Frontiers in toxicology最新文献

{"title":"Stress convulsions in rodents: within a weight-of-evidence framework for human seizure risk.","authors":"Joseph J DeGeorge, Monica R Metea","doi":"10.3389/ftox.2025.1600816","DOIUrl":"https://doi.org/10.3389/ftox.2025.1600816","url":null,"abstract":"<p><p>In research settings, rodents exhibit a well-documented sensitivity to stress-induced behavioral alterations ranging from stereotypy to convulsions. These events complicate preclinical drug safety assessments where establishing a No-Observed-Effect Level (NOEL) requires distinguishing true pharmacologic seizures from stress-related convulsions, including a type lacking electrographic cortical correlates, referred to as psychogenic nonepileptic seizures (PNES). Stress triggers in preclinical settings include environmental factors and systemic conditioning effects of investigational drugs unrelated to seizure risk. Stress-induced behaviors can bias safety assessments by creating false-positive findings of seizure liability incorrectly attributed to the test compound. This paper highlights situations when stress conditioning is present during rodent seizure liability studies and proposes a Weight-of-Evidence (WoE) approach to differentiate between drug-induced ES and stress-conditioned PNES. It supports applying context-specific criteria for regulatory considerations especially when convulsions are absent in higher species, when there are inconsistent findings across facilities, and when rodents present stereotypy and lack of neuropathological evidence of drug-induced seizures. This approach aims to minimize the misinterpretation of stress-related artifacts as true pharmacologic seizures, providing a framework for more reliable and translatable seizure liability assessments.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1600816"},"PeriodicalIF":4.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12311371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144762490","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":"Chain length-dependent mitochondrial toxicity of perfluoroalkyl carboxylic acids: insights from Mito Tox Index evaluation.","authors":"Yoonseok Kam, Lisa Winer, Natalia Romero","doi":"10.3389/ftox.2025.1582891","DOIUrl":"10.3389/ftox.2025.1582891","url":null,"abstract":"<p><strong>Introduction: </strong>Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants that accumulate in living organisms, posing significant human health risks. The toxicity mechanisms of PFAS include mitochondrial dysfunction and bioenergetic failure.</p><p><strong>Methods: </strong>This study evaluates the structure-activity relationship of PFAS compounds with mitochondrial toxicity by comparing the Mito Tox Index (MTI) of perfluoroalkyl carboxylic acids (PFCAs) varying carbon chain lengths. The MTI quantifies the extent to which substances disrupt mitochondrial function by distinguishing between mitochondrial inhibition and uncoupling. This was followed by an assessment of the effect of PFCAs on total cellular bioenergetics and impedance-based real time cell viability measurement.</p><p><strong>Results and discussion: </strong>Both inhibition and uncoupling MTI values increased with the chain length of PFCAs and severe mitochondrial inhibition was observed when uncoupling was maximized by PFCAs containing seven or more carbons within hours of exposure. The mitochondrial toxicity corresponded well to the bioenergetic failure measured by real-time ATP production rates. In contrast, there was a substantial difference between cytotoxicity and mitochondrial toxicity, despite a common trend of increased toxicity with longer chain lengths. The results suggest that PFCA-induced mitochondrial dysfunction is a key mechanism of PFAS-mediated cellular damage, primarily driven by proton leak-mediated ETC uncoupling, leading to impaired mitochondrial energy production. It also implies that MTI-based mitochondrial toxicity evaluation increases data precision in comparing PFAS effects on mitochondrial function, even identifying the mode of action, which is expected to improve in vitro toxicity prediction models.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1582891"},"PeriodicalIF":4.6,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12303941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144746368","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":"Subchronic effects of HgCl₂ on cognitive function and central inflammation in type 2 diabetic rats: involvement of BDNF and acetylcholinesterase.","authors":"Douae Benloughmari, Samir Bikri, Meriam El Aboubi, Fatima-Zahra Yassif, Youssef Aboussaleh","doi":"10.3389/ftox.2025.1610720","DOIUrl":"10.3389/ftox.2025.1610720","url":null,"abstract":"<p><strong>Introduction: </strong>Type 2 diabetes mellitus (T2DM) is a major global health concern frequently related with chronic low-grade inflammation and a spectrum of cognitive impairments, including deficits in learning and memory. Mercury chloride (HgCl₂), a widespread environmental pollutant, is recognized for its neurotoxic properties and its capacity to trigger inflammatory responses, particularly in patients with metabolic disorders such as T2DM.</p><p><strong>Aim: </strong>This study aimed to evaluate the subchronic effects of HgCl₂ on cognitive performance and neuroinflammation in a rat model of T2DM, with a particular focus on the roles of BDNF and acetylcholinesterase (AChE).