Regulatory Toxicology and Pharmacology最新文献_第3页

Re-evaluation of the reduced heart weights in male rats in a 28-day oral repeated-dose toxicity study of tetramethylammonium hydroxide 重新评估四甲基氢氧化铵 28 天口服重复剂量毒性研究中雄性大鼠心脏重量减少的情况。

IF 3 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2024-09-26 DOI: 10.1016/j.yrtph.2024.105712

We recently conducted a detailed hazard assessment of tetramethylammonium hydroxide (TMAH), a priority chemical substance under the Japan Chemical Substances Control Law. During this assessment, there was debate regarding the reduced heart weight observed in the treated male groups in the 28-day rat oral repeated-dose toxicity study. This finding was not observed in females in this study and in both sexes of oral toxicity studies for tetramethylammonium chloride (TMAC) or tetramethylammonium hydrogen phthalate (TMAHP). Unpublished individual data from the oral TMAH developmental and reproductive toxicity (DART) screening study were also obtained; no effect on heart weight was observed. In addition, background data on rat heart weight from six 28-day oral toxicity studies conducted in the same facility, year, strain, age, and breeder as the TMAH study were obtained from the Japan Existing Chemical Substances Database (JECDB). These investigations suggest that the statistically significant lower heart weight in the treated males in the 28-day toxicity study is likely caused by an incidental skewing of individuals with heavier heart weights toward control male groups and is not due to TMAH treatment. Thus, it is worthwhile to include as much relevant data as possible to confirm or refute unexpected findings in toxicity studies.

我们最近对四甲基氢氧化铵（TMAH）进行了详细的危害评估，该物质是《日本化学物质控制法》规定的重点化学物质。在评估过程中，我们发现在为期 28 天的大鼠口服重复剂量毒性研究中，经处理的雄性组心脏重量有所减轻，对此存在争议。在这项研究以及四甲基氯化铵（TMAC）或邻苯二甲酸氢四甲基铵（TMAHP）的雌雄口服毒性研究中，均未观察到这一结果。此外，还获得了口服 TMAH 发育和生殖毒性（DART）筛选研究中未公布的个体数据；未观察到对心脏重量的影响。此外，还从日本现有化学物质数据库（JECDB）中获取了六项为期 28 天的口服毒性研究的大鼠心脏重量背景数据，这些研究是在与 TMAH 研究相同的设施、年份、品系、年龄和饲养者中进行的。这些调查表明，在 28 天的毒性研究中，经处理的雄性动物的心脏重量在统计意义上显著降低，这可能是由于心脏重量较重的个体偶然偏向对照雄性动物组，而不是由于 TMAH 处理造成的。因此，值得在毒性研究中纳入尽可能多的相关数据，以证实或反驳意外发现。

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引用次数: 0

N-Nitrosamine drug substance related impurities (NDSRIs) – A proposal for the addition of subcategories to carcinogenic potency categorization approach categories 1 and 2 for NDSRIs with a molecular weight > 200 Da N-亚硝胺药物物质相关杂质（NDSRIs）--关于在致癌性分类方法类别 1 和 2 中增加分子量大于 200 Da 的 NDSRIs 子类别的建议。

IF 3 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2024-09-24 DOI: 10.1016/j.yrtph.2024.105704

The carcinogenicity potency categorization approach (CPCA) derived and harmonized by Health Authorities was a significant milestone, as it defined molecular properties that allowed for the rapid evaluation of the chemical structures of N-nitrosamine drug substance related impurities (NDSRIs) and the assignment of associated lifetime Acceptable Intake (AI) limits to inform on appropriate impurity control strategies in certain drug products. Nonetheless, it is important to continue to refine and improve on the CPCA based upon data-derived evidence. Herein, we focus on the default CPCA AI for NDSRIs, which is largely based on the small molecule N-nitrosamines (NAs). Considering the carcinogenic potency of NAs with a molecular weight >200 Da (NDSRIs molecular weight is typically 200–600 Da), we propose that in the absence of any compound specific data, the lowest lifetime Acceptable Intake for NAs, such as NDSRIs, should be 10x less (i.e., 150 ng/day) than the ICH M7 Threshold of Toxicological Concern of 1500 ng/day, (even for NDSRIs that are considered CPCA Category 1 and 2) which would conservatively result in a theoretical cancer risk of <1 in 100,000.

