Archives of Toxicology最新文献

{"title":"Proteomic characterization and lethality of the venom of the Black Judean scorpion, Hottentotta judaicus (Buthidae): expanded toxin diversity and revisited toxicological significance.","authors":"Adolfo Borges, Bruno Lomonte, Antonieta Rojas de Arias, Julián Fernández","doi":"10.1007/s00204-025-04186-x","DOIUrl":"https://doi.org/10.1007/s00204-025-04186-x","url":null,"abstract":"<p><p>The scorpion Hottentotta judaicus inhabits the Levant region of the Middle East, including Lebanon, Jordan, Palestine, and Israel. While previous research focused on its insecticidal properties and sodium-channel-targeting toxins, its venom remains largely unexplored using modern proteomic approaches. We analyzed the venom composition of H. judaicus from Lebanese specimens using nESI-MS/MS, MALDI-TOF MS, SDS-PAGE, and RP-HPLC. Venom lethality in mice was assessed (LD₅₀ = 11.87 [6.59-17.16] mg/kg, i.p.), confirming moderate toxicity to vertebrates. RP-HPLC on C₁₈ resolved 37 peaks, with 25 eluting between 20-40% acetonitrile. Reducing SDS-PAGE revealed predominant components < 10 kDa and minor bands at 31, 46, and 77 kDa. MaLDI-TOF MS detected 20 components from 1,000-12,000 m/z. A bottom-up shotgun nLC-MS/MS approach, following in-gel tryptic digestion of venom, identified 55 components across 15 protein families. Ion channel-active toxins [K⁺ (7), Na⁺ (16), Cl⁻ (1), ryanodine receptor (1)] and enzyme components (17) were predominant. This study provides proteomic evidence of H. judaicus venom components previously only identified at the transcriptomic level and reveals a richer venom profile than anticipated. Novel identified components include alternative β-subunits of lipolysis-activating proteins, as well as homologs of Olivierus martensii antimicrobial peptide inhibitor HAP-1, Leiurus hebraeus Lqhβ1, Parabuthus transvaalicus Birtoxin, and peptide Hj2a from Hottentotta jayakari exhibiting dual α/β-toxin activity on Nav1.1 channels. This expanding repertoire of potential bioactive components prompts a reevaluation of the pathophysiological consequences of H. judaicus envenomation in humans and further exploration of their potential biomedical applications.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028868","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":"Exploring experiences of the regulatory toxicology system: system-level promoters and inhibitors of new approach methodologies.","authors":"Angela Bearth, Birgit Kopainsky, Lowenna B Jones, Gunn E Vist, Trine Husøy, Camilla Svendsen, Paul Whaley, Sebastian Hoffmann, Heather M Ames, Gisle Solstad, Denise Bloch, Aleksandra Čavoški, Weihsueh A Chiu, Miles Davenport, Holly G Davies, Arianna Giusti, Thomas Hartung, Seok Kwon, Olivia J Osborne, Andrew A Rooney, Christophe Rousselle, Jennifer B Sass, Fred A Wright, Gro H Mathisen","doi":"10.1007/s00204-025-04168-z","DOIUrl":"https://doi.org/10.1007/s00204-025-04168-z","url":null,"abstract":"<p><p>The transition from traditional animal-based approaches and assessments to New Approach Methodologies (NAMs) marks a scientific revolution in regulatory toxicology, with the potential of enhancing human and environmental protection. However, implementing the effective use of NAMs in regulatory toxicology has proven to be challenging, and so far, efforts to facilitate this change frequently focus on singular technical, psychological or economic inhibitors. This article takes a system-thinking approach to these challenges, a holistic framework for describing interactive relationships between the components of a system of interest. In this case, the regulatory toxicology system. We do so by analysing and interpreting a very large qualitative data set of experts' observations, collected in a 3-day interactive workshop and three follow-up online workshops with a heterogeneous sample of experts representing major actors from the global regulatory toxicology system. We identified leverage points (where a small change within a system can have a disproportionately large effect) in the six core aspects-infrastructure, processes, culture, technology, goals, and actors-in the regulatory toxicology system to facilitate the effective use of NAMs. Identified systematic leverage points include the need for a functioning incentive structure for effectively discovering, developing, validating and using NAMs within academia, regulation, and industry; and measures that prevent or mitigate unwanted effects of using NAMs that acknowledge clashes between scientific, regulatory, political and social processes. The results serve as a basis for follow-up activities that reflect on the actual effectiveness of these levers and that develop measures for the regulatory toxicology system.