Toxicological Sciences最新文献

{"title":"Chemosensory tobacco product toxicology part 1: sensory mechanisms.","authors":"Weihong Lin, Thomas Hill, Andrea M Stroup, Samantha Emma Sarles, Tatsuya Ogura, Farhan Augustine, Sean O'Sullivan, Irfan Rahman, Risa Robinson, Sairam V Jabba, Caleb Nuss, Edward Hensel","doi":"10.1093/toxsci/kfaf090","DOIUrl":"10.1093/toxsci/kfaf090","url":null,"abstract":"<p><p>Chemosensory systems detect and discriminate a wide variety of molecules to monitor internal and external chemical environments. They initiate olfactory, gustatory, and chemesthetic sensations; influence human brain cognition and emotion; and guide a wide variety of behaviors essential for survival, including protective reactions, such as avoidance of contaminated foods and potential toxicants. Electronic nicotine delivery systems (ENDS) aerosolize e-liquids for inhaled consumption that typically contain flavorants, propylene glycol, vegetable glycerin, and nicotine. E-liquid aerosols also contain toxicants, such as formaldehyde, acetaldehyde, acrolein, and heavy metals. Chemosensory evaluation of ENDS aerosol plays an essential role in the assessment of whether a product will attract new users of all ages, as well as determining their likely use patterns, perceptions of product harm, satisfaction, and product selection. Nicotine and individual flavorant constituents stimulate multiple sensory receptor systems in complex patterns, initiating distinctive sensory perceptions depending on the chemical properties and quantity in the aerosol. There are limited data on chemosensory evaluation of ENDS aerosols and their influence on ENDS use and protective biologic mechanisms. This two-part manuscript provides an overview of (i) the physiology of the olfactory, gustatory, and chemesthetic chemosensory systems, their detection mechanisms, and their role in protective defenses; and (ii) the in vitro, in vivo, and in silico computer-based methodology available to evaluate ENDS irritants and toxicants, their impact on chemosensory pathways, the current state of the science related to e-liquid and ENDS aerosols, and challenges for future studies and scientific innovation.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"261-271"},"PeriodicalIF":4.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144708881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating the role of alveolar macrophages in tolerance to ozone.","authors":"Gregory J Smith, Morgan Nalesnik, Robert M Immormino, Jeremy M Simon, Jack R Harkema, Jason R Mock, Timothy P Moran, Samir N P Kelada","doi":"10.1093/toxsci/kfaf095","DOIUrl":"10.1093/toxsci/kfaf095","url":null,"abstract":"<p><p>Acute exposure to ozone (O3) causes pulmonary inflammation and injury in humans and animal models. In rodents, acute O3-induced inflammation and injury can be mitigated by pre-exposure to relatively low concentrations of O3, a phenomenon referred to as tolerance. Although tolerance was first described long ago, the underlying mechanisms are not known. We hypothesized that alveolar macrophages (AMs) play a key role in tolerance to O3 based on prior studies with other exposures. To enable our studies, we first generated a mouse model in which female C57BL6/NJ mice were pre-exposed to filtered air or 0.8 ppm O3 for 4 days (4 h/day), then challenged with 2 ppm O3 (3 h) 2 days later, and phenotyped for airway inflammation and injury 6 or 24 h thereafter. As expected, pre-exposure to O3 resulted in significantly reduced airway inflammation and injury 24 h following O3 challenge. Tolerance was associated with regenerative hyperplasia in the terminal bronchioles and changes in the frequency of proliferating alveolar type 2 cells. O3 pre-exposure altered the expression of ∼1,500 genes in AMs, most notably downregulation of Toll-like receptor and proinflammatory cytokine signaling pathways, suggesting AMs had become hypo-responsive. Depletion of tolerized AMs prior to acute O3 challenge did not, however, alter inflammation and injury. Additionally, adoptive transfer of tolerized AM to naïve recipient mice failed to alter responses to acute O3 challenge. In total, our results argue against an important role for AMs in tolerance to ozone and suggest that other cell types are involved.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"487-497"},"PeriodicalIF":4.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12469193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144715194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advanced Cardiotoxicity Profiling Using Field Potential Imaging with UHD-CMOS-MEA in Human iPSC-Derived Cardiomyocytes.","authors":"Naoki Matsuda, Nami Nagafuku, Kazuki Matsuda, Yuto Ishibashi, Tomohiko Taniguchi, Yusaku Matsushita, Norimasa Miyamoto, Takashi Yoshinaga, Ikuro Suzuki","doi":"10.1093/toxsci/kfaf134","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf134","url":null,"abstract":"<p><p>Accurate assessment of cardiotoxicity using human iPSC-derived cardiomyocytes is critical for ensuring drug safety during preclinical development. However, existing in vitro methodologies predominantly focus on QT interval prolongation and arrhythmia risk, often lacking the capacity to capture the complex interplay among multiple ion channels or to detect early manifestations of chronic cardiotoxicity-both of which are essential for evaluating long-term cardiac