由卫生当局制定和统一的致癌性效力分类方法（CPCA）是一个重要的里程碑，因为它定义了分子特性，从而可以快速评估与 N-亚硝胺药物物质相关的杂质（NDSRIs）的化学结构，并指定相关的终生可接受摄入量限值，为某些药物产品中适当的杂质控制策略提供信息。尽管如此，基于数据证据继续完善和改进 CPCA 仍然非常重要。在此，我们重点讨论 NDSRIs 的默认 CPCA AI，该 AI 主要基于小分子 N-亚硝胺（NAs）。考虑到分子量大于 200 Da 的 NAs 的致癌性（NDSRIs 的分子量通常为 200-600 Da），我们建议，在没有任何特定化合物数据的情况下，NDSRIs 等 NAs 的最低终生可摄入量应比 ICO 值低 10 倍（即 150 纳克/天）、150 纳克/天），低于 ICH M7 毒理学关注阈值（1500 纳克/天）（即使是被视为 CPCA 第 1 类和第 2 类的 NDSRIs）。

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引用次数: 0

The new paradigm in animal testing – “3Rs alternatives” 动物试验的新典范--"3Rs 替代品"。

IF 3 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2024-09-20 DOI: 10.1016/j.yrtph.2024.105705

Regulatory studies have revolutionised over time. Today, the focus has shifted from animal toxicity testing to non-animal for regulatory safety testing. This move is in line with the international 3Rs (Replacement, Reduction, and Refinement) principle and has also changed the regulator's perspective. The 3R principle has stimulated changes in policy, regulations, and new approaches to safety assessment in drug development in many countries. The 3Rs approach has led to the discovery and application of new technologies and more human-relevant in vitro approaches that minimise the use of animals including non-human primates, in research and improve animal welfare. In 2016, the European Medicines Agency published the Guidelines on the principles of regulatory acceptance of 3Rs testing approaches, followed by a conceptual paper in 2023 to align with current 3R standards. Additionally, the United States Food and Drug Administration passed new legislation in 2023 that no longer requires all new human drugs to be tested on animals, which will change the current testing paradigm. This review paper provides the adoption of the 3Rs and the current regulatory perspective regarding their implementation.

随着时间的推移，监管研究已经发生了革命性的变化。如今，监管安全测试的重点已从动物毒性测试转向非动物测试。这一举措符合国际 3R（替代、减少和改进）原则，也改变了监管机构的观点。3R 原则促使许多国家改变了药物开发的政策、法规和安全评估新方法。3R 方法促进了新技术和更多与人类相关的体外方法的发现和应用，从而最大限度地减少了动物（包括非人灵长类动物）在研究中的使用，并改善了动物福利。2016 年，欧洲药品管理局发布了《监管机构接受 3Rs 检测方法原则指南》，随后将于 2023 年发布概念性文件，以与现行 3R 标准保持一致。此外，美国食品和药物管理局于 2023 年通过了新法规，不再要求所有人类新药都必须进行动物试验，这将改变当前的试验范式。本综述文件介绍了 3R 的采用情况以及当前有关其实施的监管视角。

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引用次数: 0

Botanical-induced toxicity: Liver injury and botanical-drug interactions. A report on a society of Toxicology Annual Meeting symposium 植物药引起的毒性：肝损伤和植物药与药物的相互作用毒理学会年会专题讨论会报告。

IF 3 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2024-09-19 DOI: 10.1016/j.yrtph.2024.105708

Botanical supplements and herbal products are widely used by consumers for various purported health benefits, and their popularity is increasing. Some of these natural products can have adverse effects on liver function and/or interact with prescription and over-the-counter (OTC) medications. Ensuring the safety of these readily available products is a crucial public health concern; however, not all regulatory authorities require premarket safety review and/or testing. To address and discuss these and other emerging needs related to botanical safety, a symposium was held at the Society of Toxicology Annual Meeting in Salt Lake City (UT) on March 11, 2024. The symposium addressed the latest research on botanical-induced liver toxicity and botanical-drug interactions, including new approach methods to screen for toxicity, challenges in assessing the safety of botanicals, and relating human adverse events to specific products. The presentations and robust panel discussion between the speakers and audience highlighted the need for further research and collaboration to improve the safety of botanical supplements and herbal products, with the ultimate goal of protecting consumer health. Although utility of many of the modern tools presented in the symposium requires further study, the synergistic efforts of diverse experts hold promise for effective prediction and evaluation of botanical-induced hepatotoxicity and botanical-drug interaction potential.

