Regulatory Toxicology and Pharmacology最新文献

{"title":"Countdown to 2027 - maximising use of NAMs in food safety assessment: closing the gap for regulatory assessments in Europe.","authors":"Adam Wood, Franck Atienzar, Danilo Basili, Myriam Coulet, Rebeca Fernandez, Melina Galano, Maricel Marin-Kuan, Gina Montoya, Przemyslaw Piechota, Ans Punt, Elena Reale, Si Wang, Paul Hepburn","doi":"10.1016/j.yrtph.2025.105863","DOIUrl":"https://doi.org/10.1016/j.yrtph.2025.105863","url":null,"abstract":"<p><p>Safety assessments of regulated food products in the European Union (EU) largely rely on experimental animal studies. Currently, the European Commission is developing a roadmap to phase out animal testing for chemical safety assessment across all relevant pieces of legislation, including foods, while the ambition of the European Food Safety Authority (EFSA) is that by 2027, new scientific developments, i.e., new approach/non-animal methods (NAMs), will be integrated into assessments leading to \"the minimisation of animal testing\". However, considering recent requests that have been made to conduct new animal studies for some regulated products, significant progress is required to minimise further and ultimately replace animal testing in the food safety environment. To advance this, we review several NAMs amenable for use in food safety assessment and reflect on their presence in EU food safety regulation and sectoral guidance. For many years, proposals to incorporate NAMs into food safety assessments have been made with questionable regulatory impact. Therefore, we present several amendments which could be made to the EU food regulatory system and current strategies towards phasing out animal testing which, if taken up, could lead to a tangible difference in the extent of animal testing within the food safety environment. Recognising that research may be required for some of these NAMs to enhance regulatory uptake, we propose potential follow-up projects that complement recent research & innovation (R&I) needs published by EFSA which food safety stakeholders could coordinate or participate in.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105863"},"PeriodicalIF":3.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192128","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":"Mechanism and marker of voriconazole-induced liver injury: insights from a quantitative systems toxicology approach.","authors":"Qian Du, Yulan Qiu, Luting Yang, Chuhui Wang, Mengmeng Teng, Jiaojiao Chen, Yu Luo, Jinyao Sun, Taotao Wang, Siying Chen, Yalin Dong","doi":"10.1016/j.yrtph.2025.105871","DOIUrl":"https://doi.org/10.1016/j.yrtph.2025.105871","url":null,"abstract":"<p><p>Liver injury severely limits the clinical use of voriconazole. Clarifying the mechanism and markers of voriconazole-induced liver injury is of great significance. In this study, a quantitative systems toxicology model of voriconazole-induced liver injury was constructed through integrating the mechanism-based hepatoxic parameters generated from in vitro assays into a self-built physiologically based pharmacokinetic model. The hepatotoxic substances, main mechanism, dose correlation and markers of voriconazole-induced liver injury were determined according to liver injury incidence of simulated populations. The voriconazole-treated mice, voriconazole or voriconazole N-oxide (VNO)-treated HepG2 were used to validate the relationship of liver injury with oxidative stress and VNO. The results demonstrated that the incidence of voriconazole-induced liver injury was 17.9%, which was dose-dependent. VNO-induced oxidative stress contributed most to liver injury, which was manifested by reactive oxygen species (ROS) accumulation and antioxidant enzymes inhibition. Liver ROS/reactive nitrogen species baseline clearance V_max and antioxidant enzymes activities were negatively correlated to plasma liver function indicators elevation and liver adenosine triphosphate loss. We concluded that VNO-induced oxidative stress was the main cause of voriconazole-induced liver injury, and basic antioxidant capability indicators might be potential markers. This study may provide new insights for mechanism understanding and early warning of voriconazole-induced liver injury.