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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 Q1 MEDICINE, LEGAL 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

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 (TiO2) 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 TiO2. 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 TiO2 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 TiO2 genotoxicity is most likely indirect damage to DNA through generation of reactive oxygen species (ROS), are still valid.

2021 年,欧洲食品安全局(EFSA)得出结论:"因此不能排除 E 171 中可能存在的二氧化钛微粒的遗传毒性问题"。随后,Kirkland 等人(2022 年)采用综合证据权重法(WoE),对二氧化钛(TiO2)的基因毒性进行了详细审查。当时,只有 34 篇出版物符合与遗传毒性评估最相关的可靠性和质量标准,并据此得出结论,现有证据并不支持二氧化钛的直接 DNA 损伤机制。最近发表了一些监管意见,其中引用的论文描述了 Kirkland 等人(2022 年)未讨论的体外 DNA 损伤(主要是彗星)、作用模式和细胞吸收研究。此外,最近还发表了一些其他论文,或通过使用扩展搜索标准从监管意见中发现了一些其他论文。本文共审查了 70 篇未在 Kirkland 等人(2022 年)中审查过的论文,这些论文再次表明,已发表的有关二氧化钛遗传毒性的数据并不一致,通常质量较差,在某些情况下难以解释。细胞摄取研究显示了一些细胞质摄取的证据,特别是在体外处理的细胞中,但没有令人信服的核摄取证据。就遗传毒性而言,Kirkland 等人(2022 年)的结论仍然有效,即现有证据不支持二氧化钛(包括纳米形式)的直接 DNA 损伤机制,导致二氧化钛遗传毒性的主要机制很可能是通过产生活性氧 (ROS) 间接损伤 DNA。
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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 Q1 MEDICINE, LEGAL Pub Date : 2024-11-02 DOI: 10.1016/j.yrtph.2024.105735
Monika Liszewska, Katarzyna Czaja, Wojciech Korcz, Radosław Lewiński, Paweł Struciński

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.

干扰内分泌的化学品(EDCs),包括植物保护产品(PPPs)中使用的物质,是欧盟社会持续关注的问题。根据欧盟委员会第 1107/2009 号法规,应调查植保产品中使用的活性物质、安全剂和增效剂的内分泌干扰(ED)特性。法规(EU)2018/605 制定的科学标准以及欧洲化学品管理局(ECHA)/欧洲食品安全局(EFSA)的联合指南为这一评估提供了依据。欧盟委员会法规(EU)2024/1487 最近公布了安全剂和增效剂审批的数据要求,以便对这些物质进行一致的评估。评估共配制剂危害的方法目前是欧盟范围内讨论的主题。它概述了考虑来自农药以外的欧盟监管框架的信息或评估数据的必要性,如 REACH 或化妆品成分的 SCCS 申请。本文概述了:a) 当前欧盟用于识别农药内分泌干扰特性的方法;b) 可能会对植物保护产品的安全使用产生间接影响的欧洲法规相关问题;c) 对欧盟委员会旨在限制社会中与使用植物保护产品相关的 EDCs 暴露的活动进行分析。
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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 Q1 MEDICINE, LEGAL 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

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.

利用历史对照动物的数据组成虚拟对照组(VCGs)是一种创新方法,可在研究中体现 3R(减少、完善和替代对照动物的使用)原则。然而,在非啮齿动物安全性评估中,目前还没有系统地比较同期对照组(CCGs)和虚拟对照组的统计性能。VCGs和CCGs的最佳选择标准和组合也仍不明确。本研究回顾性地评估了VCGs在狗和非人灵长类动物(NHP)全身毒性研究中检测试验品对体重和临床病理学终点影响的统计性能。使用三种不同的 VCG 生成方法,对照先前报告的 22 项非啮齿类动物 1 个月口服灌胃毒性的研究结果,对体重和六项临床病理终点进行了分析。当使用与基线相比的折叠变化时,VCGs 在检测测试物相关性方面的统计灵敏度与 CCGs 相似或更高。与简单随机抽样或使用固定标准相比,按体重、年龄和研究开始年份进行倾向评分匹配的灵敏度更高。我们的分析支持这样的假设,即在非啮齿动物毒性研究中,VCGs 是一种可行的工具。
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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 Q1 MEDICINE, LEGAL 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

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.

