Regulatory Toxicology and Pharmacology最新文献

Updated assessment of the genotoxic potential of titanium dioxide based on reviews of in vitro comet, mode of action and cellular uptake studies, and recent publications. 根据对体外彗星、作用模式和细胞吸收研究的审查以及最近的出版物，对二氧化钛的遗传毒性潜力进行最新评估。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-11-02 DOI: 10.1016/j.yrtph.2024.105734

David Kirkland, Arne Burzlaff, Andreas Czich, Shareen H Doak, Paul Fowler, Stefan Pfuhler, Leon F Stankowski

{"title":"Updated assessment of the genotoxic potential of titanium dioxide based on reviews of in vitro comet, mode of action and cellular uptake studies, and recent publications.","authors":"David Kirkland, Arne Burzlaff, Andreas Czich, Shareen H Doak, Paul Fowler, Stefan Pfuhler, Leon F Stankowski","doi":"10.1016/j.yrtph.2024.105734","DOIUrl":"https://doi.org/10.1016/j.yrtph.2024.105734","url":null,"abstract":"<p><p>In 2021 the European Food Safety Authority (EFSA) concluded that \"A concern for genotoxicity of TiO2 particles that may be present in E 171 could therefore not be ruled out.\". A detailed review of the genotoxicity of titanium dioxide (TiO<sub>2</sub>) was subsequently published by Kirkland et al. (2022) using a comprehensive weight of evidence (WoE) approach in which test systems and endpoints were allocated different levels of relevance. At that time only 34 publications met the reliability and quality criteria for being most relevant in the evaluation of genotoxicity, and based on these it was concluded that the existing evidence did not support a direct DNA damaging mechanism for TiO<sub>2</sub>. Recently a number of regulatory opinions have been published, in which papers were cited that described in vitro DNA damage (mainly comet), mode of action, and cellular uptake studies that were not discussed in Kirkland et al. (2022). Furthermore, a number of additional papers have been published recently or have been identified from the regulatory opinions as a result of using extended search criteria. A total of 70 publications not previously reviewed in Kirkland et al. (2022) have been reviewed here, and again show that the published data on the genotoxicity of TiO<sub>2</sub> are inconsistent, often of poor quality, and in some cases difficult to interpret. The cellular uptake studies show some evidence of cytoplasmic uptake, particularly in cells treated in vitro, but there is no convincing evidence of nuclear uptake. In terms of genotoxicity, the conclusions of Kirkland et al. (2022) that existing evidence does not support a direct DNA damaging mechanism for titanium dioxide (including nano forms), and that the main mechanism leading to TiO<sub>2</sub> genotoxicity is most likely indirect damage to DNA through generation of reactive oxygen species (ROS), are still valid.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569010","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}

引用次数: 0

Endocrine-disrupting chemicals - pesticide regulatory issues from the EU perspective. 干扰内分泌的化学品--欧盟视角下的农药监管问题。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-11-02 DOI: 10.1016/j.yrtph.2024.105735

Monika Liszewska, Katarzyna Czaja, Wojciech Korcz, Radosław Lewiński, Paweł Struciński

{"title":"Endocrine-disrupting chemicals - pesticide regulatory issues from the EU perspective.","authors":"Monika Liszewska, Katarzyna Czaja, Wojciech Korcz, Radosław Lewiński, Paweł Struciński","doi":"10.1016/j.yrtph.2024.105735","DOIUrl":"10.1016/j.yrtph.2024.105735","url":null,"abstract":"<p><p>Endocrine-disrupting chemicals (EDCs), including substances used in plant protection products (PPPs), are a source of ongoing concern for the EU society. Under the EC Regulation 1107/2009, the endocrine-disrupting (ED) properties of active substances, safeners, and synergists used in PPPs shall be investigated. The scientific criteria established by the Regulation (EU) 2018/605 and the joint guidance of the European Chemicals Agency (ECHA)/European Food Safety Authority (EFSA) provide the basis for this assessment. Data requirements for the approval of safeners and synergists have been recently published in Commission Regulation (EU) 2024/1487, allowing a consistent assessment of these substances. The approach to assessing co-formulant hazards is currently a subject of EU-wide discussion. It outlines the necessity to take into account information or evaluation data from other than pesticides' EU regulatory frameworks, such as REACH or SCCS applications for cosmetic ingredients. This paper outlines: a) current EU approach applied for identification of endocrine disrupting properties of pesticides; b) issues related to European regulations that may have an indirect impact on the safe use of plant protection products and c) an analysis of the European Commission's activities aimed to limit exposure to EDCs associated with use of PPPs in the society.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568879","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}

