 and attenuated over time. Although limited in magnitude, these changes involved genes and pathways related to liver lipid and bile acid homeostasis, stress signaling, and detoxification. Collectively, these findings indicate that human-relevant concentrations of PS NPs do not induce overt hepatotoxic effects, while potentially modulating molecular pathways implicated in cellular processes essential for normal liver function.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"100 10","pages":"4509 - 4528"},"PeriodicalIF":10.9,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337686","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":"Structure–activity relationship of synthetic cathinones: integrated in silico, in vitro, and in vivo studies of α-PiHP analogues","authors":"Martalu D. Pazos,&nbsp;Guillermo García-Díez,&nbsp;David Pubill,&nbsp;Xavier Berzosa,&nbsp;Roger Estrada-Tejedor,&nbsp;Jorge Camarasa,&nbsp;Elena Escubedo,&nbsp;Raúl López-Arnau,&nbsp;Núria Nadal-Gratacós","doi":"10.1007/s00204-026-04483-z","DOIUrl":"10.1007/s00204-026-04483-z","url":null,"abstract":"<div><p>Synthetic cathinones represent the main group of emerging psychostimulants consumed worldwide. Structural modifications of these compounds have led to pyrovalerones, potent dopamine transporter (DAT) inhibitors associated with high abuse liability. Among them, α-pyrrolidinoisohexanophenone (α-PiHP) became the most seized pyrovalerone in the European Union in 2023. Novel analogues have rapidly appeared, yet their neuropharmacological and toxicological properties remain unknown. This study aimed to characterize α-PiHP and five structurally related derivatives (3-Me-α-PiHP, 4-Me-α-PiHP, 3-F-α-PiHP, 4-F-α-PiHP, and MDPiHP). Monoamine transporter activity was evaluated using HEK293 cells expressing human norepinephrine (hNET), hDAT, or serotonin (hSERT) transporters through uptake inhibition and binding assays. Molecular docking was performed to model interactions at hDAT. Psychostimulant, thigmotactic, and rewarding effects were evaluated in male Swiss CD-1 mice using horizontal locomotor activity, open field, and conditioned place preference paradigms. Lethality after drug administration was also assessed. All compounds potently inhibited hDAT and hNET, while displaying limited activity at hSERT. This resulted in high hDAT/hSERT ratios indicative of a stimulant-like profile and elevated abuse liability, confirmed in vivo by pronounced psychostimulant and rewarding effects. All molecules interacted with the orthosteric binding site at hDAT and displayed higher binding affinity than cocaine in in vitro and in silico studies. <i>Meta</i>-substituted analogues showed greater hDAT affinity and behavioural responses than <i>para</i>-isomers. Notably, MDPiHP exhibited the highest potency and affinity, strongest psychostimulant effects and significant lethality. These findings demonstrate that minor structural modifications markedly influence pharmacological activity of pyrovalerone derivatives, highlighting the high abuse potential and health risks associated with emerging α-PiHP analogues.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"100 11","pages":"5165 - 5180"},"PeriodicalIF":10.9,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-026-04483-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Causality analysis of toxicological mechanisms in networked systems such as adverse outcome pathway networks","authors":"Thomas Hartung,&nbsp;Karolina Kopańska,&nbsp;Alexandra Maertens,&nbsp;Paul Whaley,&nbsp;Sebastian Hoffmann","doi":"10.1007/s00204-026-04386-z","DOIUrl":"10.1007/s00204-026-04386-z","url":null,"abstract":"<div><p>This paper examines why robust causality assessment is central to toxicology yet increasingly difficult in networked biological systems, including Adverse Outcome Pathway (AOP) networks and multi-omics datasets. Classical causal frameworks (e.g., Koch/Dale reasoning and Bradford Hill-type considerations) remain useful for scoping, but they offer limited operational guidance for multifactorial, nonlinear, and feedback-dominated mechanisms. We therefore synthesize a modern toolbox for causality analysis in toxicology spanning directed acyclic graphs for explicit causal assumptions, quantitative and probabilistic approaches for integrating evidence across key events, and network/<i>dynamical</i> methods that help identify influential hubs and points of vulnerability in AOP networks. Building on evidence-based toxicology, we propose an operational workflow that links (i) structured scoping and model specification, (ii) protocolized evidence retrieval across in vivo, in vitro, in silico and human data streams, (iii) risk-of-bias appraisal and quantitative synthesis of effect sizes and dose–response, (iv) mechanistic integration and targeted perturbation assays, and (v) translation via dual-strand certainty rating (mechanistic vs difference-making evidence) and Evidence-to-Decision tables. We discuss how explainable AI can support scalable integration and transparency. A worked developmental neurotoxicity example illustrates how this pipeline can support regulatory recommendations while explicitly documenting uncertainty.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"100 11","pages":"4809 - 4834"},"PeriodicalIF":10.9,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-026-04386-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}