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028866","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":"Immunomodulatory effects of the herbicide glyphosate following occupational exposure.","authors":"Ambra Maddalon, Valentina Galbiati, Melissa Ferrian, Giuseppe Mastrangelo, Simone Meroni, Laura Dioni, Stefan Mandić-Rajčević, Claudio Colosio, Emanuela Corsini, Stefano Porru","doi":"10.1007/s00204-025-04156-3","DOIUrl":"https://doi.org/10.1007/s00204-025-04156-3","url":null,"abstract":"<p><p>Glyphosate, a widely used herbicide, has raised concerns regarding its impact on human health and the environment due to its widespread and excessive use. Adverse effects on the immune system have been reported. In this study, 26 vineyard workers in Veneto vineyards were examined before and after glyphosate applications to investigate possible immune parameter changes. Glyphosate exposure led to alterations in plasma cytokine levels, including marked increases in IL-4 and IL-5, a modest rise in IFN-γ, and a decrease in IL-8. No changes in plasma IL-12/23p40, IL17 and IL-33 were found. The IFN-γ/IL-4 ratio decreased, accompanied by changes in T cell subpopulations. Notably, a decrease in the T helper 1/T helper 2 cell ratio, attributed to reduced Th1 cells and increased Th2 cells, was observed, aligning with the elevated Th2 cytokines. A reduction in plasmatic extracellular vesicular miR-500a levels following glyphosate exposure was found, potentially contributing to the immunological findings. A slight decrease in plasma lipopolysaccharide levels in exposed workers excluded systemic inflammation from increased intestinal permeability but hinted at a possible association with glyphosate-induced microbiota dysbiosis. Since the shikimate pathway, targeted by glyphosate, is also present in Gram-negative bacteria. Overall, these findings suggest that glyphosate can affect the immune system, favoring Th2 responses. While more research is needed to establish causality with the association of glyphosate exposure with the development of allergic reactions in susceptible individuals, our results shed light on potential underlying mechanisms.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022757","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":"News and views: lysine sorbylation enters the expanding universe of posttranslational modifications.","authors":"Ramy Ashry, Oliver H Krämer","doi":"10.1007/s00204-025-04187-w","DOIUrl":"https://doi.org/10.1007/s00204-025-04187-w","url":null,"abstract":"<p><p>Opinion Letter to Sin et al (Science Advances, 2025), Sorbate induces lysine sorbylation through noncanonical activities of class I HDACs to regulate the expression of inflammation genes.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022754","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":"Interplay of oxidative stress and antioxidant mechanisms in cancer development and progression.","authors":"Klaudia Jomova, Suliman Y Alomar, Richard Valko, Lukas Fresser, Eugenie Nepovimova, Kamil Kuca, Marian Valko","doi":"10.1007/s00204-025-04146-5","DOIUrl":"https://doi.org/10.1007/s00204-025-04146-5","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Cellular systems responsible for the formation and removal of reactive oxygen species (ROS), functioning within physiological limits, are essential for maintaining intracellular redox balance. This state is known as oxidative eustress. Key redox signaling molecules, such as superoxide anion radical (O&lt;sub&gt;2&lt;/sub&gt;&lt;sup&gt;•-&lt;/sup&gt;) and hydrogen peroxide (H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt;), operate at nanomolar concentrations and are produced by NADPH oxidases (regulated by various factors), the mitochondrial electron transport chain (ETC), and numerous enzymes. In addition, cell signaling is influenced by nitric oxide (NO&lt;sup&gt;•&lt;/sup&gt;) and reactive lipid species. Disruption of ROS signaling can lead to oxidative stress, a harmful condition associated with many chronic diseases, including cancer. The dual nature of ROS is evident in premalignant and malignant cells at all stages