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105871"},"PeriodicalIF":3.0,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187845","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":"Toltrazuril sulfone (Ponazuril) residue depletion in pig tissues and estimated withdrawal intervals.","authors":"Laura M Neumann, Farha Sheela, Hiroko Enomoto, Jeremy Pittman, Ronald E Baynes","doi":"10.1016/j.yrtph.2025.105860","DOIUrl":"https://doi.org/10.1016/j.yrtph.2025.105860","url":null,"abstract":"<p><p>Ponazuril (Marquis®) is a triazine based antiprotozoal medication labeled to treat equine protozoal myeloencephalitis in the United States. Ponazuril is often used in an extra-label manner to treat coccidiosis in piglets, but tissue residue data is limited. In this study, piglets were given a single oral dose of 5 mg/kg ponazuril. Piglets (n=5) were euthanized at eleven timepoints (0, 15, 28, 43, 57, 71, 85, 99, 113, 127, and 141 days) with tissue sample collection and chromatographic analysis. The maximum residue limit (MRL) values established by the European Medicines Agency (EMA) and our laboratory limits of detection (LOD) were used as the safe levels to estimate withdrawal intervals (WDIs). Based on MRL values, the WDIs for liver, kidney, muscle and fat were approximately 72 days, 176 days, 90 days and 81 days, respectively. As this is extra-label use, any residue detected will be a violation. If the LOD was used instead of the MRL values, the WDIs would extend to as much as 130 days (liver), 270 days (kidney), 105 days (muscle), and 101 days (fat).</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105860"},"PeriodicalIF":3.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181257","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":"A multi-dimensional comparative study of 505(b)(2) NDAs approved by FDA and Class 2 NDAs approved by NMPA from 2017 to 2023: Uncovering trends, characteristics, and regulation of modified new drugs","authors":"Lixia Fu ,&nbsp;Songtao Dong ,&nbsp;Ran Xie ,&nbsp;Guoshu Jia ,&nbsp;Nan Zhao ,&nbsp;Qian Xiang ,&nbsp;Xiwei Ji ,&nbsp;Xia Zhao ,&nbsp;Xiaoyuan Chen ,&nbsp;Lingyue Ma ,&nbsp;Yimin Cui","doi":"10.1016/j.yrtph.2025.105864","DOIUrl":"10.1016/j.yrtph.2025.105864","url":null,"abstract":"<div><div>Modified new drugs are pivotal in advancing innovative therapies through repurposing existing therapeutic agents. The regulatory framework, including the pertinent regulations and policies, plays a crucial role in shaping the development and evolution of these drugs. This retrospective study systematically compared the regulatory approvals of modified new drugs via the 505(b)(2) new drug application (NDA) pathway in the United States (US) and Class 2 NDA pathway in China from 2017 to 2023, which focused on distinctions in registration classifications, availability, therapeutic indications, dosage forms, modifications, clinical advantages and clinical study designs. The findings indicate that the US has more detailed and comprehensive classification systems, as well as a higher number of approvals (417 vs. 99). Moreover, the modified new drugs approved in China still exhibit significant gaps in indication distribution, dosage forms, and modifications compared to those in the US. Notably, a greater proportion of confirmatory clinical studies were conducted for Class 2 NDAs (81.4 %) than 505(b)(2) NDAs (41.0 %), with a significant difference in the use of active controls (48.6 % in China vs. 26.4 % in the US, <em>P = 0.002</em>). Additionally, the combination of emerging technologies in modified new drugs presents both technical and regulatory challenges for authorities. It raises worthwhile questions about how regulators will evaluate medical products developed with entirely new technologies. Therefore, it is recommended that Chinese regulators refine registration classifications, reassess the positioning of modified new drugs, and expand the definition of clinical advantage within the policy and regulatory framework. These measures are essential for addressing unmet medical needs and fostering a conducive ecosystem for the advancement of modified new drugs.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105864"},"PeriodicalIF":3.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144182727","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":"Unknown confidence in chemical characterization identification levels: When tentative identifications are adequate for toxicological risk assessment of medical devices","authors":"Stephanie M. Street ,&nbsp;Rebecca A. Bader ,&nbsp;Whitney V. Christian","doi":"10.1016/j.yrtph.2025.105862","DOIUrl":"10.1016/j.yrtph.2025.105862","url":null,"abstract":"<div><div>Identifying chemicals is critical to chemical characterization and toxicological risk assessments (TRAs) for evaluating patient safety risks posed from medical devices. The burden to accurately identify substances with limited information is high. There is lack of consensus on the confidence needed for compound identifications to conduct a TRA. To address this gap, chemical characterization reports and TRAs were evaluated, and many tentatively identified