safety. Moreover, reliable prediction of pharmacological mechanisms of action remains a significant challenge. In this study, we employed field potential imaging (FPI) utilizing an ultra-high-density complementary metal-oxide-semiconductor (CMOS) microelectrode array (MEA) comprising 236,880 electrodes distributed across a 5.9 × 5.5 mm active area. With 91.9% surface coverage by 11 μm electrodes spaced at 0.25 μm, the platform achieves near single-cell resolution across the entire cardiomyocyte monolayer. This system enabled the extraction of high-resolution electrophysiological endpoints, including the number and spatial variability of excitation origins, conduction velocity, and propagation area-thereby extending the analytical capabilities beyond those of conventional MEAs. Pharmacological testing revealed compound-specific alterations: Isoproterenol increased excitation origins, mexiletine reduced conduction velocity, and E-4031 diminished propagation area. Although these agents are well characterized, their effects were visualized with unprecedented spatiotemporal resolution, reflecting their underlying mechanisms of action. Multivariate analysis incorporating both conventional and novel endpoints enabled accurate classification of mechanisms under acute conditions. Furthermore, chronic cardiotoxicity induced by low-dose doxorubicin (0.03 μM) was sensitively detected within 24 hours-earlier and at lower concentrations than previously reported-based on significant reductions in conduction velocity and propagation area. Collectively, these findings establish a high-resolution, mechanism-aware framework for in vitro cardiotoxicity profiling, offering improved predictive accuracy by capturing multi-ion channel interactions, spatial conduction abnormalities, and early signs of chronic dysfunction.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145201459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond QSARs: Quantitative Knowledge-Activity Relationships (QKARs) for Enhanced Drug Toxicity Prediction.","authors":"Ting Li, Yanyan Qu, Alexander Chen, Shraddha Thakkar, Dongying Li, Weida Tong","doi":"10.1093/toxsci/kfaf135","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf135","url":null,"abstract":"<p><p>Computational toxicology plays an important role in risk assessment and drug safety. The field has been traditionally dominated by Quantitative Structure-Activity Relationships (QSARs), which predict toxicological effects based solely on chemical structure. Although QSARs have achieved successes, their structure reliance limits drug toxicity predictions, where small structural modifications may cause major toxicity changes. Advances in artificial intelligence (AI), especially text embedding and generative AI, provide an opportunity to enhance toxicity predictions by leveraging broader chemical knowledge and its integration with structural data. In this study, we propose a novel framework, Quantitative Knowledge-Activity Relationships (QKARs), which predict toxicity using domain-specific knowledge. We developed QKAR models for two drug toxicity endpoints, drug-induced liver injury (DILI) and drug-induced cardiotoxicity (DICT), using three different knowledge representations with varying levels of knowledge. The representations based on comprehensive knowledge of the drugs yielded better prediction than those with simpler knowledge. Five ML algorithms of distinct complexity were applied in QKAR models, and we observed little association between model complexity and performance. Further, we evaluated QKARs against QSARs on the same endpoints using identical datasets. We found that QKARs consistently outperformed QSARs for DILI and DICT. Notably, QKARs demonstrated better capability than QSARs in differentiating drugs with similar structures but different liver toxicity profiles. We also investigated integrating knowledge-based and structure-based representations, Q(K + S)ARs, for further enhanced prediction accuracy. Our findings demonstrate the potential of QKARs as a robust alternative to QSARs, offering additional opportunities in drug toxicity assessments by leveraging both domain-specific knowledge and structural data.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-content Toxicological Profiling of 87 Compounds Using a 3D Mouse Mini-Testis Model: A New Approach Methodology (NAM) for Prioritizing Male Reproductive Toxicants.","authors":"Lei Yin, Jamie Chelin Hu, Menghang Xia, Xiaozhong John Yu","doi":"10.1093/toxsci/kfaf136","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf136","url":null,"abstract":"<p><p>Environmental exposure to industrial chemicals, endocrine disruptors, and pharmaceuticals has been increasingly linked to the global decline in male reproductive health. To address the urgent need for efficient and mechanistically informed toxicity screening, we developed a high-throughput, high-content screening (HTS/HCA) platform using a 3D in vitro mini-testis model. This system was used to evaluate 87 structurally diverse compounds from the National Toxicology Program (NTP) chemical library. The model incorporates murine-derived spermatogonia, Sertoli, and Leydig cells embedded in an extracellular matrix, providing a physiologically relevant environment for mechanistic toxicology. Each compound was tested across ten phenotypic endpoints, including nuclear morphology, cytoskeletal integrity (F-actin), DNA damage (γH2AX), and cell viability by using high-content imaging. Quantitative Points of Departures (PODs) were calculated and integrated into a High-content Assay Index (HCAI). Toxicological Priority Index (ToxPi) scores, derived from the PODs, enabled compound ranking and clustering. Compared to existing in vivo reproductive toxicity data, the 3D model demonstrated 91.5% sensitivity, 93.8% specificity, and 93.6% concordance (n = 64 compounds). Notably, 22 compounds lacking reproductive toxicity data were identified as potentially reproductive toxicants. Mechanistic analyses revealed that nuclear morphology, F-actin intensity, and γH2AX were the most sensitive indicators of reproductive toxicity. Cluster and category-level analysis showed that flame retardants and pesticides ranked highest in toxicity. The integration of multi-parametric data via ToxPi facilitated high-resolution chemical prioritization. Given current ethical and technical challenges in sourcing human testicular tissue or differentiating stem cells into testicular cell types, murine cells provide a reproducible and practical alternative for complex multicellular testis modeling. Our results demonstrate that the HCA-integrated 3D mini-testis model offers a robust, scalable, and mechanistically insightful platform for male reproductive toxicity screening, supporting its adoption as New Approach Methodologies (NAMs) aligned with regulatory and ethical testing goals.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploration of Oxidative Stress Mediated Genetic Toxicology Modes of Actions Using a Pathway Analysis, Connectivity Mapping and Transcriptional Benchmark Dosing Based Framework.","authors":"K Nadira De Abrew, Bastian G Selman, Mahmoud Shobair, Xiaoling Zhang, Ashley J Allemang, Stefan Pfuhler","doi":"10.1093/toxsci/kfaf137","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf137","url":null,"abstract":"<p><p>While current genetic toxicology practices can detect downstream genotoxicity effects, such as gene mutation and double strand breaks, they are unable to detect the underlying Mode of Action (MoA) of a chemical or differentiate between direct and indirect acting genotoxicants without additional modification. The Adverse Outcome Pathway (AOP) framework is a useful tool to critically identify and evaluate MOAs and can enable subsequent quantitative dose response assessments of genotoxicity endpoints. The recently developed AOP, \"Oxidative DNA damage leading to chromosomal aberrations and mutations\" (https://aopwiki.org/aops/296), pertains to one common genetic toxicology relevant MOA: oxidative stress. Reactive Oxygen Species (ROS) are key to regulating many biological processes, however, when disrupted, an excess of ROS can eventually lead to DNA damage and double-strand breaks. Here, we look at 18 compounds reported to have complete or mixed oxidative stress MOAs and use a combination of genomic tools such as Pathway analysis, Connectivity mapping and Transcriptional benchmark dose modeling to define a framework that can separate substances that test negative in vivo from true in vivo genotoxicants. TK6 cells were treated with the 18 compounds for 4 hours, parallel micronucleus and genomics experiments were performed, and in vitro micronucleus data were used to infer dose for genomics analysis. The resulting genomic data was analyzed using pathway analysis for hypothesis generation, these hypotheses were tested using Connectivity mapping (CMap) and Transcriptional benchmark dose modeling. We demonstrate that a genomics-based workflow based on in vitro methods can be used to successfully separate in vivo genotoxicants from non genotoxicants. These methods have the potential to evolve into Next Generation Risk Assessment (NGRA) tools that can be used for determining the contribution of the oxidative stress MoA in a predictive toxicology setting.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of Bone Toxicity in Drug Development: Review of Current and Emerging Technologies.","authors":"Anik Tuladhar, Magali Guffroy, Sjoerd J Finnema, Romy Christmann, Terry R Van Vleet, Shuaib Ali Khan Mayana, Stacey Fossey","doi":"10.1093/toxsci/kfaf131","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf131","url":null,"abstract":"<p><p>Assessment and characterization of bone toxicity during drug development is important to ensure the safety of new therapeutics. Drugs can affect bone composition and quality either directly on bone cells or indirectly via systemic effects, leading to alterations in bone density, remodeling and fracture risk. Drug classes known to have harmful effects on bone include antidiabetics, non-steroidal anti-inflammatory drugs (NSAIDs), antivirals, chemotherapeutics, and steroids. Various methods are available to assess and investigate bone toxicity including in vivo animal models, ex vivo organ cultures, and in vitro cell cultures. In addition to routine assessment with in vivo animal models using microscopic examination of bone and clinical pathology parameters (calcium, phosphorus and alkaline phosphatase), other tools such as serum biomarkers of bone turnover, advanced imaging approaches, and histomorphometric analyses provide additional insight into bone microarchitecture and the remodeling process. Emerging in vitro methods, such as microphysiological systems (organ-on-a-chip) technologies, simulating bone's dynamic environment, offer toxicologists useful tools to study drug-induced bone toxicity. In silico models are increasingly recognized as critical tools in assessing drug-induced bone toxicity, offering a complementary approach to traditional in vitro and in vivo methods. Mechanistic models such as pharmacokinetic-pharmacodynamic (PK-PD) frameworks simulate remodeling dynamics and simulate drug metabolism and exposure to explore risk of bone and cartilage toxicity, while finite element models simulate cellular interactions and mechanical stress responses for skeletal toxicity predictions. This review aims to evaluate key features of bone biology impacted by therapeutics with examples and describe techniques for assessing bone toxicity during drug development.