Regulatory Toxicology and Pharmacology最新文献_第6页

MODEXMO: A modular non-dietary exposure assessment approach for pesticides using dose-based dermal absorption prediction MODEXMO：一种基于剂量的皮肤吸收预测的模块化非膳食农药暴露评估方法。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-11-09 DOI: 10.1016/j.yrtph.2025.105984

Felix M. Kluxen , Korinna Wend , Christiane Wiemann , Edgars Felkers , Neil Morgan

A modular non-dietary exposure assessment approach for pesticides (PPPs) is proposed, emphasizing a dose-based prediction of dermal absorption. The Modular Dermal Exposure Model (MODEXMO) defines new nomenclature: exposure, dermal absorption and surface distribution prediction models, respectively abbreviated as EXPREMOs, DAPREMOs, SUDIPREMOs. Approach and nomenclature are generic and can be used for probabilistic models or simulation-based approaches. The modularity aids the integration of refined exposure data and enhances the adaptability of risk assessments to better reflect dynamic real-world scenarios. DAPREMOs could replace relative dermal absorption values (DAVs) by directly predicting internal exposure from external doses with a statistical model. It is well-known that absolute dermal penetration depends primarily on applied dose. EXPREMOs can predict relatively low area doses, since exposure estimates are averaged over large body surfaces, regardless of the actual residue surface distribution. While this has no consequence in the current assessment approach using DAVs, it ignores the exposure scenario-dependent spatial distributions of residue on skin, e.g., due to individual splash events during mixing and loading operations. SUDIPREMOs can refine EXPREMO-assumed default surface areas to provide DAPREMOs with more accurate inputs for different area doses in multiple exposure sub-streams.

提出了一种模块化的农药非膳食暴露评估方法，强调基于剂量的皮肤吸收预测。模块化皮肤暴露模型（MODEXMO）定义了新的命名法：暴露、皮肤吸收和表面分布预测模型，分别缩写为EXPREMOs、DAPREMOs、SUDIPREMOs。方法和命名法是通用的，可用于概率模型或基于仿真的方法。模块化有助于整合精细的暴露数据，增强风险评估的适应性，以更好地反映动态的现实世界场景。DAPREMOs可以用统计模型直接预测外部剂量的内部暴露，从而取代相对皮肤吸收值（DAVs）。众所周知，绝对皮肤渗透主要取决于施加剂量。EXPREMOs可以预测相对较低的区域剂量，因为暴露估计是在较大的身体表面上平均的，而不考虑实际残留表面分布。虽然这在目前使用dav的评估方法中没有影响，但它忽略了皮肤上残留物的暴露场景依赖的空间分布，例如，由于混合和加载操作期间的单个飞溅事件。SUDIPREMOs可以改进expremo假设的默认表面积，为DAPREMOs提供更准确的输入，用于多个暴露子流中的不同区域剂量。

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引用次数: 0

Application of error-corrected sequencing technologies for in vivo regulatory mutagenicity assessment 纠错测序技术在体内调控致突变性评估中的应用。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-11-08 DOI: 10.1016/j.yrtph.2025.105985

Carole L. Yauk , Anthony M. Lynch , Vasily N. Dobrovolsky , Maik Schuler , Stephanie L. Smith-Roe , Devon Fitzgerald , Jake Higgins , Naveed Honarvar , Frank Le Curieux , Shoji Matsumura , Sheroy Minocherhomji , Leslie Recio , Jesse J. Salk , Kei-ichi Sugiyama , Takayoshi Suzuki , John W. Wills , Francesco Marchetti

Error-corrected sequencing (ECS) is a transformative method for in vivo mutagenicity assessment, enabling direct, highly sensitive measurement of mutation frequency and spectrum. ECS addresses key limitations of the transgenic rodent (TGR) assay, including lack of integration into standard toxicity studies, restricted model availability, and limited alignment with the 3R principles. To support regulatory acceptance, an expert workgroup of the International Workshops on Genotoxicity Testing (IWGT) reviewed ECS technologies and developed consensus recommendations for its inclusion into Organisation for Economic Co-operation and Development (OECD) test guidelines. The working group agreed that ECS: produces results that are concordant with validated TGR assays; can be incorporated into standard ≥28-day repeat-dose toxicity studies; and, data interpretation should be based on overall mutation frequency compared with concurrent vehicle controls. The working group emphasized harmonized data reporting aligned with OECD principles and endorsed study designs that enable quantitative risk assessment. Overall, the working group agreed that ECS offers a significant advancement over current mutagenicity assays by enabling the use of diverse models beyond conventional TGR systems described in OECD test guideline 488. The working group fully supports the application of ECS to generate in vivo mutagenicity data for regulatory submissions and recommends its inclusion in future OECD test guidelines.