compounds were grouped into chemical classes, which may consist of all tentative identifications or a mixture of identifications, then treated as one compound. By using this approach, the confidence level of each group member was not used to modulate the outcome of the risk assessment, obviating the need for confirmed identification of each group member. By understanding the downstream confidence level utilization, the burden involved in determining confident identification for all compounds detected during chemical characterization can be reduced to aspects of compound identification that may pose higher toxicological importance. A decision tree was developed to focus the identification process on compounds of interest as well as a method to assign confidence levels. This tool can be used to reduce the burden in identifying individual confidence levels without compromising the reliability of the conclusion of the TRA.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105862"},"PeriodicalIF":3.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144182232","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":"Can acute oral in vivo toxicity testing for EU REACH be fully replaced by a QSAR method? Evaluation of the CATMoS model using chemical industry data.","authors":"Anastasia Weyrich, Niklas Peter, Nico Watzek, Sarah Michael, Birthe Lauer, Juliane Zwinkmann, Wera Teubner","doi":"10.1016/j.yrtph.2025.105861","DOIUrl":"https://doi.org/10.1016/j.yrtph.2025.105861","url":null,"abstract":"<p><p>The assessment of acute oral toxicity is a fundamental endpoint for health hazard and risk assessment and a standard information requirement under REACH. The European Commission plans to update the standard information requirements, focusing on integrating non-animal-based information, proposing CATMoS as the preferred in silico tool. We evaluated the ability of CATMoS to predict GHS classification for acute oral toxicity using 860 REACH-registered chemicals. The output parameters of CATMoS were combined with an expert judgement of data quality and nearest neighbor analysis to assign a reliability category (high, moderate, or low). In a subset of 20 chemicals, predictions showed about one third each with high, moderate, and low reliability. High reliability predictions matched the experimentally determined GHS category or an adjacent one, aligning with the variability of in vivo rat acute LD50 data. Solely relying on CATMoS output could result in accepting predictions differing by two or more hazard categories, emphasizing the need for expert judgement. In conclusion, CATMoS only in combination with expert judgement is suitable as a replacement for acute oral toxicity studies under REACH if a prediction with high reliability is available and all available information is analyzed and reported as described in the QSAR assessment framework.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105861"},"PeriodicalIF":3.0,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174328","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":"Rivastigmine as an Alternative in Physostigmine Shortage for Anticholinergic Toxicity Treatment.","authors":"Omid Mehrpour, Mario Marini, Samaneh Nakhaee","doi":"10.1016/j.yrtph.2025.105857","DOIUrl":"https://doi.org/10.1016/j.yrtph.2025.105857","url":null,"abstract":"<p><p>Anticholinergic toxicity, a medical emergency characterized by symptoms such as dry mouth, blurred vision, severe delirium, and tachycardia, necessitates prompt and effective intervention. The traditional go-to treatment has been physostigmine, a reversible cholinesterase inhibitor known for its ability to cross the blood-brain barrier (BBB). However, the occasional scarcity of physostigmine has led healthcare professionals to consider alternative treatments, with rivastigmine emerging as a potential candidate (1). This article delves into the feasibility of using rivastigmine as a substitute, focusing on its ability to penetrate the brain and its effectiveness in managing anticholinergic toxicity.