Frontiers in toxicology最新文献

{"title":"Comparative evaluation of enzymatic, acidic, and alkaline digestion protocols for organic matrix removal from lyophilized and frozen mussel samples (<i>Mytilus galloprovincialis</i>).","authors":"S Turmanova, Y Hristov, D Kiryakova, E Ivanova, P Atanasova, G Kolchakova, A Ilieva, E Mollova, A Dimitrov, N Todorov, G Grigorova","doi":"10.3389/ftox.2026.1808944","DOIUrl":"10.3389/ftox.2026.1808944","url":null,"abstract":"<p><p>Efficient removal of organic matter from biological matrices is a critical step in the analysis of microplastics in marine organisms. In this study, enzymatic (Kreon®25,000), acidic (HNO₃ + H₂O₂), and alkaline (KOH + H₂O₂) digestion protocols were comparatively evaluated for the treatment of lyophilized and frozen <i>Mytilus galloprovincialis</i> samples. Digestion efficiency was assessed gravimetrically, while the effects of the protocols on polymer integrity were examined using ATR-FTIR, HQI analysis, and microscopic observations on representative polymers (HDPE, PA, PET, PVC). All three methods demonstrated high digestion efficiencies (>96%). Acidic digestion provided rapid and stable removal of organic matter within 20 min, whereas enzymatic digestion required longer incubation times (2-24 h) but exerted the least impact on polymer integrity. Frozen samples consistently showed slightly higher digestion efficiencies compared to lyophilized ones, likely due to preserved tissue hydration facilitating reagent penetration. Microscopic and spectroscopic analyses revealed that HDPE and PET maintained their structural and chemical integrity under all treatments, whereas PA and PVC exhibited surface alterations after acidic digestion. Enzymatic and alkaline protocols did not produce visible or spectral changes in any polymer type. Based on these findings, the enzymatic protocol was selected for recovery experiments. Mass-corrected recovery values ranged from 92.87% to 95.36% for PA, PET, and PVC, and 75.69% for HDPE, indicating that the method allows effective isolation of most polymers while preserving their integrity. The results demonstrate that although all digestion methods are efficient in removing organic matter, enzymatic digestion provides the most reliable approach for microplastic analysis in <i>Mytilus galloprovincialis</i>, ensuring both high digestion efficiency and preservation of polymer characteristics.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1808944"},"PeriodicalIF":5.1,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13124124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147790965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From beauty to burden: mapping the health and psychosocial impacts of fragrances and cosmetic products use in the UAE.","authors":"Sharifa AlBlooshi, Mariam Al Ali, Dana N Abdelrahim, Suheir Awadalla","doi":"10.3389/ftox.2026.1758512","DOIUrl":"10.3389/ftox.2026.1758512","url":null,"abstract":"<p><strong>Background: </strong>The dynamic beauty care sector in the Middle East is on an upward trend in the UAE; however, concerns persist about the side effects of this industry, attributed to chemical exposure, which is believed to contribute to skin problems and other health issues. In the UAE, there is a lack of data on consumer usage, awareness, and the health effects associated with it.</p><p><strong>Methods: </strong>This study presents the results of an online survey administered to 461 female subjects in the United Arab Emirates as part of a cross-sectional study. The survey consisted of 55 questions on product use, knowledge, attitudes, safety measures, and potential adverse health effects. Descriptive statistics and logistic regression analysis were applied to identify predictors of adverse reactions.</p><p><strong>Results: </strong>Among the 461 participants, most were aged 18-29 years (55.7%) and university educated (68.3%). The application of scent and makeup was almost widespread, as 91.5% of users applied scented products daily, and 100% of users mentioned cosmetics, 36.4% of respondents reported health problems caused by the use of these products, with the most common issues being persistent respiratory problems (16.3%), headaches (15.8%), and skin irritation (11.9%). Knowledge of fragrance safety was moderate, with only 43.8% recognizing that fragrances contain complex chemical mixtures. The study demonstrated daily cosmetic use in 75.1% of individuals who frequently perform allergy tests, and limited safety practices in 6.7% of these individuals. While allergy testing was protective, logistic regression analysis revealed that younger age, higher education, a history of allergies, and frequent product use were predictors of adverse events. This has led to the association of widespread use of fragrances and cosmetics amongst women in the UAE with major respiratory and dermatological problems.