International Journal of Toxicology最新文献

{"title":"Corrigendum to Subchronic Toxicity and Teratogenicity Studies of Mycoprotein From <i>Fusarium compactum</i> MM-135 in Rats.","authors":"","doi":"10.1177/10915818261444880","DOIUrl":"https://doi.org/10.1177/10915818261444880","url":null,"abstract":"","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"10915818261444880"},"PeriodicalIF":1.0,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pre-clinical Safety Assessment of Quercetagetin: Insights From Repeated-Dose Toxicity and Genotoxicity Studies.","authors":"Abhijith Subrahmanya, Sripathy Ravichandran, Surya Narayan Naick M, Samit B Kadam","doi":"10.1177/10915818261446279","DOIUrl":"https://doi.org/10.1177/10915818261446279","url":null,"abstract":"<p><p>Quercetagetin (QG) is a naturally occurring flavonoid found in marigold (<i>Tagetes erecta</i>). It has garnered attention for its potential to support immune health, regulate blood sugar levels, and enhance metabolism. Yet, unlike the closely related compound quercetin (QC), QG has an extra hydroxyl (-OH) group at the C-6 position of the flavonoid A-ring, whereas quercetin has only a hydrogen atom at that position, which has raised safety concerns. QG has not been thoroughly studied for long-term safety. To fill this gap, we conducted a 90-day study in rats to assess the response to repeated oral doses of QG. The QG-administered group of animals received 500, 1000, or 3000 mg/kg bw per day, and we monitored a wide range of health indicators, from body weight and food intake to blood chemistry, hormone levels, and indicators of organ health. The results were reassuring as there were no changes in the urine parameters, deaths, clinical signs, or changes in growth or eye health. Changes were non-adverse and/or of no significant toxicological concern in blood, and organ weight differences were minor and not associated with any tissue damage. Based on these findings, the No Observed Adverse Effect Level (NOAEL) was established at 3000 mg/kg bw/day, the highest dose tested.We also tested QG for mutagenicity/clastogenicity using standard genotoxic assays, including bacterial mutation tests and micronucleus assays in CHO-k1 cells (in vitro) and <i>Swiss albino</i> mice (in vivo). Across all systems, QG showed no evidence of mutagenicity and/or clastogenicity.</p>","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"10915818261446279"},"PeriodicalIF":1.0,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advanced Glycation End Products Induce Cuproptosis and Then Promote the Activation and Migration of Cardiac Fibroblasts.","authors":"Jian Xiao, Zan-Hua Shi, Xin-Hua Ma, Dao-Miao Xu, Guang-Feng Ming","doi":"10.1177/10915818261443964","DOIUrl":"https://doi.org/10.1177/10915818261443964","url":null,"abstract":"<p><p>Excessive advanced glycation end products (AGEs) can lead to cardiovascular diseases such as myocardial fibrosis (MF). Although studies have found that AGEs induce cuproptosis, and cuproptosis promotes fibrosis, it has not been confirmed whether AGEs promote MF through cuproptosis. AGEs increased intracellular copper levels, promoted the expression of solute carrier family 31 member 1 (SLC31A1), and downregulated the expression of ferredoxin 1 (FDX1), lipoic acid synthetase (LIAS), lipoylated (Lip)-dihydrolipoamide S-succinyltransferase (DLST), and Lip-dihydrolipoamide S-acetyltransferase (DLAT) in cardiac fibroblasts (CFs). All of these key cuproptosis regulatory gene expression abnormalities indicate that cuproptosis is induced. AGEs also decreased adenosine triphosphate content and inhibited the activities of mitochondrial complexes I and III, but these regulatory effects were significantly weakened after SLC31A1 downregulation. Meanwhile, AGEs significantly promoted the expression of alpha smooth muscle actin, collagen I, collagen III, and transforming growth factor-β1, while SLC31A1 siRNA or copper chelator ammonium tetrathiomolybdate (TTM) blocked these promoting effects. Similarly, CuCl₂ also induced fibrosis gene expression, while SLC31A1 overexpression (SLC31A1-O) further enhanced these effects, but TTM reduced CF activation induced by CuCl₂ plus SLC31A1-O. In addition, AGEs significantly promoted cell migration and enhanced the expression and secretion of matrix metalloproteinase (MMP)-2 and MMP-9, while SLC31A1 siRNA or TTM weakened these effects. SLC31A1-O plus copper treatment also had similar effects to AGEs, and these effects could also be blocked by TTM. Therefore, AGEs enhance copper transport by promoting SLC31A1 expression, which leads to intracellular copper overload and then induces cuproptosis, and finally promotes CF activation and migration.