of tumor development, including proliferation, migration/invasion, angiogenesis, inflammation, immune evasion, and metastasis. ROS can promote tumor formation by regulating immune cells, mitochondrial metabolism, DNA methylation, DNA damage [such as the DNA oxidation product, 8-oxo-dG, resulting from hydroxyl radical (&lt;sup&gt;•&lt;/sup&gt;OH) attack], and other mechanisms. The tumor-promoting activity mediated by H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; manifests through the promotion of epithelial-to-mesenchymal transition (EMT) and the formation of the tumor microenvironment (TME) by tumor-associated macrophages. While ROS are vital for tumor initiation and growth, their excessive production can also have anticancer effects by inducing senescence, apoptosis, or necrosis. ROS-related anticancer mechanisms include mitochondrial dysfunction, p53-dependent apoptosis, iron-dependent ferroptosis, activation of endoplasmic reticulum stress, inhibition of growth signaling pathways (such as the epidermal growth factor pathway, EGF), among others. Tumor cells employ a range of adaptive mechanisms to effectively maintain ROS levels within a dynamic range that promotes proliferation while preventing cell death. This regulation is achieved by fine-tuning the effects of antioxidants throughout all stages of cancer. During early tumor development, characterized by increased oncogene-induced oxidative stress, cancer cells depend on glutathione (GSH) and upregulated antioxidant gene expression controlled by nuclear factor erythroid 2-related factor 2 (NRF2) to maintain redox balance. The opposing roles of certain antioxidant enzymes, such as Mn-SOD (SOD2), illustrate the same duality as ROS, acting as potential tumor suppressors during early carcinogenesis and as tumor promoters during metastasis. Low-molecular-weight antioxidants such as vitamins C (ascorbate) and E (tocopherols), carotenoids (e.g., lycopene, β-carotene), flavonoids (e.g., quercetin), and isoflavones demonstrate effective antioxidant activity in vitro, but their anticancer effects in clinical settings remain unproven. Understanding the influence of ","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991535","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 metabolic profiling and structure-metabolism relationships of substituted acetyl fentanyl-type new psychoactive substances.","authors":"Xuan Luo, Qian Li, Kejian Huang, Xiaofeng Liu, Ning Yang, Qiulian Luo","doi":"10.1007/s00204-025-04179-w","DOIUrl":"10.1007/s00204-025-04179-w","url":null,"abstract":"<p><p>The abuse of fentanyl-type new psychoactive substances (F-NPS), which exhibit the four defining characteristics of new psychoactive substances (third-generation drugs), poses a severe threat to social stability and public health. The derivatization strategy investigated in this study, involving six substituted acetyl F-NPS across two substitution patterns, represents the primary approach for generating a new F-NPS. Using an in vitro human liver microsome metabolic model coupled with liquid chromatography-ion trap tandem time-of-flight mass spectrometry, we identified characteristic metabolism profiles of F-NPS corresponding to derivatization modifications while elucidating the structural effects on metabolism. This study revealed that, first, metabolism via amide hydrolysis was affected by concurrent hydrolysis at adjacent positions, rather than being solely determined by carbonyl carbon electrophilicity. Second, metabolism via N-oxidation and N-dealkylation shared a common initial intermediate, with the latter being triggered by α-hydroxylation of the phenethyl group. Third, metabolism via N-oxidation exhibited reduced susceptibility to structural changes owing to the contradictory bond orientations of the substituents on the piperidine ring between the parent drug and its N-oxide metabolite. Fourth, stable geminal diol metabolites were identified in the substituted acetyl F-NPS metabolites via mass spectrometric fragmentation. This research deepens the understanding of structure-metabolism relationships among F-NPS, providing critical foundational data for developing predictive metabolisms for emerging F-NPS and offering scientific support for drug abuse surveillance and prevention strategies.