</p><p><strong>Materials and methods: </strong>The experimental design included four groups: control, HgCl₂-treated, diabetic, and diabetic rats treated with HgCl₂. T2DM was induced by intraperitoneal injections of streptozotocin (STZ) and nicotinamide (NA). Rats in the HgCl₂-exposed groups received an oral dose of 0.375 mg/kg/day for 45 consecutive days. Cognitive performance was assessed using behavioral tests targeting spatial learning, recognition memory, and working memory. Additionally, hippocampal and prefrontal cortex (PFC) levels of TNF-α, IL-6, BDNF, and AChE activity were measured to evaluate neuroinflammatory and neurotoxic responses.</p><p><strong>Results: </strong>The findings revealed a significant increase in fasting blood glucose levels in both diabetic and HgCl₂-treated diabetic groups compared to controls (P < 0.001). Moreover, HgCl₂ administration in diabetic rats led to a more pronounced impairment in cognitive functions compared to untreated diabetic rats (P < 0.05). These deficits were associated with enhanced neuroinflammatory markers (TNF-α and IL-6), decreased AChE activity, and reduced BDNF expression in the PFC and hippocampus (P < 0.05).</p><p><strong>Conclusion: </strong>Overall, these results highlight the synergistic impact of hyperglycemia and HgCl₂ exposure in exacerbating neuroinflammation and cognitive decline, suggesting a critical interaction between metabolic and environmental neurotoxic factors.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1610720"},"PeriodicalIF":4.6,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12301335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144735881","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":"25 years of research and regulation: Is nanotechnology safe to commercialize?","authors":"Kirsten Rasmussen, Phil Sayre, Andrej Kobe, Mar Gonzalez, Hubert Rauscher","doi":"10.3389/ftox.2025.1629813","DOIUrl":"10.3389/ftox.2025.1629813","url":null,"abstract":"<p><p>This paper examines the global communities' regulatory and scientific advancements in nanotechnology and nanomaterials since 2000. It explores some similarities and differences in nanomaterial safety compared to general chemical safety. The paper provides an overview of the encountered challenges and how far they have been resolved, as well as information on how different countries' legislators have addressed nanomaterials, including safety assessment in (new) legislation. Challenges arose due to the unique physico-chemical properties of some nanomaterials and included the lack of i) a regulatory definition, ii) applicable regulatory test methods, including methods for physico-chemical characterization and for ecotoxicological effects, as well as sample preparation and dosimetry, iii) assessment and modelling of human, especially occupational, and environmental exposure to nanomaterials, iv) quantification of nanomaterial in complex media, v) systems for collecting the data generated and ensuring FAIR (Findable, Accessible, Interoperable and Re-usable) and quality data, vi) reference nanomaterials, and vii) a frame for nanotechnology governance. The paper highlights the role of the Organisation for Economic Co-operation and Development (OECD) in building a global, regulatory understanding of nanotechnology and nanomaterials, as well as the OECD's achievements of developing nano-specific test guidelines. The paper identifies areas, such as alternative test methods, availability of reference nanomaterials, comparable data and FAIR data, analytical tools for quantifying nanomaterials in (complex) matrices that are still under-addressed. It gives a wider perspective of Governance of Advanced Materials including nanomaterials, also illustrated by carbon nanotubes used in batteries for electric vehicles, to also aid their commercialization. In the EU, the policy context is moving towards a holistic governance approach embracing sustainability dimensions.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1629813"},"PeriodicalIF":4.6,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12286942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710062","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":"Arsenic toxicity in the <i>Drosophila</i> brain at single cell resolution.","authors":"Anurag Chaturvedi, Vijay Shankar, Bibhu Simkhada, Rachel A Lyman, Patrick Freymuth, Elisabeth Howansky, Katelynne M Collins, Trudy F C Mackay, Robert R H Anholt","doi":"10.3389/ftox.2025.1636431","DOIUrl":"10.3389/ftox.2025.1636431","url":null,"abstract":"<p><p>Arsenic is an ubiquitous environmental toxicant with harmful physiological effects, including neurotoxicity. Modulation of arsenic-induced gene expression in the brain cannot be readily studied in human subjects. However, <i>Drosophila</i> allows quantification of transcriptional responses to neurotoxins at single cell resolution across the entire brain in a single analysis. We exposed <i>Drosophila melanogaster</i> to a chronic dose of NaAsO₂ that does not cause rapid lethality and measured survival and negative geotaxis as a proxy of sensorimotor integration. Females survive longer than males but show earlier physiological impairment in climbing ability. Single-nuclei RNA sequencing showed widespread sex-antagonistic transcriptional responses with modulation of gene expression in females biased toward neuronal cell populations and in males toward glial cells. However, differentially expressed genes implicate similar biological pathways. Evolutionary conservation of fundamental processes of the nervous system enabled us to translate arsenic-induced changes in transcript abundances from the <i>Drosophila</i> model to orthologous human neurogenetic networks.