消费者广泛使用植物补充剂和草药产品，以获得各种所谓的健康益处，其受欢迎程度也在不断提高。其中一些天然产品可能会对肝功能产生不良影响和/或与处方药和非处方药（OTC）发生相互作用。确保这些唾手可得的产品的安全性是公众健康的一个关键问题；然而，并非所有监管机构都要求进行上市前安全审查和/或测试。为了解决和讨论这些问题以及与植物药安全性相关的其他新需求，2024 年 3 月 11 日在盐湖城（犹他州）举行的毒理学学会年会上召开了一次研讨会。研讨会讨论了植物药引起的肝脏毒性和植物药与药物相互作用的最新研究，包括筛选毒性的新方法、评估植物药安全性的挑战以及将人类不良事件与特定产品联系起来。演讲者与听众之间的发言和热烈的小组讨论强调了进一步研究和合作的必要性，以提高植物补充剂和草药产品的安全性，最终达到保护消费者健康的目的。虽然研讨会上介绍的许多现代工具的实用性还需要进一步研究，但不同专家的协同努力为有效预测和评估植物药引起的肝毒性和植物药与药物相互作用的可能性带来了希望。

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引用次数: 0

Residue depletion profiles and withdrawal intervals of florfenicol and its metabolite florfenicol amine in plasma and milk of lactating goats after repeated subcutaneous administrations 重复皮下注射后哺乳山羊血浆和乳汁中氟苯尼考及其代谢物氟苯尼考胺的残留消耗曲线和停药间隔时间。

IF 3 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2024-09-18 DOI: 10.1016/j.yrtph.2024.105707

Florfenicol is a broad-spectrum and bacteriostatic antibiotic with a time-dependent killing action. It is commonly used to treat respiratory diseases in goats in an extra-label manner. This study aimed to determine the plasma pharmacokinetics and milk residue depletion profiles and calculate the milk withdrawal interval (WDI) of florfenicol and its main metabolite florfenicol amine in lactating goats. Five healthy lactating goats were administered with 40 mg/kg florfenicol by subcutaneous injection, twice, 96 h apart. Plasma and milk samples were collected up to 864 h post the first injection. Non-compartmental analysis was used to estimate the plasma pharmacokinetic parameters. Milk WDIs were calculated using the U.S. Food and Drug Administration (FDA) method and European Medicines Agency (EMA) method. A Monte Carlo simulation was performed to generate simulated data for five virtual animals to meet the data requirement of the FDA method. The calculated milk WDIs based on florfenicol, florfenicol amine, and the combined (the sum of florfenicol and florfenicol amine) were 720.28, 690.45, and 872.69 h after the last injection using the FDA method. In conclusion, this study improves our understanding on the plasma pharmacokinetics and milk residue depletion kinetics of florfenicol and florfenicol amine in lactating ruminants after subcutaneous injections.

氟苯尼考是一种广谱抑菌抗生素，具有时间依赖性杀菌作用。它通常以标签外的方式用于治疗山羊的呼吸道疾病。本研究旨在确定氟苯尼考及其主要代谢物氟苯尼考胺在哺乳山羊体内的血浆药代动力学和乳汁残留消耗曲线，并计算断奶间隔（WDI）。对五只健康的泌乳山羊皮下注射 40 mg/kg 氟苯尼考，两次间隔 96 小时。在第一次注射后的 864 小时内采集血浆和牛奶样本。采用非室分析法估算血浆药代动力学参数。牛奶 WDI 采用美国食品药品管理局 (FDA) 方法和欧洲药品管理局 (EMA) 方法计算。为满足 FDA 方法的数据要求，对五只虚拟动物进行了蒙特卡罗模拟，以生成模拟数据。根据氟苯尼考、氟苯尼考胺和组合（氟苯尼考和氟苯尼考胺之和）计算出的牛奶WDI分别为最后一次注射后的720.28、690.45和872.69小时。总之，本研究加深了我们对泌乳反刍动物皮下注射氟苯尼考和氟苯尼考胺后血浆药代动力学和乳汁残留消耗动力学的了解。

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引用次数: 0

Neurobehavioral assessment of BMEDA by modified Irwin test in Sprague-Dawley rats 通过改良欧文试验对 Sprague-Dawley 大鼠进行 BMEDA 神经行为评估。

IF 3 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2024-09-17 DOI: 10.1016/j.yrtph.2024.105703