错误校正测序（ECS）是体内突变性评估的一种变革性方法，可以直接、高灵敏度地测量突变频率和谱。ECS解决了转基因啮齿动物（TGR）试验的主要局限性，包括缺乏与标准毒性研究的整合，模型可用性受限，以及与3R原则的有限一致性。为了支持监管认可，国际遗传毒性测试研讨会（IWGT）的一个专家工作组审查了ECS技术，并制定了将其纳入经济合作与发展组织（OECD）测试指南的共识建议。工作组一致认为，ECS产生的结果与经过验证的TGR分析一致；可纳入标准≥28天重复给药毒性研究；并且，数据解释应基于与同时进行的载体对照相比的总体突变频率。工作组强调了符合经合组织原则的统一数据报告，并认可了能够进行定量风险评估的研究设计。总体而言，工作组一致认为，ECS通过使用不同的模型，超越OECD测试指南488中描述的传统TGR系统，为当前的致突变性分析提供了重大进步。工作组完全支持将ECS应用于生成体内诱变性数据以提交监管机构，并建议将其纳入未来的经合组织测试指南。

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引用次数: 0

Applicability of kinetically-based maximum dose studies for hazard and risk assessments of the fungicide fluoxapiprolin 基于动力学的最大剂量研究在杀菌剂氟沙匹prolin危害和风险评估中的适用性。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-11-06 DOI: 10.1016/j.yrtph.2025.105983

Kim Z. Travis , Richard W. Lewis , Christine Barreau , Bastian Becker , Philippe F. Kennel

Fluoxapiprolin is a new fungicide developed for the control of oomycetes that damage crops such as tomato, potato, grapes and leafy vegetables. Human safety studies have shown no toxicity clearly attributable to fluoxapiprolin, highlighting its favourable toxicological profile compared to many other fungicides. It meets all human health risk assessment criteria without difficulty. However, fluoxapiprolin was tested up to a Kinetically-Derived Maximum Dose (KMD) rather than the conventional limit dose, making it necessary to justify this approach in the context of regulatory hazard assessment. Official guidance documents encourage the application of KMD approaches under specific conditions. In the case of fluoxapiprolin, oral absorption was shown to become saturated as doses increased, supporting the selection of the high dose in long-term studies based on a KMD rather than using a fixed limit dose. Even if a limit dose had been used, systemic exposure would have been only about twice as high as that observed at the KMD. Given the absence of treatment-related toxicity in any study and the relatively small difference in systemic exposure, the toxicological database is considered sufficient to identify relevant hazards and to support a robust human health risk assessment.

氟沙匹prolin是一种新型杀菌剂，用于控制危害番茄、马铃薯、葡萄和叶菜等作物的卵菌。人体安全性研究表明，氟沙匹prolin没有明显的毒性，与许多其他杀菌剂相比，它具有良好的毒理学特征。它毫无困难地满足所有人类健康风险评估标准。然而，氟沙匹prolin的测试达到了动力学衍生的最大剂量（KMD），而不是传统的极限剂量，因此有必要在监管危害评估的背景下证明这种方法的合理性。官方指导文件鼓励在特定条件下应用KMD方法。就氟沙匹普罗林而言，口服吸收随着剂量的增加而趋于饱和，这支持在基于KMD的长期研究中选择高剂量，而不是使用固定的极限剂量。即使使用了限制剂量，全身暴露也只会比在KMD观察到的高两倍左右。鉴于在任何研究中都没有发现与治疗有关的毒性，而且全身接触的差异也相对较小，毒理学数据库被认为足以确定相关的危害，并支持进行强有力的人类健康风险评估。

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引用次数: 0

Retraction notice to “Repeated dose 28-day oral toxicity study of DEAE-Dextran in mice: An advancement in safety chemotherapeutics” [Regul. Toxicol. Pharm. 88 (2017) 262–272] 对“deae -葡聚糖小鼠28天重复剂量口服毒性研究：安全化疗药物的进展”的撤回通知[Regul]。Toxicol。医药杂志，88(2017):262-272。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-11-04 DOI: 10.1016/j.yrtph.2025.105982

引用次数: 0

Retraction notice to “Acute and sub-acute toxicological evaluation of lyophilized Nymphaea x rubra Roxb. ex Andrews rhizome extract” [Regul. Toxicol. Pharm. 88 (2017) 12–21] “冻干锦花的急性和亚急性毒理学评价”撤回通知。前安德鲁斯根茎提取物”[Regul。Toxicol。医药，88(2017)12-21。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-11-03 DOI: 10.1016/j.yrtph.2025.105981