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1758512"},"PeriodicalIF":5.1,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13124122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147790972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of polyvinyl chloride microplastics with different particle sizes on growth, physiology, and intestinal microbiota of <i>Macrobrachium rosenbergii</i>.","authors":"Qiaoyan Zhou, Yakun Wang, Jie Wei, Tianhui Jiao, Sikai Xu, Kunhao Hong, Yayi Huang, Zikang Tu, Yurong Zhang, Yongchun Huang, Lingyun Yu","doi":"10.3389/ftox.2026.1797231","DOIUrl":"10.3389/ftox.2026.1797231","url":null,"abstract":"<p><strong>Background: </strong>This study addresses a critical knowledge gap regarding the long-term, multi-size-dependent toxic effects of polyvinyl chloride microplastics (PVC-MPs) on economically important freshwater aquaculture species, specifically the giant freshwater prawn (Macrobrachium rosenbergii). Given the severe microplastic pollution in intensive aquaculture regions like China's Pearl River Delta, understanding these impacts is vital for ecological risk assessment and sustainable aquaculture.</p><p><strong>Methods: </strong>Post-larval M. rosenbergii were exposed to environmentally relevant concentrations (1 mg/L) of fluorescent PVC-MPs of three particle sizes (30, 60, 90 μm) for 28 days, followed by a 14-day recovery period in clean water. A comprehensive analysis was conducted, including assessments of growth and survival, microplastic accumulation, tissue ultrastructure and apoptosis, gene expression related to antioxidant defense, immunity, and growth, and intestinal microbiota composition.</p><p><strong>Results: </strong>Exposure to PVC-MPs significantly inhibited growth and reduced survival, with the 90 μm particles showing the strongest effect. MPs accumulated in gills and intestines within one day and entered the circulatory system. They caused significant ultrastructural damage and increased apoptosis in gills, intestines, and hepatopancreas. Molecular responses showed an initial upregulation followed by suppression of antioxidant and immune-related genes after long-term exposure. Gut microbiota analysis revealed dysbiosis, characterized by decreased Firmicutes and increased Proteobacteria. Recovery experiments indicated particle-size-dependent clearance: large (90 μm) MPs were completely eliminated within 14 days, while smaller particles (30, 60 μm) persisted in tissues.</p><p><strong>Conclusion: </strong>PVC-MPs impair M. rosenbergii growth through physical damage, oxidative stress, immune suppression, and gut microbiota dysbiosis, with toxicity and clearance efficiency being particle-size-dependent. These findings provide insights into the ecological risks of microplastics in aquaculture.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1797231"},"PeriodicalIF":5.1,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13105459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147790990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Organ-specific bioaccumulation and deterministic health risk assessment of selected heavy metal(loid)s in commercial fish from a southern harbor region (Nagapattinam).","authors":"Suryapratap Ray, Rahul Vashishth","doi":"10.3389/ftox.2026.1773891","DOIUrl":"10.3389/ftox.2026.1773891","url":null,"abstract":"<p><strong>Introduction: </strong>Heavy metal contamination of coastal waters results in bioaccumulation in fish, posing a significant route of human exposure via seafood consumption. The present study focuses on organ-specific metal distribution and associated health risk indices in three important fish species from the Nagapattinam coast, India.</p><p><strong>Methods: </strong>In the current study, three species of fish (<i>Nemipterus japonicus</i>, <i>Oreochromis mossambicus</i>, and <i>Lates calcarifer</i>) were considered with three biological replicates per species obtained from local fish markets of Nagapattinam, Tamil Nadu, India, during January-February 2024. The HM profiling was performed on three organs: liver, gills, and muscle tissues. HMs, including arsenic (As), cadmium (Cd), chromium (Cr), mercury (Hg), lead (Pb), strontium (Sr), and vanadium (V), were analyzed using inductively coupled plasma mass spectrometry (ICP-MS).