Regulatory Toxicology and Pharmacology最新文献_第2页

Risk (Re)assessment of N-Methyl-N-nitrosophenethylamine for use in computing risk levels of N-Nitrosamine drug substance related impurities 用于计算n -亚硝胺类药物相关杂质风险水平的n -甲基-n -亚硝基苯基乙胺的风险（再）评估

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-06-16 DOI: 10.1016/j.yrtph.2025.105888

David R. Woolley , George E. Johnson , Kevin P. Cross

{"title":"Risk (Re)assessment of N-Methyl-N-nitrosophenethylamine for use in computing risk levels of N-Nitrosamine drug substance related impurities","authors":"David R. Woolley , George E. Johnson , Kevin P. Cross","doi":"10.1016/j.yrtph.2025.105888","DOIUrl":"10.1016/j.yrtph.2025.105888","url":null,"abstract":"<div><div>Management of N-Nitrosamine impurity levels in pharmaceutical drug substances and products is guided by ICH M7 where N-nitrosamines are defined as Cohorts of Concern. Regulatory agencies have suggested using read-across of rodent carcinogenicity TD50 values for structurally similar compounds to assess the potency of various data-poor N-nitrosamines. The TD50 for N-Methyl-N-nitrosophenethylamine (NMPEA) as reported in the CPDB with a harmonic mean TD50 value 7.88 μg/kg/day (or an Acceptable Intake (AI) level of 8 ng/day) did not follow the recommendations of ICH M7. Mixed tissues (oesophagus, forestomach, tongue, and nasal cavity) were combined into a single group termed “upper gastro-intestinal tract”. Upon examination of the original data, the oesophagus was considered the most sensitive organ of effect. The TD50 value for the oesophagus was recalculated to 40.1 μg/kg/day (or an AI of 40.1 ng/day). Subsequently, Benchmark Dose (BMD) analysis was performed on the same data set yielding a BMD10 of 3.06–17.6 μg/kg/day in rat (or Permitted Daily Exposure range of 306–1760 ng/day). Theses updated values are 5 times (or higher than) the current AI level of 8 ng/day and could result in significantly higher AI limits for marketed drug impurities that use NMPEA as a suitable analog (e.g., N-nitroso- nortriptyline) to derive an AI.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105888"},"PeriodicalIF":3.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144298736","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

Analysis of cellular and gene therapy product reviews in the United States 美国细胞和基因治疗产品评论分析。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-06-16 DOI: 10.1016/j.yrtph.2025.105885

Cheng-Fang Weng, Jhe-Yuan Dong, Shiuan-Fei Lin, Ai-Lei Jiang, Yu-Li Cheng, Lin-Chau Chang

{"title":"Analysis of cellular and gene therapy product reviews in the United States","authors":"Cheng-Fang Weng, Jhe-Yuan Dong, Shiuan-Fei Lin, Ai-Lei Jiang, Yu-Li Cheng, Lin-Chau Chang","doi":"10.1016/j.yrtph.2025.105885","DOIUrl":"10.1016/j.yrtph.2025.105885","url":null,"abstract":"<div><div>The emergence of cellular and gene therapy (CGT) products has profoundly transformed healthcare by addressing previously unmet medical needs. However, developing these innovative therapies presents complex regulatory challenges that require thorough examination. This study aimed to identify strategies to mitigate potential delays or rejections in the CGT approval process. By analyzing review documents from the United States Food and Drug Administration, we found that quality concerns were the primary focus of Complete Response letters and postmarketing commitments, while safety concerns predominantly shaped postmarketing requirements, reflecting persistent uncertainties around CGTs. The unique characteristics of CGTs were also evident in their individualized clinical trial designs. Although the regulatory landscape is intricate, the increasing diversity of CGTs and accumulated experience have clarified key product-specific challenges. To facilitate approvals, it is crucial for applicants to address these deficiencies early, while we recommend that regulatory authorities re-evaluate the scope of utilizing postmarketing requirements. Enhanced collaboration among academia, industry, and regulatory authorities is essential to identify balanced, effective strategies, while continuous information gathering and monitoring are vital to ensure the safe, long-term administration of approved CGTs.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105885"},"PeriodicalIF":3.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326734","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