引用次数: 0

Statistical applications of virtual control groups to nonrodent animal toxicity studies: An initial evaluation. 虚拟对照组在非啮齿动物毒性研究中的统计应用：初步评估。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-10-31 DOI: 10.1016/j.yrtph.2024.105733

Dingzhou Li, Jeonifer Garren, Raja Mangipudy, Matthew Martin, Lindsay Tomlinson, Nichole R Vansell

{"title":"Statistical applications of virtual control groups to nonrodent animal toxicity studies: An initial evaluation.","authors":"Dingzhou Li, Jeonifer Garren, Raja Mangipudy, Matthew Martin, Lindsay Tomlinson, Nichole R Vansell","doi":"10.1016/j.yrtph.2024.105733","DOIUrl":"10.1016/j.yrtph.2024.105733","url":null,"abstract":"<p><p>Utilization of data from historical control animals to form virtual control groups (VCGs) is an innovative approach to embody the 3Rs (reduce, refine, and replace use of control animals) principle in research. However, there is no available systematic comparison of statistical performance between concurrent control groups (CCGs) and VCGs in nonrodent safety assessment. The optimal selection criteria and combination of VCGs and CCGs also remain unclear. This study retrospectively evaluated VCGs' statistical performance to detect test article effects on body weight and clinical pathology endpoints in dog and nonhuman primate (NHP) systemic toxicity studies. Body weight and six clinical pathology endpoints were analyzed against the reported study findings from a cohort of 22 previously reported nonrodent 1-month oral gavage toxicity using three different methods of generating VCGs. When the fold change from baseline was used, VCGs yielded a similar or higher statistical sensitivity to detect test article relatedness than CCGs. Compared to simple random sampling or using fixed criteria, the propensity score matching by BW, age, and year of study initiation yielded higher sensitivities. Our analysis supports the hypothesis that VCGs can be a viable instrument in nonrodent toxicity studies.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564866","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}

引用次数: 0

Opportunities and Challenges for Use of Minipigs in Nonclinical Pharmaceutical Development: Results of a Follow-Up IQ DruSafe Survey. 在非临床药物开发中使用迷你猪的机遇与挑战：IQ DruSafe 调查的后续结果。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-10-29 DOI: 10.1016/j.yrtph.2024.105729

David O Clarke, Kaushik Datta, Kevin French, Michael W Leach, Drew Olaharski, Susanne Mohr, Devon Strein, Jeannine Bussiere, Bianca Feyen, Beatrice E Gauthier, Michael Graziano, Joanna Harding, Kenneth Hershman, Binod Jacob, Shaofei Ji, Robert Lange, Smita Salian-Mehta, Brian Sayers, Nicole Thomas, Thierry Flandre