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1636431"},"PeriodicalIF":4.6,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12287011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710063","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":"Unlocking liver physiology: comprehensive pathway maps for mechanistic understanding.","authors":"Luiz Ladeira, Anouk Verhoeven, Jonas van Ertvelde, Jian Jiang, Alessio Gamba, Julen Sanz-Serrano, Tamara Vanhaecke, Harm J Heusinkveld, Ramiro Jover, Mathieu Vinken, Liesbet Geris, Bernard Staumont","doi":"10.3389/ftox.2025.1619651","DOIUrl":"10.3389/ftox.2025.1619651","url":null,"abstract":"<p><strong>Aims: </strong><i>In silico</i> methods provide a resourceful toolbox for new approach methodologies (NAMs). They can revolutionize chemical safety assessment by offering more efficient and human-relevant alternatives to traditional animal testing. In this study, we introduce two Liver Physiological Maps (PMs); comprehensive and machine-readable graphical representations of the intricate mechanisms governing two major liver functions.</p><p><strong>Methods: </strong>Two PMs were developed through manual literature curation, integrating data from established pathway resources and domain expert knowledge. Cell-type specificity was validated using Human Protein Atlas datasets. An interactive version is available online for exploration. Cross-comparison analysis with existing Adverse Outcome Pathway (AOP) networks was performed to benchmark physiological coverage and identify knowledge gaps.</p><p><strong>Results: </strong>The LiverLipidPM focuses on liver lipid metabolism, detailing pathways involved in fatty acid synthesis, triglycerides, cholesterol metabolism, and lipid catabolism in hepatocytes. And the LiverBilePM represents bile acid biosynthesis and secretion processes, detailing biosynthesis, transport, and secretion processes between hepatocytes and cholangiocytes. Both maps integrate metabolism with signaling pathways and regulatory networks. The interactive maps enable visualization of molecular pathways, linkage to external ontologies, and overlay of experimental data. Comparative analysis revealed unique mechanisms to each map and overlaps with existing AOP networks. Chemical-target queries identified new potential targets in both PMs, which might represent new molecular initiating events for AOP network extension.</p><p><strong>Conclusion: </strong>The developed liver PMs serve as valuable resources for hepatology research, with a special focus on hepatotoxicity, supporting the refinement of AOP networks and the development of human-oriented <i>in vitro</i> test batteries for chemical toxicity assessment. These maps provide a foundation for creating computational models and mode-of-action ontologies while potentially extending their utility to systems biology and drug discovery applications.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1619651"},"PeriodicalIF":3.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12277266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683643","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: Associations of environmental pollution with pro-oxidant, antioxidant and inflammatory markers in pregnant mothers and newborns.","authors":"Antonin Ambroz, Jiri Klema, Andrea Rossnerova, Alena Milcova, Anna Pastorkova, Jana Pulkrabova, Ondrej Parizek, Veronika Gomersall, Tomas Gramblicka, Jaroslav Zelenka, Tomas Ruml, Nikola Vrzackova, Milos Veleminsky, Newroz Hasan, Jan Topinka, Radim J Sram, Pavel Rossner","doi":"10.3389/ftox.2025.1650125","DOIUrl":"10.3389/ftox.2025.1650125","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.3389/ftox.2025.1572486.].</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1650125"},"PeriodicalIF":3.6,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12272343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144676726","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":"Toxicity of glyphosate accelerates neurodegeneration in <i>Caenorhabditis elegans</i> model of Alzheimer's disease.","authors":"Nisha Rani, Mohammad Mumtaz Alam, Suhel Parvez","doi":"10.3389/ftox.2025.1578230","DOIUrl":"10.3389/ftox.2025.1578230","url":null,"abstract":"<p><strong>Introduction: </strong>Pesticide-related environmental contamination poses a growing global concern, threatening human health, wildlife, and ecosystems. Glyphosate (N-phosphonomethyl-glycine, GLY), a widely used organophosphorus herbicide, has been associated with neurotoxic effects. This study investigates the potential neurodegenerative impact of glyphosate using a Caenorhabditis elegans Alzheimer's disease (AD) model.</p><p><strong>Methods: </strong>Transgenic <i>C. elegans</i> strain CL4176, which expresses human amyloid-beta (Aβ1-42) upon temperature induction, was exposed to various concentrations of glyphosate (12, 15, 18.5, 20, and 25 mg/L) for 24 hours. Behavioral assays (body bends, head thrashes, body length, and pharyngeal pumping), oxidative stress markers (catalase activity), and Aβ protein expression were evaluated.</p><p><strong>Results: </strong>Glyphosate exposure induced a concentration-dependent decline in locomotor and feeding behaviors. Catalase activity was significantly reduced, indicating elevated oxidative stress. Additionally, a marked increase in Aβ1-42 protein expression was observed in glyphosate-treated CL4176 worms.