Transforming the Evaluation of Agrochemicals: A Conceptual Model 转化农用化学品评价：一个概念模型。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-06-16 DOI: 10.1016/j.yrtph.2025.105889

Bhuller Yadvinder , Bishop Patricia , Cope Rhian , Corvaro Marco , Richard A. Currie , Gina M. Hilton , Mehta Jyotigna , Puglisi Raechel , Douglas C. Wolf , Sandrine E. Deglin

{"title":"Transforming the Evaluation of Agrochemicals: A Conceptual Model","authors":"Bhuller Yadvinder , Bishop Patricia , Cope Rhian , Corvaro Marco , Richard A. Currie , Gina M. Hilton , Mehta Jyotigna , Puglisi Raechel , Douglas C. Wolf , Sandrine E. Deglin","doi":"10.1016/j.yrtph.2025.105889","DOIUrl":"10.1016/j.yrtph.2025.105889","url":null,"abstract":"<div><div>Globally, regulatory authorities face the challenge of integrating advances in science and technology into existing frameworks for agrochemical risk assessment. Addressing this challenge is critical to meeting the demands of food safety and quality for a growing population. To support this shift, the Health and Environmental Sciences Institute (HESI) convened a multi-stakeholder committee of international scientists. Through a problem formulation-led strategy, the committee developed the Transforming the Evaluation of Agrochemicals (TEA) conceptual model to guide the adoption of new methods, best practices, and technologies into regulatory practice for agrochemical safety. The core of the model incorporates the well-established tiered approach routinely used for identifying and characterizing hazards and assessing exposures; however, the model strategically identifies three sequential elements: exposure-led, adaptability, and inclusion of new science. The central core is then surrounded by layers with additional elements, namely: fit-for-purpose over time, adapt to global need, adapt to local need, create incentives, data sharing and transparency, and build trust. Collectively, these ten elements and their intersections result in a novel, TEA conceptual model with elements that have not been simultaneously implemented in any regulatory data package to date. In providing guiding principles, two examples of regulatory applications, and a concise summary of how this model supports an opportunity to go beyond next generation risk assessments focused primarily on alternative approaches to animal testing, we demonstrate the utility of the TEA conceptual model as a tool and mechanism supporting a structured and systematic application towards the intended transformation of agrochemical evaluations.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105889"},"PeriodicalIF":3.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326735","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

Effects of anti-oxidants, NOX inhibitor (DPI), and anti-apoptotic pathways on carbohydrate metabolism and liver function in acute aluminum phosphide toxicity exposed rats 抗氧化剂、氮氧化物抑制剂（DPI）和抗凋亡途径对急性磷化铝中毒大鼠碳水化合物代谢和肝功能的影响

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-06-16 DOI: 10.1016/j.yrtph.2025.105890

Samaneh Nakhaee , Alireza Kooshki , Omid Mehrpour , Mehran Hosseini , Khadijeh Farrokhfall

{"title":"Effects of anti-oxidants, NOX inhibitor (DPI), and anti-apoptotic pathways on carbohydrate metabolism and liver function in acute aluminum phosphide toxicity exposed rats","authors":"Samaneh Nakhaee , Alireza Kooshki , Omid Mehrpour , Mehran Hosseini , Khadijeh Farrokhfall","doi":"10.1016/j.yrtph.2025.105890","DOIUrl":"10.1016/j.yrtph.2025.105890","url":null,"abstract":"<div><div>Aluminum phosphide (AlP) is widely used in suicide attempts. We evaluated the effects of Diphenylene iodonium (DPI), N- N-acetyl cysteine (NAC), and Nivocasan therapeutics on AlP toxicity. Thirty rats were kept in five groups: control (receiving normal saline); the remaining groups were exposed to oral AlP, and treatments (NAC, DPI, and Nivocasan). Liver function tests (LFTs), serum and liver oxidative markers, insulin, glucose, tumor necrosis factor−α (TNF-α), serum and islets interleukin 1β (IL-1β), and glucose-stimulated insulin secretion through islet isolation were assessed. LFTs significantly increased in AlP poisoned animals, and NAC, DPI, and Nivocasan decreased their levels to near control (P < 0.05). DPI and Nivocasan recovered AlP-induced hypoglycemia. Plasma catalase, GPx, and MDA increased in the AlP group, and NAC, DPI, and Nivocasan had protective effects (P < 0.05). DPI significantly decreased serum TNF-α, and NAC decreased IL-1β levels. NAC reversed AlP-induced lower insulin secretion (P < 0.05). Aluminum phosphide (AlP) induces hypoglycemia and liver damage. AlP-related hypoglycemia is associated with elevated inflammatory and oxidative stress markers and impaired insulin secretion from pancreatic islets which improved by NAC. DPI and Nivocasan treat hypoglycemia. DPI and NAC were effective in reducing inflammatory markers.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105890"},"PeriodicalIF":3.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144314135","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