{"title":"Opportunities and Challenges for Use of Minipigs in Nonclinical Pharmaceutical Development: Results of a Follow-Up IQ DruSafe Survey.","authors":"David O Clarke, Kaushik Datta, Kevin French, Michael W Leach, Drew Olaharski, Susanne Mohr, Devon Strein, Jeannine Bussiere, Bianca Feyen, Beatrice E Gauthier, Michael Graziano, Joanna Harding, Kenneth Hershman, Binod Jacob, Shaofei Ji, Robert Lange, Smita Salian-Mehta, Brian Sayers, Nicole Thomas, Thierry Flandre","doi":"10.1016/j.yrtph.2024.105729","DOIUrl":"https://doi.org/10.1016/j.yrtph.2024.105729","url":null,"abstract":"<p><p>Minipigs are valid nonrodent species infrequently utilized for pharmaceutical research and development (R&D) compared with dogs or nonhuman primates (NHPs). A 2022 IQ DruSafe survey revealed a modest increase in minipig use by pharmaceutical companies compared with a prior 2014 survey, primarily in the development of oral small molecules and parenteral protein molecules. Some companies considered using minipigs more often due to NHP shortages and regional ethical concerns with using NHPs and dogs. However, for most pharmaceutical companies, minipigs still represent ≤5% of their nonrodent animal use. Key challenges noted by companies to wider adoption of minipigs were high test article requirement, limited historical control data, and lack of relevant reagents or assays. Additionally, some companies expressed uncertainties about contract research organization (CRO) capabilities and experience, a perception not shared by respondent CROs. These latest survey results indicate persistence of many concerns previously identified in 2014. Several case studies are included to illustrate areas of expanded minipig use as well as the challenges that hinder broader adoption. Ongoing, focused, and industry-wide initiatives to address the identified or perceived challenges may lead to more frequent or routine consideration of minipigs as a test species in pharmaceutical R&D.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558611","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}

引用次数: 0

Toxicological evaluation of vanadium and derivation of a parenteral tolerable intake value for medical devices. 钒的毒理学评估和医疗器械肠外耐受摄入值的推导。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-10-28 DOI: 10.1016/j.yrtph.2024.105732

Charlotte E Laupheimer, Yana Kolianchuk, Rex E FitzGerald, Martin F Wilks, Arne Jaksch

引用次数: 0

The analytical evaluation threshold for inorganic metal extractables and leachables analysis of medical devices. 医疗器械无机金属萃取物和浸出物分析的分析评估阈值。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-10-25 DOI: 10.1016/j.yrtph.2024.105725

Chad P Satori, Catherine D Christensen, Stephanie M Street, Mikaelle Giffin, Christopher M Pohl, Whitney V Christian

{"title":"The analytical evaluation threshold for inorganic metal extractables and leachables analysis of medical devices.","authors":"Chad P Satori, Catherine D Christensen, Stephanie M Street, Mikaelle Giffin, Christopher M Pohl, Whitney V Christian","doi":"10.1016/j.yrtph.2024.105725","DOIUrl":"https://doi.org/10.1016/j.yrtph.2024.105725","url":null,"abstract":"<p><p>Chemical characterization of medical devices uses the analytical evaluation threshold (AET) to determine reportable organic extractables, as these chemicals may be of toxicological concern and should be addressed via toxicological risk assessment. The AET is not applicable to metal extractables due to the exclusion of toxicity data on inorganics from the dataset used to derive dose-based threshold (DBT) values. This results in minimal guidance for reporting metal extractables. Herein, an AET for metals, or mAET, is proposed as a reporting threshold for individual metal extractables. The mAET can ensure metals are reported that are at quantities that may present a patient safety risk. This may reduce the number of metals reported in a chemical characterization report, improving the efficiency of the overall biocompatibility evaluation by removing unneeded effort and resource time. Conversely, an analytical method's ability to report all metals at toxicologically relevant levels can be confirmed by comparing method sensitivity to mAET values. DBTs were developed for 70 metals, permitting mAET values to be determined. These mAET values were then compared to metal reporting limits from 13 previously conducted chemical characterization studies, which used varying extraction designs and analytical methods, to determine the impact of the mAET.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569009","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}

引用次数: 0

Preclinical evaluation of abuse potential of the peripherally-restricted kappa opioid receptor agonist HSK21542 外周限制卡巴阿片受体激动剂 HSK21542 滥用潜力的临床前评估。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-10-23 DOI: 10.1016/j.yrtph.2024.105731