The neurobehavioral assessment of N,N-bis(2-mercapatoethly)-N′,N′-diethylenediamine (BMEDA), which can form a chelate with rhenium-188 (¹⁸⁸Re) to produce the ¹⁸⁸Re-BMEDA-liposome, was evaluated. The purpose of this study was to evaluate the potential neurobehavioral changes by using the functional observational battery observation procedures when intravenous injection of BMEDA to Sprague-Dawley rats. Rats were administered BMEDA at dose levels of 1, 2, and 5 mg/kg. No mortalities were observed. There are some observations related to BMEDA treatment found in the 5 mg/kg dose group at 10 min post-dose. Tremor was observed in one male rat and seven female rats. The increased respiration, vocalization, not easy to handle and/or loss of tone in the limb were observed in both males and females, and increased body temperature was observed in male animals. Based on the results, a single intravenous dose of BMEDA administered to rats resulted in increased respiration, vocalization, not easy to handle and/or loss of tone in the limb increasing at the dose level of 5 mg/kg. No neurobehavioral effects were noted after BMEDA administration up to the dose level of 2 mg/kg. The information of this study will provides a point of reference to design appropriately therapeutic studies for future human use.

N,N-双（2-巯基乙醇）-N',N'-二乙二胺（BMEDA）可与铼-188（188Re）形成螯合物，生成188Re-BMEDA-脂质体，本研究对BMEDA的神经行为评估进行了评估。本研究的目的是采用功能观察电池观察程序，评估 Sprague-Dawley 大鼠静脉注射 BMEDA 后可能出现的神经行为变化。给大鼠注射的 BMEDA 剂量分别为 1、2 和 5 毫克/千克。未观察到大鼠死亡。在剂量为 5 毫克/千克的剂量组中，用药后 10 分钟观察到一些与 BMEDA 治疗相关的现象。1 只雄性大鼠和 7 只雌性大鼠出现震颤。在雄性和雌性大鼠中均观察到呼吸加快、发声、不易操控和/或肢体失去张力，在雄性大鼠中观察到体温升高。根据研究结果，给大鼠静脉注射单剂量的 BMEDA，当剂量为 5 毫克/千克时，会导致呼吸加快、发声、不易操控和/或肢体张力减弱。给大鼠注射 2 毫克/千克剂量的 BMEDA 后，未发现神经行为方面的影响。这项研究的信息将为今后设计适当的治疗研究提供参考。

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引用次数: 0

Building knowledge of NAMs through risk science 评论：通过风险科学积累非杀伤人员地雷知识。

IF 3 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2024-09-16 DOI: 10.1016/j.yrtph.2024.105702

The 12th World Congress on Alternatives and Animal Use in the Life Sciences provided a platform for mobilizing and exchanging knowledge on the advancements in science and technology. It also provided an opportunity for experts to discuss how to accelerate the adoption of new strategies and tools. One of these recommendations advocated the need to bridge the gap between the next generation of scientists who have yet to learn about ‘New Approach Methodologies’ (NAMs) and the current generation of thought leaders who have pioneered the development and validation of these non-animal approaches to toxicological risk assessment. Consequently, a mini-course, held at Canada's University of Ottawa, was developed for students, aged 13–16 years, interested in learning about risk science and how NAMs can be used to inform human health risk assessment. This course also served as a platform for creating a virtual training roadmap, provided in this paper, thereby bringing this knowledge to a broader audience of learners who are establishing their careers in the field of risk science.

第十二届世界生命科学替代品和动物使用大会为动员和交流有关科技进步的知识提供了一个平台。大会还为专家们提供了一个讨论如何加快采用新战略和新工具的机会。其中一项建议主张，有必要缩小尚未了解 "新方法"（NAMs）的下一代科学家与率先开发和验证这些非动物毒理学风险评估方法的当代思想领袖之间的差距。因此，在加拿大渥太华大学为 13 至 16 岁有兴趣了解风险科学以及如何利用 NAMs 为人类健康风险评估提供信息的学生开设了一门小型课程。该课程也是创建本文所提供的虚拟培训路线图的平台，从而将这一知识带给更多正在风险科学领域开创事业的学习者。

引用次数: 0

Reevaluating safety pharmacology respiratory studies within the ICH S7A core battery: A multi-company evaluation of preclinical utility and clinical translation 重新评估 ICH S7A 核心电池中的安全药理学呼吸研究：临床前实用性和临床转化的多公司评估。

IF 3 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2024-09-16 DOI: 10.1016/j.yrtph.2024.105706