Strategies to reduce the use of non-human primates in development of oncology ADCs with cytotoxic payloads. 减少使用非人类灵长类动物开发具有细胞毒性有效载荷的肿瘤adc的策略。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-06-15 DOI: 10.1016/j.yrtph.2025.105887

Sherry L Ralston, Li Li, Donna Lee, Darcey Clark, Andrew Dropsey, Haley Neff-LaFord, Payal Rana, Lucinda Weir, Radhakrishna Sura, Natalie Waterhouse

{"title":"Strategies to reduce the use of non-human primates in development of oncology ADCs with cytotoxic payloads.","authors":"Sherry L Ralston, Li Li, Donna Lee, Darcey Clark, Andrew Dropsey, Haley Neff-LaFord, Payal Rana, Lucinda Weir, Radhakrishna Sura, Natalie Waterhouse","doi":"10.1016/j.yrtph.2025.105887","DOIUrl":"https://doi.org/10.1016/j.yrtph.2025.105887","url":null,"abstract":"<p><p>The use of non-human primates (NHP) for the nonclinical development of biologics can be necessary to assess the potential safety risks in humans. An IQ DruSafe Working Group (WG) conducted a survey on the use of NHP in toxicology studies used to develop antibody drug conjugates (ADCs) with cytotoxic payloads for oncology treatment. The survey addressed whether a Good Laboratory Practice (GLP) 3-month NHP study provides additional safety information relative to the 1-month GLP NHP or relative to the 3-month GLP rodent study. Questions from the survey included whether a 3-month NHP study was conducted and if so, were the results similar or not to the 3-month rodent study or the 1-month NHP study, if the toxicities observed were consistent with the expected toxicities of the ADC payload, and whether the toxicities translated to that observed in the clinic. In addition, survey questions addressed study design elements particularly related to the number of animals used in studies. Survey results indicated that target organ toxicities were generally similar between studies, were translatable to humans, and most were attributed to the payload. Overall, the survey results support opportunities to reduce NHP use in the development of ADCs with cytotoxic payloads in oncology.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105887"},"PeriodicalIF":3.0,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144317796","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

Learning from experience: A retrospective analysis of read-across strategies for surfactants under REACH 从经验中学习：REACH法规下表面活性剂解读策略的回顾性分析

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-06-06 DOI: 10.1016/j.yrtph.2025.105884

Barbara G. Schmitt , Jayne Roberts , Lauren Kavanagh , James Dawick , Nicole Frijus-Plessen , Erik Houthoff , Joanna Klapacz , Diederik Schowanek , Quan Shi , Mengying Zhang , Geoff Hodges