Kushal Kumar , Sabeena Sharma , Ashish Kumar , Pushpender Bhardwaj , Kalpana barhwal , Sunil Kumar Hota (Scientist ‘D’)

引用次数: 0

Enhancing pesticide risk assessment processes at the US Environmental Protection Agency 加强美国环境保护署的农药风险评估程序。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-10-26 DOI: 10.1016/j.yrtph.2025.105959

Gina M. Hilton , Penelope A. Fenner-Crisp , William L. Jordan , Amy J. Clippinger , Douglas C. Wolf

The United States Environmental Protection Agency (USEPA) has long championed the use of the most modern toxicity testing approaches to meet its pesticide registration mandates, often collaborating with stakeholders to develop and implement innovative approaches that strengthen environmental and human health protections. Despite these efforts, the adoption of 21st-century testing approaches in pesticide registration has been slowed by various factors, including limited resources, inefficient processes for establishing confidence in new methods, and the retention of outdated data requirements codified in the Code of Federal Regulations. This paper provides a brief overview of the current USEPA legislative landscape for pesticide toxicity testing, describes the progress and remaining challenges in using new testing approaches to fulfill regulatory requirements, and highlights opportunities to address these challenges and enhance protection of human health and the environment.

美国环境保护署（USEPA）长期以来一直倡导使用最现代的毒性测试方法来履行其农药登记任务，并经常与利益攸关方合作制定和实施加强环境和人类健康保护的创新方法。尽管做出了这些努力，但由于资源有限、对新方法建立信心的流程效率低下以及保留《联邦法规法典》中规定的过时数据要求等各种因素，在农药登记中采用21世纪测试方法的速度有所放缓。本文简要概述了目前美国环保署在农药毒性测试方面的立法概况，描述了在使用新的测试方法来满足监管要求方面的进展和仍然存在的挑战，并强调了解决这些挑战并加强对人类健康和环境的保护的机会。

引用次数: 0

Real-world safety of fruquininib in refractory metastatic colorectal cancer: A cross-database study fruquininib治疗难治性转移性结直肠癌的实际安全性：一项跨数据库研究

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-10-25 DOI: 10.1016/j.yrtph.2025.105973

Qian Guo , Meirong Shan , Yanhua Fu , Ni Li , Chu Wu , Wei Gao

This study utilized real-world data from the U.S. FDA Adverse Event Reporting System and the WHO VigiAccess database to identify and characterize safety signals associated with fruquintinib, providing insights for clinical practice and regulatory decision-making. Through a retrospective analysis of adverse event (AE) reports for fruquintinib from these two databases, disproportionality analysis methods such as the Proportional Reporting Ratio (PRR) and Reporting Odds Ratio (ROR) were employed to detect potential pharmacovigilance signals, with cross-database consistency evaluated. The analysis revealed 4641 and 3909 AEs associated with fruquintinib in the FAERS and VigiAccess databases, respectively. The study identified several AEs not currently documented in the drug label, including dysphonia and pain. In the FAERS database, significant signals were detected in systems not covered by the label, such as blood and lymphatic, psychiatric, immune, reproductive, and ear disorders. Other unreported signals included myelosuppression, headache, dizziness, and dyspnea. In conclusion, this study not only confirmed known adverse reactions to fruquintinib but also uncovered several potential new safety signals. These findings underscore the importance of ongoing post-marketing safety monitoring to optimize the drug's risk-benefit profile. The results provide critical safety information for clinicians managing refractory metastatic colorectal cancer with fruquintinib, supporting more vigilant patient management.

本研究利用来自美国FDA不良事件报告系统和WHO VigiAccess数据库的真实数据来识别和表征与fruquininib相关的安全信号，为临床实践和监管决策提供见解。通过对这两个数据库中fruquininib不良事件（AE）报告的回顾性分析，采用比例报告比（PRR）和报告优势比（ROR）等歧化分析方法检测潜在的药物警戒信号，并评估跨数据库一致性。分析显示FAERS和VigiAccess数据库中与fruquininib相关的ae分别为4641例和3909例。该研究确定了几种目前未在药物标签上记录的不良反应，包括语音障碍和疼痛。在FAERS数据库中，在标签未涵盖的系统中检测到重要信号，例如血液和淋巴，精神，免疫，生殖和耳部疾病。其他未报道的信号包括骨髓抑制、头痛、头晕和呼吸困难。总之，本研究不仅证实了fruquininib已知的不良反应，还发现了几个潜在的新安全信号。这些发现强调了持续进行上市后安全性监测以优化药物风险-收益概况的重要性。结果为临床医生使用fruquininib治疗难治性转移性结直肠癌提供了关键的安全性信息，支持更加警惕的患者管理。