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145151110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vitro models of the male reproductive system: applications for developmental and reproductive toxicology.","authors":"Brad C Hansen, Kayenat S Aryeh, Lillian X Lindell, Gabriel K Lau, Tristan M Nicholson, Elaine M Faustman, Edward J Kelly","doi":"10.1093/toxsci/kfaf132","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf132","url":null,"abstract":"<p><p>There is a paucity of in vitro models to study the male reproductive system. Proper function of the reproductive system is critical for endocrine function, growth and development, and fertility. Without practical in vitro screening models, reproductive toxicities can be missed in early drug development or standard toxicological batteries. Successful in vitro models of the male reproductive system need to recapitulate the dynamic nature of the testis, considering the formation of the testicular niches from gonadal differentiation through puberty and the post-pubertal activity of the paracrine and endocrine signals that support spermatogenesis. In vitro approaches are reviewed that model primordial germ cell differentiation, gonadal morphogenesis, fetal steroidogenesis, neonatal reproductive development, and adult testicular niche dynamics to present opportunities for inclusion of male reproductive toxicity screening within a toxicological battery. The utility of cells derived from model organisms, differentiated from iPSCs, and obtained from donated human tissue are discussed. The field of reproductive and developmental toxicology is primed for expansion in in vitro model availability as complex in vitro model development continues to accelerate and fit-for-purpose model approaches are adopted in toxicological and drug development pipelines. This review highlights the current limitations and emerging opportunities in male reproductive in vitro models, providing a roadmap for integrating these systems into toxicology testing and drug development workflows. It highlights the need for developmentally benchmarked, physiologically relevant, and multicellular models to fill existing gaps and improve translatability.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145151114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Streamlined format for Toxicological Sciences: still your science, your journal.","authors":"Barbara L Kaplan, Jeffrey M Peters","doi":"10.1093/toxsci/kfaf125","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf125","url":null,"abstract":"","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics of cannabidiol and its metabolites in rhesus monkeys and New Zealand white rabbits.","authors":"Qiangen Wu, Luísa Camacho, John Talpos, Svitlana Shpyleva, R Daniel Mellon, J Edward Fisher, Michelle Vanlandingham, Patricia Shores, Gonçalo Gamboa da Costa, Frederick A Beland","doi":"10.1093/toxsci/kfaf129","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf129","url":null,"abstract":"<p><p>Cannabidiol (CBD) is extensively metabolized in humans, with 7-carboxy-CBD being the major metabolite. The biotransformation of CBD in mice, rats, and dogs differs from that in humans. We have investigated if the pharmacokinetics of CBD in rhesus monkeys and New Zealand White rabbits is similar to humans by measuring serum levels of CBD and its phase I and II metabolites after single intragastric (77.5 mg/kg body weight) or intravenous (3.9 mg/kg body weight) CBD doses. In rhesus monkeys, intragastric CBD yielded a maximum concentration (Cmax) of 241.6 nM (males) and 476.5 nM (females), with a terminal half-life (T1/2) of 11.6 and 15.4 hours. The area under the curve from zero to infinity (AUC0-inf) was 5,376 nM*hr (males) and 7,366 nM*hr (females), with bioavailability of 2.5% and 5.5%. 7-Carboxy-CBD showed a Cmax of 334.7 nM (males) and 655.4 nM (females), with AUC0-inf 1.5-1.6 times higher than CBD. The levels of other metabolites were minimal. In rabbits, intragastric CBD resulted in a Cmax of 76.6 nM (males) and 117.1 nM (females), with a T1/2 of 11.1 and 14.9 hours. The AUC0-inf was 1,443 nM*hr (males) and 1,645 nM*hr (females), with bioavailability of 2.1-2.2%. 7-Carboxy-CBD levels were significantly higher than CBD, with a Cmax of 11,631 nM (males) and 13,278 nM (females), and an AUC0-inf 120-133 times higher. In contrast to rhesus monkeys, New Zealand White rabbits exhibit a CBD metabolic profile similar to humans, with high levels of 7-carboxy-CBD, making them a promising model for studying CBD metabolism-driven toxicity.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}