</p>","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"10915818261443964"},"PeriodicalIF":1.0,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147728887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sub-Cytotoxic Mitochondrial Stress in Cardiomyocytes and Whole-Organism Toxicity in <i>C. elegans</i> Induced by Molnupiravir.","authors":"Zehra Keskin, Ebru Didem Kuran, Meltem Gulec, Gul Ozhan, Aysenur Gunaydin-Akyildiz","doi":"10.1177/10915818261440558","DOIUrl":"https://doi.org/10.1177/10915818261440558","url":null,"abstract":"<p><p>Many antiviral agents are known to induce off-target mitochondrial toxicity due to the prokaryotic origin of mitochondria. Mitochondrial dysfunction is frequently linked to cardiotoxicity. We aimed to elucidate the mitochondrial toxicity profile of molnupiravir via focusing on mitochondrial dynamics, biogenesis, and oxidative stress in cardiac cells. Mitochondrial function was evaluated by luminometric measurement of ATP (adenosine triphosphate) content, and flow cytometric analysis of mitochondrial membrane potential, and mitochondrial mass. The expression levels of genes involved in mitochondrial fusion-fission were assessed by RT-PCR. In addition, molecular docking analysis was performed to evaluate the interaction between molnupiravir and the dynamin related-protein DRP1. Protein carbonylation was determined as an oxidative stress parameter. Toxicity evaluation was further investigated in <i>Caenorhabditis elegans</i> to support the in vitro findings at the organismal level. Molnupiravir exposure led to a significant dose-dependent reduction in intracellular ATP level and mitochondrial mass, accompanied by increased protein carbonylation. Mitochondrial membrane potential remained slightly increased. Alterations in the expression of genes regulating mitochondrial dynamics suggested an imbalance between fusion and fission processes, while mitochondrial biogenesis-related signaling was progressively suppressed. <i>C. elegans</i> exposed to higher concentrations of the drug (20-500 µM) exhibited significant lifespan reduction at all doses. Molecular docking analysis demonstrated a moderate binding affinity of molnupiravir to DRP1, supporting a potential direct interaction with mitochondrial fission machinery. In conclusion, our results demonstrate that molnupiravir induces mitochondrial stress through oxidative damage, impaired biogenesis, and altered dynamics, emphasizing the need for careful evaluation of mitochondrial safety of molnupiravir in cardiac tissue.</p>","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"10915818261440558"},"PeriodicalIF":1.0,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147638755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety Assessment of Dodecanedioic Acid (Dodecanedioic Acid Disodium Salt) Using Genotoxicity and Repeated 28-day Oral Toxicological Evaluation.","authors":"Deepali Sharma, Mangi Lal Choudhary, Pragati Bawankar, Sagar Kadam, Shruthy R Prasad, Dhanashree Jadhav, Mahalakshmi Raj, Mital Ravalji, Margitta Dziwenka, Katrina V Emmel","doi":"10.1177/10915818261431749","DOIUrl":"https://doi.org/10.1177/10915818261431749","url":null,"abstract":"<p><p>To evaluate the safety of Metabolyte™ (sodium dodecanedioate) for human consumption, results from <i>in vitro</i> and <i>in vivo</i> studies are reported, including a bacterial reverse mutation assay, an <i>in vitro</i> mammalian chromosome aberration test, an <i>in vivo</i> mammalian bone marrow micronucleus test, an <i>in vivo</i> mammalian bone marrow chromosome aberration test, and a 28-day repeat-dose oral toxicological evaluation. Metabolyte™ was not mutagenic in the <i>in vitro</i> and <i>in vivo</i> studies. In the 28-day study, Wistar rats were administered Metabolyte™ by gavage at doses of 0 (G1), 3250 (G2), 6500 (G3), and 13,100 (G4) mg test article/kg bw/day. Histological examination did not reveal any test item related lesions. In the G3 and G4 dose groups, significantly altered electrolyte levels and decrease in sodium and chloride levels in males, and increase in calcium and phosphorous in females, are indicative of possible kidney malfunction. The observed significant increase in triglycerides in G4 males and G3 and G4 females and bile acid in G3 and G4 males and G4 females, decrease in globulin and concurrent increase in albumin/globulin ratio in G4 males, and increase/decrease in ALT in G4 males and females indicate liver malfunction. Significant alterations in motor activity were observed, along with an increase in alkaline phosphatase, in G3 and G4 female animals. Significant changes in absolute relative weight of kidney and liver were detected in G4 females. The NOAEL was considered to be 3250 mg/kg bw/day, as at this dose there were no toxicologically relevant treatment-related findings in male or female rats.