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105857"},"PeriodicalIF":3.0,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143335","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":"How useful are 3-month repeat-dose toxicology studies for the development of T cell engagers for oncology indications?","authors":"Petra Lutterbuese, d'Argouges Sandrine, Matthias Friedrich, Christine Mollica, Famke Aeffner, Jonathan Werner, Benno Rattel, Oliver Thomas","doi":"10.1016/j.yrtph.2025.105859","DOIUrl":"https://doi.org/10.1016/j.yrtph.2025.105859","url":null,"abstract":"<p><p>Development of T cell engagers (TCEs) for oncology indications is regulated mainly by ICH S6 and S9. Investigational new drug applications are usually supported by a 1-month toxicology study in a relevant animal species. Before the start of registrational clinical trials, a longer-duration toxicology study, typically 3 months, is performed in the same species to support marketing. As longer-term studies with human-specific biologics in animal species can be hampered by development of anti-drug antibodies and TCEs are quick-acting molecules, we analyzed the value of 3-month toxicology studies for some of our TCEs. We present data from 1- and, where applicable, 3-month toxicology studies for 4 TCE programs and describe our interactions with regulatory agencies. In none of the cases did the 3-month studies reveal new information to influence further the respective clinical development plans. Considering 3Rs (Replacement, Reduction and Refinement) in pharmaceutical development, we highlight that 3-month studies with TCEs don't always offer additional safety insights. Therefore, alternative strategies should be evaluated and conduct of 3-month studies carefully considered in the light of 3Rs and discussed case-by-case with health authorities.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105859"},"PeriodicalIF":3.0,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143328","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":"Elucidation of 28 day repeated oral dose induced genotoxicity potential of nickel (II) oxide nanoparticles in wistar albino rats","authors":"Naresh Dumala ,&nbsp;Srilekha Chintala ,&nbsp;Bhanuramya Mangalampalli ,&nbsp;Rekhadevi Perumalla Venkata","doi":"10.1016/j.yrtph.2025.105858","DOIUrl":"10.1016/j.yrtph.2025.105858","url":null,"abstract":"<div><div>Nanotechnology has revolutionized industrial processing and human life by the applications of nanoparticles (NPs), especially the metal oxide ones. Nickel oxide (NiO) NPs have been used in applications including electronics and biosensors. Occupational and accidental exposure to these NPs for longer durations is apparent and the same may lead to significant health risks. In the present study, we have elucidated the genotoxic ability of NiO-NPs post repeated oral exposure for 28 days in Wistar albino rats at 50, 100, and 200 mg/kg body weight doses. A dose dependent percentage tail DNA was recorded in the peripheral blood lymphocyte, liver and bone marrow cells on rats at all the doses tested. The micronucleus and CA tests using bone marrow cells showed the prominent DNA damage potential of NiO-NPs corroborating the comet assay results. Primary interaction of NiO-NPs or nickel ions generated from NiO-NPs and secondary interaction of reactive oxygen species generated in response to NiO-NPs toxic insult with the DNA are the suspected reasons for observed genotoxicity. This study highlights the probability of DNA damaging effects in non-target organisms when exposed to NiO-NPs for a long time. Investigations to elucidate the NiO-NPs mediated adverse effects on terrestrial organisms are warranted.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"161 ","pages":"Article 105858"},"PeriodicalIF":3.0,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144139214","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":"Reproductive and developmental toxicity risk assessment for 4-methylimidazole.","authors":"Anthony R Scialli","doi":"10.1016/j.yrtph.2025.105856","DOIUrl":"https://doi.org/10.1016/j.yrtph.2025.105856","url":null,"abstract":"<p><p>4-Methylimidazole (4-MEI) is present in caramel color for food and beverages and as a by-product of the thermal treatment of food. A risk assessment for 4-methylimidazole reproductive and developmental effects was conducted using data from a National Toxicology Program Reproductive Assessment by Continuous Breeding and using 90^th percentile dietary exposure data from the U.S. Food and Drug Administration. The National Toxicology Program reported reproductive and developmental toxicity in Sprague Dawley rats from high dietary exposure to 4-MEI. Using the benchmark dose method of modeling dose-response curves, the lowest margin of exposure (MOE) was 1489. Using the traditional no observed adverse effect level (NOAEL)/lowest observed adverse effect level (LOAEL), the margin of exposure at the 90^th percentile human consumption was 735. MOEs of 100 or greater are considered to be of low concern. In conclusion, human exposure to 4-MEI in the diet in the United States is not expected to confer risk to reproduction or development.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105856"},"PeriodicalIF":3.0,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143331","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}