{"title":"Learning from experience: A retrospective analysis of read-across strategies for surfactants under REACH","authors":"Barbara G. Schmitt , Jayne Roberts , Lauren Kavanagh , James Dawick , Nicole Frijus-Plessen , Erik Houthoff , Joanna Klapacz , Diederik Schowanek , Quan Shi , Mengying Zhang , Geoff Hodges","doi":"10.1016/j.yrtph.2025.105884","DOIUrl":"10.1016/j.yrtph.2025.105884","url":null,"abstract":"<div><div>Read-across is a widely used adaptation to address information requirements under REACH. However, registrants submitting for the 2010 and 2013 deadline have often failed to satisfy regulatory requirements from ECHA's point of view. Due to their complex composition and unique physicochemical properties, surfactants are posing major challenges in this respect.</div><div>With the aim to improve future submissions and prevent unnecessary animal testing, read-across-related discussions of 72 ECHA Final Decisions on Compliance Checks and Testing Proposal Evaluations of 24 major surfactant groups were analysed in-depth, and causes for acceptance or rejection were identified.</div><div>Key drivers of regulatory acceptance/rejection were presence or absence of composition information, considerations on structural similarity as well as availability and nature of bridging studies.</div><div>Several elements were identified that may be easily improved in future REACH dossiers without the need for additional animal testing. Other cases revealed uncertainty of expectations by ECHA, highlighting the need for improved communication during the dossier preparation.</div><div>Notably, no example for acceptance of read-across based on non-animal New Approach Methodologies (NAMs) was identified in this analysis. Owing to the benefits that non-animal NAMs may present as supporting information, all stakeholders are encouraged to contribute to an increase of regulatory acceptance.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105884"},"PeriodicalIF":3.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144241237","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

Assessment of endocrine disruptors in the European Union: Current regulatory framework, use of new approach methodologies (NAMs) and recommendations for improvements 欧盟对内分泌干扰物的评估：现行监管框架，新方法方法（NAMs）的使用和改进建议。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-06-06 DOI: 10.1016/j.yrtph.2025.105883

Marie Louise Holmer , Rikke Donchil Holmberg , Caroline Despicht , Nora Bouftas , Marta Axelstad , Anna Beronius , Johanna Zilliacus , Majorie Van Duursen , Terje Svingen

{"title":"Assessment of endocrine disruptors in the European Union: Current regulatory framework, use of new approach methodologies (NAMs) and recommendations for improvements","authors":"Marie Louise Holmer , Rikke Donchil Holmberg , Caroline Despicht , Nora Bouftas , Marta Axelstad , Anna Beronius , Johanna Zilliacus , Majorie Van Duursen , Terje Svingen","doi":"10.1016/j.yrtph.2025.105883","DOIUrl":"10.1016/j.yrtph.2025.105883","url":null,"abstract":"<div><div>Exposure to endocrine disruptors (EDs) are associated with significant risks to human health and the environment. The European Union (EU) thus prioritizes their identification and regulation and is developing a roadmap to phase out animal testing in chemical safety assessments while advancing New Approach Methodologies (NAMs). This review outlines EU's practices for ED identification, focusing on the use of NAMs, as well as Defined Approaches and read-across. We assessed the current EU framework under the Classification, Labelling and Packaging (CLP) Regulation, the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), the Plant Protection Products Regulation (PPPR), and the Biocidal Products Regulation (BPR), evaluating current use of NAMs and reflection on potential future use. We find that EU legislation and guidance documents allow the use of NAMs in ED identification, including for assessment of endocrine activity and adversity. However, guidance on predicting adversity using NAMs remains limited, and ED identifications have largely depended on animal data to assess endocrine-mediated adversity. Continued <em>in vivo</em> testing until reliable methodologies are accepted as alternatives and routinely applied is required. The report concludes with short- and long-term recommendations for updates to the information requirements across regulations and further development of methods to predict endocrine-mediated adversity.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105883"},"PeriodicalIF":3.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144249293","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

Regulatory practices on the genotoxicity testing of nanomaterials and outlook for the future 纳米材料遗传毒性检测的监管实践及未来展望。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-06-06 DOI: 10.1016/j.yrtph.2025.105881

Cristina Andreoli , Maria Dusinska , Cecilia Bossa , Chiara Laura Battistelli , Maria João Silva , Henriqueta Louro