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引用次数: 0

Relationship between dietary pesticide intake and urinary excretion: a pilot study using duplicate portion analysis 饮食农药摄入与尿排泄的关系：一项使用重复部分分析的初步研究

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-10-25 DOI: 10.1016/j.yrtph.2025.105972

Nina C. Wieland , Daniel M. Figueiredo , Hans Mol , Neus González , Nelson Abrantes , Virginia Aparicio , Isabel Campos , Josefina Contreras , Alcon Francisco , Matjaž Glavan , Tanja Blagus , Vita Dolžan , Paula Harkes , Trine Nørgaard , Vivi Schlünssen , Igor Pasković , Marija Polić Pasković , Martien Graumans , Ad M.J. Ragas , Frans G.M. Russel , Paul T.J. Scheepers

Dietary uptake is estimated using residue data from food commodities and predicting the effect of food processing, such as peeling. The aim of this study was to explore the value of the analysis of duplicate portions supplemented by the analysis of urinary metabolites. Forty-three participants, consuming organic and non-organic diets collected a duplicate portion of food and beverages for 24 h. Urine was collected up to 36 h to account for metabolism and prolonged excretion of metabolites. Pesticide residues were analysed in food portions and urine samples using LC-MS/MS and GC-MS/MS. Multiple pesticide residues were detected per food portion. Out of 183 pesticides, 86 were detected in the diet. Glyphosate and AMPA were detected in 42 % and 30 % of all urine samples, respectively, while detection in the diet was low. A positive relationship between dietary intake and urinary excretion was found for 2,4-D and MCPA. No diet-urine relationship was observed for glyphosate and AMPA, indicating contribution from external routes of exposure. Hazard index (HI) indicated no exposure above the acceptable daily intake (ADI) for all participants. This study demonstrates how DPA combined with urine analysis gives insight into contribution of diet to total pesticide exposure compared to standard monitoring.

膳食摄取量是根据食品商品的残留物数据估计的，并预测食品加工（如削皮）的影响。本研究的目的是探讨以尿液代谢物分析为补充的重复部分分析的价值。食用有机和非有机饮食的43名参与者在24小时内收集了相同部分的食物和饮料。收集尿液长达36小时，以解释代谢和代谢物排泄的延长。采用LC-MS/MS和GC-MS/MS对食品和尿液样品中的农药残留进行了分析。每份食物均检出多种农药残留。在183种农药中，饮食中检出86种农药。在所有尿液样本中，草甘膦和AMPA的检出率分别为42%和30%，而在饮食中的检出率较低。膳食摄入量与尿排泄之间存在正相关关系，发现2,4- d和MCPA。没有观察到草甘膦和AMPA的饮食与尿液的关系，表明外部暴露途径的贡献。危害指数（HI）表明所有参与者的暴露量均未超过每日可接受摄入量（ADI）。这项研究表明，与标准监测相比，DPA结合尿液分析如何深入了解饮食对农药总暴露的贡献。

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引用次数: 0

Report on the European Partnership for Alternative Approaches to Animal Testing (EPAA) “New Approach Methodology (NAMs) User Forum”, 30–31 October 2024, Helsinki, Finland 欧洲动物试验替代方法伙伴关系报告（EPAA）“新方法方法论（NAMs）用户论坛”，2024年10月30日至31日，芬兰赫尔辛基

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-10-24 DOI: 10.1016/j.yrtph.2025.105980

Mark T.D. Cronin , Sophie Cable , Christian Desaintes , Sylvia E. Escher , Ellen Hessel , Ellen Fritsche , Petra Kern , Gavin Maxwell , Gladys Ouedraogo , Tomasz Sobanski , Matthias Wehr , Andrew White

The European Partnership for Alternative Approaches to Animal Testing (EPAA) held the “New Approach Methodology (NAMs) User Forum” at the European Chemicals Agency, Helsinki, Finland on 30–October 31, 2024. The User Forum brought together stakeholders from regulatory agencies, industry, non-governmental organisations (NGOs) and academia, as well as European Union competent authorities. Lessons learned from applying NAMs for regulatory use were provided by the European Food Safety Authority (EFSA) and European Chemicals Agency (ECHA). Progress in the development of the developmental and neurotoxicity in vitro battery (DNT IVB) and Alternative Safety Profiling Algorithm (ASPA) were described, as well as five case studies describing uses of NAMs for chemical safety assessment. The presentations confirmed progress in NAMs and, in particular, the value of tiered testing strategies to bring together different lines of evidence. Specifically, tiered testing strategies for non-animal information are organised into three tiers, which may be relevant to hazard, exposure and toxicokinetic information. Progress into, and the needs for improvement of, the tiered strategies were discussed with a particular focus on the types of NAMs (in silico and in vitro) that may be required at each tier and the how confidence may be assigned to making a decision.