</p><p><strong>Results: </strong>The concentrations were found to be in the range of 0.025-21.53 μg kg^-1. Upon non-carcinogenic risk assessment, the target hazard quotient (THQ) for all species was found to be <1 for both adults and children, indicating low non-carcinogenic risk associated with the consumption of the selected species under the assumed intake scenario. In contrast, the cancer risk (CR) value for chromium in <i>Nemipterus japonicus</i> was found to be elevated (children: 1643.58 × 10^-6 and adults: 939.19 × 10^-6), assuming a conservative worst-case exposure scenario in which total chromium is considered as Cr(VI), potentially inflating cancer risk estimates.</p><p><strong>Discussion: </strong>Overall, the findings suggest low non-carcinogenic risk under average consumption conditions; however, the estimated carcinogenic risk for chromium exceeded the commonly referenced acceptable threshold under conservative assumptions and should therefore be interpreted with caution. These results highlight the need for further investigation, particularly chromium speciation analysis, to refine risk estimates for fish consumed from the Nagapattinam marketplace.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1773891"},"PeriodicalIF":5.1,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13105457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147790988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protective effect of <i>Carica papaya</i> ethanolic leaf extract against lead-induced toxicity in Wistar rats.","authors":"Richard Haakonde, Golden Zyambo, Katendi Changula, Roy Mwenechanya, Kaampwe Mayovu Muzandu","doi":"10.3389/ftox.2026.1762172","DOIUrl":"10.3389/ftox.2026.1762172","url":null,"abstract":"<p><strong>Introduction: </strong>Lead poisoning remains a significant public health issue globally, with varied negative health outcomes, particularly in developing countries. Lead is a pervasive environmental pollutant that induces systemic toxicity, largely through oxidative stress resulting from its tissue bioaccumulation and disruption of normal physiological processes in a biological system. Plant-derived chelators and antioxidants may provide low-cost strategies to mitigate Pb-induced damage in both humans and animals. This study was aimed at evaluating the protective effect of <i>Carica papaya</i> leaf ethanolic extract against lead-induced toxicity in Wistar rats.</p><p><strong>Methods: </strong>The protective effect of <i>Carica papaya</i> leaf ethanolic extract was evaluated in Wistar rats exposed to Pb - acetate, 50 mg/kg body weight. Thirty animals were assigned to six groups (n = 5) and treated for 30 days with vehicle - double distilled water, Pb - acetate alone, or Pb - acetate in combination with <i>Carica papaya</i> leaf ethanolic extract (50, 100, 200 and 400 mg/kg body weight). Weekly changes in body weight were monitored across all exposure groups. Lead concentrations were then quantified in blood, liver, kidney, and bone tissues. Additionally, oxidative stress and lipid peroxidation were evaluated by measuring malondialdehyde levels in liver homogenates for all treatment groups.</p><p><strong>Results and discussion: </strong>Pb - acetate exposure led to significant Pb accumulation in blood, liver, kidney, and bone, as well as increased hepatic malondialdehyde levels (<i>p</i><0.05). Co-administration of the extract particularly at doses ≥100 mg/kg BW, showed significant corresponding reduction of Pb accumulation in blood, liver, and kidney, and liver malondialdehyde levels. This study provides preliminary indications that <i>Carica papaya</i> leaf ethanolic extract may provide protection against Pb-induced toxicity, likely through its flavonoid and phenolic chelation and antioxidant activities, coupled with Pb tissue deposition mitigation. These findings suggest Carica papaya leaf ethanolic extract could have potential, to be a low-cost phytotherapeutic candidate for managing Pb poisoning.