</p>","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"10915818261431749"},"PeriodicalIF":1.0,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147443669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editor's Note.","authors":"","doi":"10.1177/10915818261431887","DOIUrl":"https://doi.org/10.1177/10915818261431887","url":null,"abstract":"","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"10915818261431887"},"PeriodicalIF":1.0,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147390069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Industry Perspective on Key Considerations for the ICH S13 Guidance: Nonclinical Safety Evaluations of Oligonucleotide-Based Therapeutics.","authors":"Jennifer D Sisler, Patrik Andersson, Alan Brown, Carole Harbison, Onyi Irrechukwu, Helen Lightfoot, Michaël Maes, Sucheta Mukherjee, Joel D Parry, Justin Schumacher, Anna Westlind Johnsson, Yi Yang, Tod A Harper","doi":"10.1177/10915818261417235","DOIUrl":"10.1177/10915818261417235","url":null,"abstract":"<p><p>Oligonucleotide therapeutics (ONTs) are a growing class of nucleic acid-based therapies with the potential to treat a variety of diseases through several different mechanisms of action (MoA). The most prevalent MoA entails the inhibition of therapeutically relevant levels of protein expression via mRNA degradation, exemplified by numerous approved ONTs. ONTs have unique physicochemical properties, pharmacokinetic characteristics, and MoAs that are distinct from other drug classes. The result can be a disconnect between the administered dose, plasma drug concentrations, pharmacodynamics, and toxicity. Thus, ONT development poses unique scientific and regulatory challenges that are not fully addressed by current International Council for Harmonisation (ICH) guidelines. The complexity of ONT development has recently been recognized with the acceptance of the new ICH topic proposal \"ICH S13-Nonclinical Safety Evaluation of Oligonucleotide-based Therapeutics.\" In preparation for the ICH S13 Step 2 public consultation period, the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) DruSafe ONT Working Group convened to identify and discuss key considerations for ONT development, and to communicate areas where regulatory clarity and harmonization are most needed. Specifically, these include strategies to assess off-target toxicities, safety pharmacology, general toxicity studies, First-In-Human dose selection, genotoxicity studies, reproductive and developmental toxicity studies, carcinogenicity assessments, and the appropriate use of a surrogate molecule in development. The intended goals of this paper are to provide a means for communicating input towards the ICH process and to provide a resource for assisting with the public review of the draft ICH S13 Guidance.</p>","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"127-135"},"PeriodicalIF":1.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13053874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146018490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathology as a Core Discipline in the Biological Evaluation of Medical Devices.","authors":"Kathleen A Funk, JoAnn C L Schuh, Brad Bolon, Valerie Thomas, Jeffrey I Everitt, Abraham Nyska, Jaime Paulin","doi":"10.1177/10915818251388381","DOIUrl":"10.1177/10915818251388381","url":null,"abstract":"<p><p>The device development process encompasses an intersection of biological, physical, and engineering sciences principles culminating in translation of data from nonclinical animal studies to predict potential tissue responses in human patients. Evaluation of tissue reactions to the implanted device relies heavily on the core discipline of toxicologic pathology. Historically and currently, a disconnect between physical and biological scientists is highlighted by the frequent miscommunications due to differences in scientific language and divergent approaches to animal study design and/or data generation and interpretation. To facilitate communication among biologists, engineers, and materials scientists in the medical device community, this article provides fundamental principles and key resources necessary for rational pathology evaluation of tissue responses to implanted devices from the expert perspective of experienced toxicologic pathologists. The unique contributions of toxicologic pathologists to developing and marketing medical devices will be discussed, emphasizing the role of expert pathologists in balancing scientific issues with respect to evaluating biological responses and regulatory considerations. Additionally, discrepancies will be addressed that may arise if regulatory guidance is applied rigidly rather than adjusted as warranted by the context-specific evidence to best answer particular safety-related questions.</p>","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"157-170"},"PeriodicalIF":1.