Optimization of ICH safety guideline studies for inclusion into regulatory submissions is critical for resource conservation, animal use reduction, and efficient drug development. The ICH S7A guidance for Safety Pharmacology (SP) studies adopted in 2001 identified the core battery of studies to evaluate the acute safety of putative pharmaceutical molecules prior to First in Human (FIH) trials. To assess the utility of respiratory studies in predicting clinical AE's, seven pharmaceutical companies pooled preclinical and clinical respiratory findings. A large database of novel molecules included all relevant data from standard S7A respiratory (n = 459) and FIH studies (n = 309). The data were analyzed with respect to the progression of these molecules, clinical adverse event reporting of these same molecules, and achieved exposures. These S7A respiratory assay findings had no impact on compound progression, and only 12 of 309 drug candidates were ‘positive’ preclinically and reported a respiratory-related AE in clinical trials (i.e. cough, dyspnea, etc.), an overall incidence rate of 3.9%. Contingency tables/statistics support a lack of concordance of these preclinical assays. Overall, our extensive analysis clearly indicated that the preclinical respiratory assay fails to provide any prognostic value for detecting clinically relevant respiratory adverse events.

优化 ICH 安全性指南研究以纳入监管申请对于节约资源、减少动物使用和高效药物开发至关重要。2001 年通过的 ICH S7A 安全药理学（SP）研究指南确定了在首次人体试验（FIH）之前评估潜在药物分子急性安全性的核心研究系列。为了评估呼吸系统研究在预测临床 AE 方面的效用，七家制药公司汇集了临床前和临床呼吸系统研究结果。新型分子的大型数据库包括标准 S7A 呼吸系统研究（n = 459）和 FIH 研究（n = 309）的所有相关数据。分析数据涉及这些分子的进展、这些分子的临床不良事件报告以及达到的暴露量。这些 S7A 呼吸检测结果对化合物的进展没有影响，309 种候选药物中只有 12 种在临床前呈 "阳性"，并在临床试验中报告了呼吸相关的 AE（如咳嗽、呼吸困难等），总发生率为 3.9%。或然率表/统计数据表明这些临床前检测结果缺乏一致性。总之，我们的大量分析清楚地表明，临床前呼吸测定无法为检测临床相关的呼吸不良事件提供任何预后价值。

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引用次数: 0

PBPK modeling demonstrates that exposure time adjustment is unnecessary for setting an acute manganese inhalation exposure guideline PBPK 模型表明，在制定急性锰吸入暴露指南时，无需对暴露时间进行调整

IF 3 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2024-09-07 DOI: 10.1016/j.yrtph.2024.105698

引用次数: 0

Food for thought — Paving the way for a UK roadmap towards optimum consumer safety: Development, Endorsement and Regulatory acceptance of New Approach Methodologies (NAMs) in Chemical Risk Assessment and Beyond 启发思考--为英国实现最佳消费者安全路线图铺平道路：化学品风险评估及其他领域新方法 (NAM) 的开发、认可和监管验收。

IF 3 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2024-09-07 DOI: 10.1016/j.yrtph.2024.105701

Advances in biosciences, chemistry, technology, and computer sciences have resulted in the unparalleled development of candidate New Approach Methodologies over the last few years. Many of these are potentially invaluable in the safety assessment of chemicals, but very few have been adopted for regulatory decision making. There is an immediate opportunity to use NAMs in safety assessment where the vision is to be able to predict risk more rapidly, accurately, and efficiently to further assure consumer safety.

In order to achieve this, the UK Food Standards Agency (FSA) and the Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT) have developed a roadmap towards acceptance and integration of these new approach methodologies into safety and risk assessments for regulatory decision making. The roadmap provides a UK blueprint for the transition of NAMs from the research laboratory to their use in regulatory decision making. This will require close collaboration across disciplines (chemists, toxicologists, informaticians, risk assessors and others), and across chemical sectors, to develop, verify and utilise appropriate models. Linking up internationally, and harmonization will be fundamental.

过去几年来，生物科学、化学、技术和计算机科学的进步促使候选的 "新方法 "得到了空前的发展。其中许多方法在化学品安全评估中具有潜在的价值，但很少被监管决策所采用。目前，在安全评估中使用新方法的机会非常迫切，我们的愿景是能够更快速、准确、高效地预测风险，从而进一步确保消费者的安全。为了实现这一目标，英国食品标准局 (FSA) 和食品、消费品和环境中的化学品毒性委员会 (COT) 制定了一份路线图，旨在接受这些新方法并将其整合到安全和风险评估中，以利于监管决策。该路线图为英国提供了一个蓝图，将非吸收剂从研究实验室过渡到监管决策中使用。这将需要跨学科（化学家、毒理学家、信息学家、风险评估员等）和跨化学领域的密切合作，以开发、验证和利用适当的模型。国际间的联系和协调将是至关重要的。

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引用次数: 0