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1762172"},"PeriodicalIF":5.1,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13105474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147790998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Towards learning and memory risk assessment with human brain organoids: barriers and opportunities.","authors":"Ronit Mohapatra, Dowlette-Mary Alam El Din, Hanyu Zhao, Thomas Hartung, Lena Smirnova","doi":"10.3389/ftox.2026.1783893","DOIUrl":"10.3389/ftox.2026.1783893","url":null,"abstract":"<p><p>Neurodevelopmental conditions, including autism spectrum disorder, intellectual disability, and learning disabilities, as well as neurodegenerative disorders, affect millions of people in the United States alone. Both genetic and environmental factors contribute to their onset, yet traditional neurotoxicity testing often fails to identify specific risks or mechanisms underlying cognitive impairment. Human brain organoids (hBOs), also called neural organoids or brain microphysiological systems, are three-dimensional (3D) stem cell-derived models that recapitulate key features of human brain development and offer greater physiological relevance than traditional 2D <i>in vitro</i> or animal models. The emerging field of \"organoid intelligence\" integrates these systems with advanced bioengineering and artificial intelligence to model higher-order neural functions and assess learning and memory-relevant endpoints that were previously less explored <i>in vitro</i>. Despite this promise, we have identified four key barriers that hinder the application of hBOs for the hazard identification phase of functional neurotoxic risk assessments: [1] limited maturity and regional complexity, [2] lack of high-throughput defined procedures for assessing cognitive development and function <i>in vitro</i>, [3] limited standardization for reproducibility, and [4] challenges in translating <i>in vitro</i> results to human health outcomes. Here, we outline current efforts to overcome these challenges, i.e., scientific, technical, and regulatory advances. We also illustrate how hBO-based assays can be applied to advance both mechanistic understanding and the regulatory evaluation of environmental (developmental) neurotoxicants, using heavy metals as a model.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1783893"},"PeriodicalIF":5.1,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13105461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147790953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An <i>In vitro</i> assessment of the genotoxic potential of short-, medium-, and long-chain triacylglycerides.","authors":"Sydney Schreppler, Nikifar Lazouski, Lars Damen, Roy Hoffmans, Dejan Petrovic, Kathleen C Alexander","doi":"10.3389/ftox.2026.1807786","DOIUrl":"10.3389/ftox.2026.1807786","url":null,"abstract":"<p><p>The genotoxic potential of a mixture of short-, medium-, and long-chain triacylglycerides (SMLCT), a novel synthetic fat intended as a non-animal alternative for food applications, was evaluated using a standard battery of <i>in vitro</i> assays in accordance with OECD Test Guidelines. Studies included a bacterial reverse mutation assay (OECD Test Guideline 471) with <i>Salmonella</i> Typhimurium and <i>Escherichia coli</i> strains at concentrations up to 5000 µg/plate; an <i>in vitro</i> mammalian gene mutation test in L5178Y mouse lymphoma cells (OECD Test Guideline 490) at concentrations up to 31 μg/mL; and an <i>in vitro</i> micronucleus assay in cultured human peripheral blood lymphocytes (OECD Test Guideline 487) at concentrations up to 7.8 μg/mL. Across all assays, SMLCT did not induce biologically relevant increases in revertant colonies, mutant frequencies, or micronucleated binucleated cells. These findings indicate that SMLCT is neither mutagenic nor clastogenic under the conditions of the studies, supporting its safety for use as a dietary fat ingredient in finished food.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1807786"},"PeriodicalIF":5.1,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13099124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147790841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: <i>In Vitro</i> BBB triculture assay and preliminary computational model development to predict brain exposure.","authors":"Zhuangyan Monica Xu, James P Sluka, Charlie C Zhang, Gregory Knipp","doi":"10.3389/ftox.2026.1836636","DOIUrl":"https://doi.org/10.3389/ftox.2026.1836636","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.3389/ftox.2026.1781588.].