与狗或非人灵长类动物 (NHP) 相比,迷你猪是有效的非啮齿类动物物种,很少被用于药物研发 (R&D)。2022 年 IQ DruSafe 调查显示,与 2014 年的上一次调查相比,制药公司使用迷你猪的情况略有增加,主要用于开发口服小分子药物和肠外蛋白分子药物。一些公司考虑更频繁地使用迷你猪,原因是NHP短缺以及使用NHP和狗的地区伦理问题。然而,对于大多数制药公司而言,迷你猪仍占其非啮齿动物使用量的 ≤5%。公司指出,更广泛采用迷你猪所面临的主要挑战是试验品要求高、历史对照数据有限以及缺乏相关试剂或检测方法。此外,一些公司对合同研究组织 (CRO) 的能力和经验表示不确定,而受访的 CRO 并不认同这种看法。最新调查结果显示,2014 年发现的许多问题依然存在。调查还包括几个案例研究,以说明微型机器人的扩大应用领域以及阻碍更广泛应用的挑战。为解决已发现或感知到的挑战而采取的持续、集中和全行业范围的举措,可能会促使在制药研发中更频繁或更常规地考虑将迷你猪作为试验物种。
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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 Q1 MEDICINE, LEGAL 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

Vanadium is used in alloys, batteries as well as catalyst and is a known impurity in medical devices and pharmaceuticals. The present work describes the calculation of a parenteral tolerable intake (TI) for vanadium by chronic exposure in implantable medical devices per ISO 10993-17:2023, the applicable standard. The 2023 update of ISO 10993-17 [1] introduces new uncertainty factors (UFs) for calculating a TI. Therefore, we noted differences between the ISO guidance and the ICH Q3D guidance on Permissible Daily Exposure (PDE) for parental elemental pharmaceutical impurities. We derived a TI of 0.20 μg V/kg/day based on the updated ISO guidance, and a PDE of 0.24 μg V/kg/day based on ICH guidance. The latter is considered a more realistic estimate.

钒用于合金、电池和催化剂,也是医疗器械和药品中的一种已知杂质。本研究介绍了根据 ISO 10993-17:2023(适用标准)计算植入式医疗器械中长期接触钒的肠外耐受摄入量(TI)。ISO 10993-17[1]的2023更新版引入了计算TI的新不确定系数(UF)。因此,我们注意到 ISO 指南与 ICH Q3D 指南中关于亲元素药物杂质每日允许暴露量 (PDE) 的不同之处。根据最新的 ISO 指南,我们得出 TI 为 0.20 μg V/kg/day,而根据 ICH 指南,PDE 为 0.24 μg V/kg/day。后者被认为是更切合实际的估计值。
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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 Q1 MEDICINE, LEGAL 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

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.

医疗器械的化学特征描述使用分析评估阈值 (AET) 来确定可报告的有机萃取物,因为这些化学品可能会引起毒理学关注,应通过毒理学风险评估来解决。由于用于推导基于剂量的阈值 (DBT) 的数据集中不包含无机物的毒性数据,因此 AET 并不适用于金属萃取物。这导致对金属萃取物报告的指导极少。在此,建议将金属的 AET 或 mAET 作为单个金属萃取物的报告阈值。mAET 可确保报告的金属数量可能会对患者安全构成风险。这可以减少化学特性报告中报告的金属数量,通过减少不必要的工作量和资源时间来提高整个生物相容性评估的效率。相反,通过比较方法灵敏度和 mAET 值,可以确认分析方法是否有能力报告毒理学相关水平的所有金属。针对 70 种金属开发了 DBT,从而确定了 mAET 值。然后将这些 mAET 值与之前进行的 13 项化学特性研究(采用不同的提取设计和分析方法)中的金属报告限值进行比较,以确定 mAET 的影响。
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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 Q1 MEDICINE, LEGAL Pub Date : 2024-10-23 DOI: 10.1016/j.yrtph.2024.105731
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.
HSK21542 是一种外周限制性卡巴阿片受体 (KOR) 激动剂,开发用于疼痛治疗。由于阿片受体激活会引起中枢神经系统药理学方面的问题,如身体依赖性和成瘾可能性,因此在批准上市前需要对 HSK21542 的滥用可能性进行评估。HSK21542 的临床前滥用潜力评估包括以下研究:1)静脉自我给药研究,探讨大鼠自我给药瑞芬太尼的相对强化效力;2)大鼠药物辨别研究,探讨 HSK21542 在大鼠辨别戊唑醇时的药理相似性;3)大鼠条件性位置偏好(CPP)范式,以测试奖励效应;4)大鼠自然身体依赖-自发戒断研究,对长期接受 HSK21542 治疗的大鼠进行研究;5)纳洛酮沉淀戒断试验,在长期接触 HSK21542 后评估其身体依赖潜力。结果表明,HSK21542 没有正强化效应的行为学证据,也没有与戊佐辛相似的鉴别刺激效应。HSK21542 也不会在大鼠体内产生 CPP。此外,HSK21542 在大鼠体内长期治疗也不会产生自发戒断或纳洛酮诱发的戒断。总之,这些临床前研究结果表明,HSK21542 在动物体内没有滥用潜力,这也证明其在人体中的滥用潜力较低。
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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 Q1 MEDICINE, LEGAL 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

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.