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940370","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":"Effects of an environmentally relevant mixture of organophosphate esters on the phenotype and function of HepG2 liver cells.","authors":"Dongwei Yu, Barbara F Hales, Bernard Robaire","doi":"10.1007/s00204-025-04173-2","DOIUrl":"https://doi.org/10.1007/s00204-025-04173-2","url":null,"abstract":"<p><p>Organophosphate esters (OPEs), commonly used as flame retardants and plasticizers, are ubiquitous environmental contaminants, with high concentrations found in indoor house dust. Previously, we have reported that individual OPEs have adverse effects on HepG2 liver cells. However, real-world exposure involves mixtures of OPEs. In this study, we investigated the effects of an environmentally relevant mixture of OPEs, detected in Canadian house dust, on HepG2 cell phenotype and function. Using high-content imaging, we found that this mixture increased cytotoxicity and lipid droplet size, while lysosomes were the most effected endpoint. We used the DQ-BSA degradation assay to assess the function of lysosomes and confocal microscopy to confirm the status of lysosomal transcription factor EB (TFEB). We then tested lysosomal enzyme activities to determine potential downstream effects. OPE mixture induced concentration-dependent increases in the degradation capacity of lysosomes and elevated nuclear translocation of TFEB when compared to controls. Increased activities of downstream lysosomal acid lipase (LAL) and cathepsin B (CTSB) validated the activation of TFEB and its downstream effect of lysosome biogenesis. Together, these data demonstrate that exposure to an environmentally relevant OPE mixture adversely affects liver cell survival, phenotype, and lysosome functions, providing potential mechanistic insight into consequences of OPE exposure and increased risk of liver damage associated with disrupted lipid and lysosome homeostasis. This study also highlights the importance of evaluating real-world chemical exposures as mixtures rather than as individual compounds.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940326","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":"Associations between environmental phthalates exposure and maternal thyroid hormone levels during pregnancy.","authors":"Lin Tao, Shimin Xiong, Lulu Dai, Dengqing Liao, Yuan-Zhong Zhou, Xubo Shen","doi":"10.1007/s00204-025-04172-3","DOIUrl":"https://doi.org/10.1007/s00204-025-04172-3","url":null,"abstract":"<p><p>Phthalates (PAEs) are well-recognized endocrine-disrupting compounds. Despite their established status as such, the association between maternal exposure to PAEs during pregnancy and the levels of maternal thyroid hormones remains a subject of considerable debate. To shed light on this contentious issue, we conducted an investigation involving 1,156 pregnant women from the Zunyi birth cohort. The aim was to elucidate the relationship between urinary metabolites of PAEs and serum thyroid hormones during the gestational period. In this study, we employed a linear mixed-effects model (LMM) to assess the correlation between PAE metabolites and thyroid hormones. Additionally, restricted cubic spline (RCS) analysis was utilized to explore the dose-response relationship between these PAE metabolites and thyroid hormones. Furthermore, Bayesian kernel machine regression (BKMR) was applied to determine the potential overall effects and to uncover any non-linear relationships that might exist. Our results revealed that several PAE metabolites, namely, monomethyl phthalate (MMP), mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-isobutyl phthalate (MIBP), mono(2-ethyl-5-oxohexyl) phthalate (MOP), and monobenzyl phthalate (MBZP), were associated with correlations involving total thyroxine (TT4), free triiodothyronine (FT3), and free thyroxine (FT4). Subsequently, the restricted cubic spline (RCS) analyses demonstrated a clear dose-response relationship between the PAE metabolites and maternal thyroid hormones, with MEHP, MBZP, MIBP, and MBZP emerging as the major contributors to this relationship. Finally, the BKMR model indicated a non-linear relationship, specifically an inverted U-shaped relationship, between maternal exposure to PAEs during pregnancy and the levels of TT4, FT3, and FT4. Collectively, our findings strongly suggest that exposure to PAEs during pregnancy has a detrimental impact on the secretion of maternal thyroid hormones. To safeguard the health of both the mother and the fetus, it is advisable to minimize exposure to phthalates during pregnancy and to monitor any alterations in thyroid hormone levels closely.