</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1836636"},"PeriodicalIF":4.6,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13095177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147791006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exposure to manganese during juvenile development increases microglial activation in the hippocampus following systemic infection with A/California/04/2009 Influenza A H1N1 virus.","authors":"Megan R Hager, Adam J Schuller, Omar A Yanouri, Collin M Bantle, Richard J Smeyne, Ronald B Tjalkens","doi":"10.3389/ftox.2026.1789730","DOIUrl":"10.3389/ftox.2026.1789730","url":null,"abstract":"<p><p>Up to 80% of patients with Parkinson's Disease (PD) develop dementia within 20 years of diagnosis. Although the etiology of PD and related neurodegenerative disorders is poorly understood, risk factors including environmental toxicants and viral infections are linked to disease onset and progression. Exposure to high doses of the essential element, manganese (Mn), causes neurotoxicity associated with parkinsonian symptoms and cognitive impairment in humans. Additionally, epidemiologic studies indicate that viral infections increase risk of developing PD. Previously, our lab demonstrated that mice exposed to Mn during juvenile development showed greater neuroinflammatory changes in microglia within the substantia nigra following systemic infection with H1N1 influenza virus (California/04/09 influenza A) than mice infected without prior exposure to Mn. In the present study, this murine dual-hit model was employed to investigate how juvenile Mn exposure alters H1N1-induced neuropathology and glial morphology in the hippocampus. Mice were exposed to Mn in drinking water from post-natal day 21-51 and then intranasally infected with 10³ TCID₅₀ A/California/04/2009 H1N1. To assess histopathology following this exposure paradigm, we performed high-content microscopy and machine learning-based image analysis of H&E and IHC-stained sections spanning the hippocampus to quantify pyknotic neurons and reactive microglia. We report a significant increase in the number of pyknotic neurons in the dentate gyrus as well as morphologic changes in microglia that are consistent with inflammatory activation. Our findings highlight the capacity of combined juvenile manganese exposure and adult viral infection to induce substantial microgliosis in the hippocampus.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1789730"},"PeriodicalIF":5.1,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13082759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147700938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A large-scale concordance study of toxicity findings across preclinical species and humans for small molecules and biologics.","authors":"Xin Liu, Fan Fan","doi":"10.3389/ftox.2026.1731947","DOIUrl":"10.3389/ftox.2026.1731947","url":null,"abstract":"<p><p>Translating preclinical safety findings into reliable insights for human risk assessment remains a fundamental challenge in drug development. Prior preclinical-clinical concordance studies have been constrained by limited drug coverage, reliance on identical-term matching for adverse events (AEs), and limited consideration of species, modality, exposure, and biological or mechanistic context. To address these gaps, we assembled a large cross-species concordance dataset, integrating standardized preclinical and clinical safety data for 7,565 marketed and investigational drugs from PharmaPendium and OFF-X. Our framework employs likelihood ratios to reduce prevalence bias and extends concordance assessment beyond identical-term matches to include semantically and mechanistically related AE pairs. Stratified analyses by species, modality, and exposure-matched subsets further refined translational relevance, while integration of on- and off-target annotations supports mechanistic interpretation and potential screening. Using this approach, we identified 850 significant identical-term AEs and 2,833 additional unique endpoints from cross-term associations. To promote reproducibility and transparency in animal research, we provide open access to the analytic code and statistical results via an interactive web application. An accompanying multi-agent AI system (ToxAgents) enables standardized querying and interpretation of concordance results. Together, these resources extend previous foundational efforts and establish a shared, data-driven platform to advance translational safety science, support evidence-based study design aligned with the 3Rs principles, and ultimately contribute to the development of safer medicines to improve human health.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1731947"},"PeriodicalIF":5.1,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13082757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147700904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}