在越来越多地应用系统思维和建模与模拟(M&S)技术的推动下,药物产品开发和监管科学的格局正在发生变化,尤其是从生物制药的角度来看。在此背景下,可以通过应用质量设计(QbD)原则和 M&S,特别是通过定义临床相关溶出度规范(CRDS),实现以患者为中心的质量标准。为此,必须将体外结果与药物产品的体内性能联系起来,这强调了探索生物制药工具转化能力的必要性。基于生理学的 M&S 分析为整合药物、药物产品和目标生物体的生物特性提供了一条独特的途径,以研究它们在药代动力学反应中的相互作用。因此,基于生理学的生物药剂学建模(PBBM)在全球范围内被越来越多地用于支持药物开发和监管应用。在巴西,模型信息药物开发(MIDD)政策和战略项目尚未建立,限制了 M&S 技术的适用性。本文借鉴巴西国家药品管理局-学术界 PBBM 工作组(WG)的经验,评估了巴西药物计量学(PMx)面临的机遇和挑战,并提出了推动在监管决策中采用 M&S 分析的策略。
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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 Q1 MEDICINE, LEGAL Pub Date : 2024-10-20 DOI: 10.1016/j.yrtph.2024.105727
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).
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.
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.
植物保护产品(PPPs)需要经过严格的安全评估。在欧洲,针对操作人员、工人、旁观者和居民的非饮食风险评估非常保守,因为这一领域的暴露科学历来数据贫乏。欧洲作物生命协会(CLE)旗下各公司已开展合作,生成新数据并汇集现有数据,以完善欧洲食品安全局(EFSA)非饮食暴露指南(2022 年)规定的方法。本文总结了从开发农业操作人员暴露模型 (AOEM) 开始的主要活动,并涵盖了完善旁观者、居民和重新进入工人评估的现有方法的项目,包括旁观者居民果园葡萄园 (BROV) 项目、改进喷洒漂移旁观者和居民暴露评估模型 (BREAM)、完善蒸汽吸入评估的建议,以及可脱落叶面残留 (DFR) 数据的荟萃分析。此外,还介绍了一项对使用封闭式转移系统的益处进行量化的研究、对当前风险评估范例中固有的复合保守性的评估,以及 SeedTROPEX 工作组对新种子处理模型的开发。这些由行业主导的活动强调了非食用接触在购买力平价登记过程中的关键作用,并反映了在确保安全的同时为农民提供有效作物保护解决方案的持续承诺。
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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 Q1 MEDICINE, LEGAL Pub Date : 2024-10-20 DOI: 10.1016/j.yrtph.2024.105730
Nitrosamine drug substance-related impurities (NDSRIs) are a sub-category of N-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 N-nitroso-nortriptyline, N-nitroso-fluoxetine, N-nitroso-desmethyl-diphenhydramine, N-nitroso-duloxetine, N-nitroso-lorcaserin, N-nitroso-varenicline, and N-nitroso-sertraline, induced concentration-dependent increases in micronuclei after bioactivation with hamster liver S9. These NDSRIs were also mutagenic in the TK and HPRT 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.
亚硝胺药物物质相关杂质(NDSRIs)是 N-亚硝胺药物杂质的一个亚类,与相应的活性药物成分具有结构相似性。人们对 NDSRIs 的致突变性知之甚少。我们曾使用增强艾姆斯试验(EAT)对一系列 NDSRIs 进行过测试。在这项后续研究中,我们进一步检测了其中 15 种 NDSRI 在人类 TK6 细胞中的遗传毒性和诱变性。七种 EAT 阳性的 NDSRIs(包括 N-亚硝基-去甲替普林、N-亚硝基-氟西汀、N-亚硝基-去甲二苯海拉明、N-亚硝基-度洛西汀、N-亚硝基-洛卡色林、N-亚硝基-伐尼克兰和 N-亚硝基-舍曲林)在与仓鼠肝脏 S9 进行生物活化后会诱发浓度依赖性的微核增加。在 TK 和 HPRT 基因突变试验中,这些 NDSRIs 也具有诱变性,这与它们的 EAT 阳性结果一致。在有仓鼠肝脏 S9 存在的情况下,8 种 EAT 阴性的 NDSRI 在微核试验中呈阴性,诱导突变的作用也呈阴性。利用内源表达单一人类细胞色素 P450(CYP)的 TK6 细胞,我们发现 CYP2C19、CYP2B6、CYP2A6 和 CYP3A4 是激活这些 NDSRIs 遗传毒性和诱变性的关键酶。总体而言,仓鼠 S9 介导的 TK6 细胞诱变性结果与在 EAT 中观察到的结果一致,表明 NDSRIs 在不同测试系统中产生的诱变反应具有一致性。这些数据支持使用 EAT 对 NDSRIs 进行危害识别和安全评估。
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引用次数: 0
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Regulatory Toxicology and Pharmacology
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