欧洲动物试验替代方法伙伴关系（EPAA）于2024年10月30日至31日在芬兰赫尔辛基的欧洲化学品管理局举行了“新方法方法论（NAMs）用户论坛”。用户论坛汇集了来自监管机构、工业界、非政府组织（ngo）和学术界以及欧盟主管当局的利益相关者。欧洲食品安全局（EFSA）和欧洲化学品管理局（ECHA）提供了申请NAMs用于监管用途的经验教训。介绍了发育和神经毒性体外电池（DNT IVB）和替代安全分析算法（ASPA）的发展进展，以及描述NAMs用于化学品安全评估的五个案例研究。报告确认了NAMs的进展，特别是分层测试策略的价值，以汇集不同的证据线。具体来说，非动物信息的分层测试策略被分为三个层次，这可能与危害、暴露和毒性动力学信息有关。讨论了分层战略的进展和改进的需要，特别侧重于每一层可能需要的NAMs类型（在计算机上和体外）以及如何为决策分配信心。

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引用次数: 0

Minimizing use of nonhuman primates to inform risk to fertility and of adverse pregnancy outcomes with pharmaceuticals 尽量减少使用非人类灵长类动物来告知生育风险和药物不良妊娠结局

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-10-24 DOI: 10.1016/j.yrtph.2025.105971

Christopher J. Bowman , Ann Baker , Diann L. Blanset , Kimberly C. Brannen , Gary J. Chellman , Brian Enright , Wendy Halpern , Bethany R. Hannas , Kazushige Maki , Fumito Mikashima , Shermaine Mitchell-Ryan , Eve Mylchreest , Manjunatha K. Nanjappa , Helen Prior , Puck Roos , Dinesh Stanislaus , Angela R. Stermer , Jane Stewart , Katie Turner , Steven van Cruchten , Peter Theunissen

An assessment of potential developmental and reproductive toxicity (DART) is generally required to support clinical trials and marketing of pharmaceuticals. Although typically performed in rodents and rabbits, nonhuman primates (NHPs) are often used when they are the only pharmacologically relevant species. Regulatory guidances allow for weight of evidence (WoE) risk assessment for DART such that mature NHPs may not be needed to confirm expected or low risk of adverse pregnancy outcome. As such, there are numerous examples of WoE strategies to inform risk of adverse pregnancy outcome, but fewer to assess risk to male and/or female fertility, although emerging data indicate mature NHPs have limited impact on fertility risk assessment in product labels. Mature NHP data are most impactful to fill safety gaps when there are no relevant data from other species, limited information to establish WoE, and/or limited human data is available to characterize risk. In this review, we propose a detailed decision tree and examples to inform risk of adverse pregnancy outcome or male/female fertility impact by emphasizing and prioritizing WoE supplemented by experimental data where necessary, including use of NHPs as a last resort. Additional refinements to NHP use are also summarized.

通常需要对潜在的发育和生殖毒性（DART）进行评估，以支持药物的临床试验和销售。虽然通常在啮齿动物和兔子中进行，但当它们是唯一的药理学相关物种时，通常使用非人灵长类动物（NHPs）。监管指南允许对DART进行证据权重（WoE）风险评估，因此可能不需要成熟的NHPs来确认预期或低风险的不良妊娠结局。因此，尽管新出现的数据表明，成熟的NHPs对产品标签上的生育风险评估影响有限，但有许多用于告知不良妊娠结局风险的WoE策略的例子，但用于评估男性和/或女性生育风险的例子较少。当没有来自其他物种的相关数据、建立疾病风险的信息有限和/或可用于表征风险的人类数据有限时，成熟的非传染性疾病数据对填补安全空白最具影响力。在这篇综述中，我们提出了一个详细的决策树和例子，通过强调和优先考虑WoE，并在必要时辅以实验数据，包括将NHPs作为最后的手段，来告知不良妊娠结局或男性/女性生育影响的风险。还总结了NHP使用的其他改进。

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引用次数: 0