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940314","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":"The deglycosylated metabolite of 2,3,5,4'-tetrahydroxystilbene-2-O-β-D- glucoside contributes to immune-mediated hepatotoxicity induced by Polygonum multiflorum.","authors":"Ying Li, Yuwei Hu, Xiaoli Meng, Paul Thomson, Dongsheng Ouyang, Dean Naisbitt, Tai Rao","doi":"10.1007/s00204-025-04171-4","DOIUrl":"https://doi.org/10.1007/s00204-025-04171-4","url":null,"abstract":"<p><p>Polygonum multiflorum (PM) has been reported to cause immune-mediated idiosyncratic liver injury. 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (THSG) has been identified as a hepatotoxic constituent responsible for PM-induced hepatotoxicity. Covalent protein modification by reactive metabolites plays a crucial role in herb and drug-induced liver injury. Whether it is essential for the hepatotoxicity of THSG needs further clarification. THSG can be hydrolyzed into its aglycone 2,3,5,4'-tetrahydroxystilbene (THS). This study aims to investigate the impact of THS on liver injury and elucidate its underlying mechanism. Metabolism of THSG and covalent modification of cysteine residues by THS were identified by mass spectrometry and proteomics. Hepatotoxicity and T-cell immune response induced by THS were evaluated in vitro and in vivo. The immunological mechanism was investigated using PBMC from healthy donors. THS was detected in both the liver and blood samples after oral administration of THSG to mice. Cysteine-based covalent modification of glutathione (GSH), glutathione S-transferase Pi (GSTP) and hepatic proteins by THS was identified. Liver injury accompanied by inflammatory cell infiltration and T-cell activation were observed in vivo and in vitro with THS treatment. PBMCs from healthy donors and drug-specific T-cell clones (TCCs) could be activated by THS possibly through the hapten pathway. THS, the deglycosylated metabolite of THSG, functions as a hapten by covalently binding to proteins to induce cellular stress and activate T-cells, which may contribute to PM-induced hepatotoxicity.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940310","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":"Revolutionizing toxicological risk assessment: integrative advances in new approach methodologies (NAMs) and precision toxicology.","authors":"Qiu-Shuang Sheng, Bin Liu, Xiao Wang, Lei Hua, Shou-Cheng Zhao, Xiao-Zhong Sun, Mu-Yang Li, Xiang-Yu Zhang, Jia-Xu Wang, Pei-Li Hu","doi":"10.1007/s00204-025-04169-y","DOIUrl":"https://doi.org/10.1007/s00204-025-04169-y","url":null,"abstract":"<p><p>Traditional toxicological paradigms, reliant on animal testing and simplistic in vitro models, face significant limitations, including prolonged timelines, high costs, and poor translational predictability due to interspecies differences. This review highlights the transformative potential of New Approach Methodologies (NAMs) in overcoming these challenges. Key advancements include Organ-on-a-Chip (OoC) platforms that emulate human organ physiology and multi-organ crosstalk, significantly improving predictive accuracy. Integration of multi-omics technologies (genomics, proteomics, metabolomics) provides unprecedented mechanistic insights into toxicity pathways. Computational toxicology, leveraging machine learning and QSAR modeling, enables high-throughput hazard prioritization and risk prediction. While NAMs offer human-relevant, efficient alternatives for chemical safety evaluation, critical bottlenecks remain. These involve insufficient physiological complexity in current in vitro models, interpretability limitations of AI-driven approaches, challenges in quantifying mixture toxicity and low-dose effects, and a lag in regulatory adoption. Emerging strategies like probabilistic risk assessment, AI-driven exposomics, and tiered testing paradigms hold promise for addressing chemical mixture risks and personalized exposures. Future progress requires interdisciplinary collaboration to refine microphysiological systems, harmonize regulatory frameworks with scientific innovation, and establish open-access data repositories, paving the way for precision toxicology and sustainable chemical risk management.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940399","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}