{"title":"Preclinical evaluation of abuse potential of the peripherally-restricted kappa opioid receptor agonist HSK21542","authors":"","doi":"10.1016/j.yrtph.2024.105731","DOIUrl":"10.1016/j.yrtph.2024.105731","url":null,"abstract":"<div><div>HSK21542 is a peripherally-restricted kappa opioid receptor (KOR) agonist developed for pain treatment. Because of the CNS pharmacological concern of opioid receptor activation, such as physical dependence and addiction potential, an assessment of abuse potential of HSK21542 was required prior to marketing approval. The preclinical abuse potential assessments for HSK21542 included the following studies: 1) intravenous self-administration study to explore the relative reinforcing efficacy in rats self-administering remifentanil; 2) rat drug discrimination study to examine the pharmacological similarity of the interoceptive or subjective effects of HSK21542 in rats discriminating pentazocine; 3) rat conditioned place preference (CPP) paradigm to test the rewarding effects; 4) rat natural physical dependence-spontaneous withdrawal study in rats chronically treated with HSK21542; 5) naloxone-precipitated withdrawal assay following chronic HSK21542 exposure to evaluate its physical dependence potential. The results showed that HSK21542 was devoid of behavioral evidence of positive reinforcing effect and did not share similar discriminative stimulus effects with pentazocine. HSK21542 also did not produce CPP in rats. In addition, HSK21542 did not produce spontaneous withdrawal or naloxone-precipitated withdrawal in rats with chronic treatments. Collectively, these preclinical findings suggest that HSK21542 has no abuse potential in animals, which demonstrate low abuse potential in humans.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506670","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}

引用次数: 0

Experiences and initiatives on pharmacokinetic modeling and simulation data analysis: Perspectives from the Brazilian Health Regulatory Agency (ANVISA). 药物动力学建模和模拟数据分析方面的经验和举措：巴西卫生监管局（ANVISA）的观点。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-10-22 DOI: 10.1016/j.yrtph.2024.105728

Luiza Novaes Borges, Eduardo Agostinho Freitas Fernandes, Érico Miroro de Oliveira, Victor Gomes Pereira, Andréa Diniz

{"title":"Experiences and initiatives on pharmacokinetic modeling and simulation data analysis: Perspectives from the Brazilian Health Regulatory Agency (ANVISA).","authors":"Luiza Novaes Borges, Eduardo Agostinho Freitas Fernandes, Érico Miroro de Oliveira, Victor Gomes Pereira, Andréa Diniz","doi":"10.1016/j.yrtph.2024.105728","DOIUrl":"10.1016/j.yrtph.2024.105728","url":null,"abstract":"<p><p>The landscape of drug product development and regulatory sciences is evolving, driven by the increasing application of systems thinking and modeling and simulation (M&S) techniques, especially from a biopharmaceutics perspective. Patient-centric quality standards can be achieved within this context through the application of quality by design (QbD) principles and M&S, specifically by defining clinically relevant dissolution specifications (CRDS). To this end, it is essential to bridge in vitro results to drug product in vivo performance, emphasizing the need to explore the translational capacity of biopharmaceutics tools. Physiologically based M&S analyses offer a unique avenue for integrating the drug, drug product, and biological properties of a target organism to study their interactions on the pharmacokinetic response. Accordingly, Physiologically Based Biopharmaceutics Modeling (PBBM) has seen increasing use to support drug development and regulatory applications globally. In Brazil, a Model-Informed Drug Development (MIDD) policy and strategic project are not yet established, limiting applicability of M&S techniques. Drawing from the experience of the ANVISA-Academia PBBM Working Group (WG), this article assesses the opportunities and challenges for pharmacometrics (PMx) in Brazil and proposes strategies to advance the adoption of M&S analyses into regulatory decision-making.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506669","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}

引用次数: 0

Data collection initiatives of the crop protection industry – A mission to improve non-dietary risk assessment in Europe 作物保护行业的数据收集倡议--改善欧洲非饮食风险评估的使命。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-10-20 DOI: 10.1016/j.yrtph.2024.105727