</p><p><strong>Discussion: </strong>These findings suggest that glyphosate exacerbates Aβ toxicity and induces AD-like phenotypes in the <i>C. elegans</i> model through behavioral impairment, oxidative stress, and increased Aβ accumulation. Glyphosate's potential contribution to neurodegenerative processes warrants further investigation.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1578230"},"PeriodicalIF":3.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144644301","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":"Tributyl phosphate as a type of environmental endocrine disruptor associated with liver fibrosis: insights from NHANES and <i>in vitro</i> validation.","authors":"Liwei Yang, Aipeng Ju, Yawen Huang, Huibin Jiang, Jiaming Ye, Wen Qi, Liting Zhou","doi":"10.3389/ftox.2025.1623830","DOIUrl":"10.3389/ftox.2025.1623830","url":null,"abstract":"<p><strong>Background: </strong>Environmental endocrine disruptors (EEDs) had been proved as significant risk factors for liver fibrosis. However, which specific pollutants predominantly related to liver fibrosis remain unidentified. This study was aimed to screen in the specific EEDs using NHANES data and further validate the findings in BRL-3A hepatocytes.</p><p><strong>Methods: </strong>A total of 5,843 adult participants (≥18 years) incorporating data on EEDs/metabolites, demographics, lifestyle factors, and vibration-controlled transient elastography (VCTE) measurements were gated from the NHANES. Advanced analytical methods including LASSO regression, multivariable logistic regression, and restricted cubic spline (RCS) modeling were implemented for pollutant screening. <i>In vitro</i> validation involved treating BRL-3A hepatocytes with identified EEDs, followed by comprehensive assessment of fibrotic markers through quantitative PCR, Western blotting, and extracellular matrix component analysis.</p><p><strong>Results: </strong>Di-n-butyl phthalate (DBuP), the metabolites of tributyl phosphate (TBP), was demonstrated to be the strongest EEDs associated with liver fibrosis (<i>P</i> < 0.05). Mechanistic studies revealed that 1 μM TBP significantly elevated extracellular matrix components (HA: +130%, Ⅳ-Col: +22%) through MMP9 upregulation at both transcriptional (1.8-fold increase) and translational (1.73-fold increase) levels in hepatocytes.</p><p><strong>Conclusion: </strong>Our findings establish TBP as a novel environmental determinant positively correlated with liver fibrosis in U.S. adults. The profibrotic effects appear mediated through transcriptional activation of extracellular matrix remodeling genes, particularly via MMP9 pathway modulation.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1623830"},"PeriodicalIF":3.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144644302","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 advancement in developmental and reproductive toxicity (DART) risk assessment: evaluation of a bioactivity and exposure-based NAM toolbox.","authors":"Iris Mueller, Ashraf Abdelkhaliq, Paul Carmichael, Matthew Dent, Marleen Feliksik, Luke Flatt, Jade Houghton, José M Horcas Nieto, Amer Jamalpoor, Predrag Kukic, Sophie Malcomber, Beate Nicol, Gopal Pawar, Claire Peart, Katarzyna Przybylak, Magdalena Sawicka, Katy Wilson, Kathryn Wolton","doi":"10.3389/ftox.2025.1602065","DOIUrl":"10.3389/ftox.2025.1602065","url":null,"abstract":"<p><p>Traditional chemical safety assessment involves identifying the lowest level of a chemical that impacts endpoints measured in standardized animal studies to establish human exposure limits. <i>In vitro</i> assays have shown promise in providing points of departure that can be protective of human health when combined with exposure predictions into a bioactivity:exposure ratio (BER). Using a combination of broad screening tools and DART-targeted assays, we previously demonstrated high biological coverage of this NAM toolbox against a list of DART-relevant genes and pathways. To fully transition to an animal-free paradigm, it is crucial to establish confidence that these <i>in vitro</i> assays sufficiently represent the DART toxicity mechanisms, ensuring a level of protection that is safe for non-pregnant adults, pregnant women, and fetal populations. In this proof-of-concept study, we have extended the toolbox to include additional <i>in vitro</i> and <i>in silico</i> tools and have performed an evaluation using 37 benchmark compounds across 49 exposure scenarios. According to existing regulatory opinions, 18 of these scenarios would be considered high-risk chemical exposures from a DART perspective. Our DART NAM toolbox approach identified 17 out of these 18 high-risk scenarios. We further investigated the impact of population-based changes in pregnancy and the fetus on internal exposures by evaluating human clinical data where available for the 37 compounds. In most instances, the variability resulting from pregnancy or gestational changes falls within the range of toxicokinetic variability observed in the general population. This work demonstrates that protective safety decisions can be made for DART without generating new animal test data.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1602065"},"PeriodicalIF":3.6,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256496/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144638785","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}