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145563977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ozone Preexposure Exacerbates Septic Lung Injury Through ADAR1 Modulation and Pyroptosis Activation.","authors":"Quanzhen Wang, Yajun Liu, Yuke Zhang, Lei Zhou, Tiangang Zhou, Fen Liu, Huanqin Chen, Zhiming Jiang","doi":"10.1177/10915818251391421","DOIUrl":"10.1177/10915818251391421","url":null,"abstract":"<p><p>Chronic ozone exposure in urban environments compromises lung function, predisposing individuals to severe sepsis outcomes from common infections. Pyroptosis, a type of programmed cell death, is implicated in sepsis and lung injury, and its regulation is crucial for understanding disease severity. We focused on pyroptosis due to its role in inflammation, tissue damage, and organ dysfunction in septic patients, as well as its link to ozone exposure through inflammasome activation. To elucidate the underlying molecular mechanisms, we integrated bioinformatics and experimental approaches. We analyzed public genomic data repositories to identify pyroptosis-related genes and those linked to sepsis and ozone-induced lung injury. Three pyroptosis-related genes (caspase-1, interleukin-1β, and gasdersmin D) were upregulated, while adenosine deaminase acting on RNA 1 (ADAR1) was downregulated. To validate these findings, mice were exposed to ozone followed by lipopolysaccharide-induced sepsis. After 12 hours, lung tissue damage, inflammation, and pyroptosis were assessed. Two-way ANOVA revealed significant LPS × ozone interactions, with one-way ANOVA showing dose-dependent ozone effects on inflammation and pyroptosis. Results confirmed the bioinformatics predictions, showing ADAR1 levels initially increased in septic mice but declined with ozone exposure. Concurrently, ozone exacerbated caspase-1-mediated pyroptosis in lung tissue. Our findings demonstrate that ozone preexposure worsens septic lung injury by modulating ADAR1 and pyroptosis. By elucidating the ADAR1-pyroptosis interplay, this study highlights a novel mechanism contributing to the pathogenesis of ozone-induced lung injury in sepsis, revealing ADAR1 as a key regulatory molecule.</p>","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"198-211"},"PeriodicalIF":1.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145504077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FDA/CDER/OND Experience With New Approach Methodologies (NAMs).","authors":"Jia Yao, Jackye Peretz, Ilona Bebenek, Amy Avila, Tessie Alapatt, Bo Lee, Dakshesh Patel, Paul Brown, Karen Davis-Bruno","doi":"10.1177/10915818251384270","DOIUrl":"10.1177/10915818251384270","url":null,"abstract":"<p><p>The U.S. Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER), and Office of New Drugs (OND) has continuously encouraged the submission of nonclinical tests utilizing new approach methodologies (NAMs) and sponsor engagement with regulators to optimize NAM utility in supporting the safety and efficacy of new drugs. Previously, we published an FDA/CDER perspective on nonclinical testing strategies, discussed the opportunities and challenges of using NAMs to replace, reduce, and refine animal testing in drug development, and reported gaps and challenges underserved by existing nonclinical testing approaches that CDER Pharmacology/Toxicology reviewers face. Here, we demonstrate how FDA/CDER has historically incorporated NAMs into standard nonclinical assessments, describing how specific tests became validated and internationally accepted alternatives to animal testing for regulatory decision-making. We also provide a CDER/OND Pharmacology/Toxicology reviewer perspective on NAMs submitted to support new drug development, in an effort to provide insight into our experience with NAMs submitted for CDER-regulated products. Furthermore, we provide a CDER/OND Pharmacology/Toxicology reviewer perspective on the future of NAM incorporation into nonclinical development programs for new drugs as scientific technology continues to evolve. Ultimately, we hope that by sharing the FDA/CDER/OND experience with NAMs thus far and providing considerations for refining NAM submissions, we will (1) illustrate our scientific approach to evaluating NAM submissions, (2) reiterate FDA/CDER's steadfast commitment to the 3Rs, and (3) foster confidence in our continued efforts to encourage nonclinical test NAM submissions for regulatory decision-making, while maintaining our mission to protect public health and patients from unintended harm.</p>","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"136-156"},"PeriodicalIF":1.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12666506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145504037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}