{"title":"Data collection initiatives of the crop protection industry – A mission to improve non-dietary risk assessment in Europe","authors":"","doi":"10.1016/j.yrtph.2024.105727","DOIUrl":"10.1016/j.yrtph.2024.105727","url":null,"abstract":"<div><div>Plant protection products (PPPs) undergo rigorous safety assessments. In Europe, non-dietary risk assessments for operators, workers, bystanders and residents are highly conservative as this area of exposure science has historically been data poor. CropLife Europe (CLE) companies have collaborated to generate new data and pool existing data to refine the approaches prescribed by the European Food Safety Authority (EFSA) guidance on non-dietary exposure (2022).</div><div>This article summarises key activities, beginning with the development of the Agricultural Operator Exposure Model (AOEM) and covers projects which refine current approaches to bystander, resident and re-entry worker assessment, including the Bystander Resident Orchards Vineyards (BROV) project, improvements to the Bystander and Resident Exposure Assessment Model for spray drift (BREAM), proposals for refined vapour inhalation assessments, and a meta-analysis of Dislodgeable Foliar Residue (DFR) data. A study quantifying the benefits of using closed transfer systems, an appraisal of the inherent compounded conservatism in current risk assessment paradigms and the development of a new seed treatment model by the SeedTROPEX taskforce are also introduced.</div><div>These industry-led activities underscore the critical role of non-dietary exposure in the registration process for PPPs and reflect an ongoing commitment to provide farmers with effective crop protection solutions while ensuring safety.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473312","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}

引用次数: 0

Mutagenicity and genotoxicity evaluation of 15 nitrosamine drug substance-related impurities in human TK6 cells 15 种亚硝胺药物相关杂质在人类 TK6 细胞中的突变性和遗传毒性评估。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-10-20 DOI: 10.1016/j.yrtph.2024.105730

{"title":"Mutagenicity and genotoxicity evaluation of 15 nitrosamine drug substance-related impurities in human TK6 cells","authors":"","doi":"10.1016/j.yrtph.2024.105730","DOIUrl":"10.1016/j.yrtph.2024.105730","url":null,"abstract":"<div><div>Nitrosamine drug substance-related impurities (NDSRIs) are a sub-category of <em>N</em>-nitrosamine drug impurities that share structural similarity to the corresponding active pharmaceutical ingredient. The mutagenicity of NDSRIs is poorly understood. We previously tested a series of NDSRIs using the Enhanced Ames Test (EAT). In this follow-up study, we further examined the genotoxicity and mutagenicity of 15 of these NDSRIs in human TK6 cells. Seven EAT-positive NDSRIs, including <em>N</em>-nitroso-nortriptyline, <em>N</em>-nitroso-fluoxetine, <em>N</em>-nitroso-desmethyl-diphenhydramine, <em>N</em>-nitroso-duloxetine, <em>N</em>-nitroso-lorcaserin, <em>N</em>-nitroso-varenicline, and <em>N</em>-nitroso-sertraline, induced concentration-dependent increases in micronuclei after bioactivation with hamster liver S9. These NDSRIs were also mutagenic in the <em>TK</em> and <em>HPRT</em> gene mutation assays, consistent with their positive EAT results. In the presence of hamster liver S9, the eight EAT-negative NDSRIs were negative in the micronucleus assay and negative for mutation induction. Using TK6 cells endogenously expressing a single human cytochrome P450 (CYP), we found that CYP2C19, CYP2B6, CYP2A6, and CYP3A4 are key enzymes activating the genotoxicity and mutagenicity of these NDSRIs. Overall, the hamster S9-mediated TK6 cell mutagenicity results agreed with those observed in the EAT, indicating consistency in the mutagenic responses produced by NDSRIs across different testing systems. These data support the use of EAT for hazard identification and safety assessment of NDSRIs.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473314","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}

引用次数: 0