{"title":"Regulatory practices on the genotoxicity testing of nanomaterials and outlook for the future","authors":"Cristina Andreoli , Maria Dusinska , Cecilia Bossa , Chiara Laura Battistelli , Maria João Silva , Henriqueta Louro","doi":"10.1016/j.yrtph.2025.105881","DOIUrl":"10.1016/j.yrtph.2025.105881","url":null,"abstract":"<div><div>The toxicity of nanomaterials(NMs) is closely tied to their physicochemical properties, such as size, shape, surface chemistry, stability in biological medium, and state of agglomeration as well to their uptake by cells. Key deficiencies in standardized testing approaches have been identified and tackled in recent years. Within the landscape of new approach methods (NAMs), the aim of this work is to review existing approaches for genotoxicity testing of the NMs under different regulatory domains, with a perspective on the development of NAMs that can solve longstanding difficulties in NMs’ risk assessment. It critically examines international and European Union guidelines, highlighting the need for harmonization and the potential of NAMs to drive next-generation risk assessment. However, further collaboration, research and validation are essential to gain wider acceptance and applicability. The contribution of innovative technological approaches based on big data, artificial intelligence and machine learning, may pave powerful comparisons among different sectors and grouping strategies that will furtherance innovation in the nanotoxicology research. The future outlook for the genotoxicity testing of NMs will depend on increased cooperation between regulatory agencies, researchers, and industry stakeholders. Key steps toward overcoming current obstacles include establishing clearer pathways for data sharing, standardizing testing protocols, and fostering greater international collaboration.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105881"},"PeriodicalIF":3.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144249294","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

Radon concentration and physicochemical properties measurement and internal exposure assessment in different brands of commercial soft drinks consumed in Türkiye 在日本消费的不同品牌商业软饮料的氡浓度、物理化学性质测量和内部暴露评估

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-06-06 DOI: 10.1016/j.yrtph.2025.105880

Dalal A.O. Sultan , Şeref Turhan , Ergin Murat Altuner , Temel Kan Bakır

{"title":"Radon concentration and physicochemical properties measurement and internal exposure assessment in different brands of commercial soft drinks consumed in Türkiye","authors":"Dalal A.O. Sultan , Şeref Turhan , Ergin Murat Altuner , Temel Kan Bakır","doi":"10.1016/j.yrtph.2025.105880","DOIUrl":"10.1016/j.yrtph.2025.105880","url":null,"abstract":"<div><div>Energy drinks (EDs) are soft drinks with energy-boosting ingredients such as caffeine, taurine, vitamin B, and herbal extracts. In this study, the first-ever radon activity concentrations of thirty-five canned ED samples from mostly preferred sixteen assorted brands consumed in Türkiye were analyzed by using a monitoring system. Also, radiological risk resulting from internal exposure due to the ionizing radiation emitted from radon, and its short-lived decay daughters were assessed for adults. Additionally, some physicochemical parameters of ED samples were determined by well-known instruments. Radon activity concentrations analyzed in ED samples ranged from 21.3 ± 0.8 to 37.5 ± 1.8 mBq/L and these values are significantly below the limits recommended for drinking water by the US Environmental Protection Agency and the European Union directive. The values of physicochemical parameters determined for ED samples ranged 2.56 to 4.30 (pH), 593 to 3030 μS/cm (electrical conductivity), 525–2680 mg/L (total dissolved solids) and 1.30–13.20 % (Brix values). Since the annual effective doses estimated based on the annual consumption of soft drinks and EDs per capita in Türkiye are well below the individual dose criterion of 100 μSv, the radiological risk is at a negligible level.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105880"},"PeriodicalIF":3.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144241361","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

Utilizing metabolism-based structure-activity relationships and biokinetic modeling for toxicological evaluation: A case study on L-menthyl D-Lactate 利用基于代谢的构效关系和生物动力学模型进行毒理学评价：以l -乳酸薄荷酯为例。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-05-30 DOI: 10.1016/j.yrtph.2025.105872

Corie Ellison , Jillian Blubaugh , Sierra Engled , Mike Karb , Cathy Lester , Cindy Obringer , Kara Woeller

{"title":"Utilizing metabolism-based structure-activity relationships and biokinetic modeling for toxicological evaluation: A case study on L-menthyl D-Lactate","authors":"Corie Ellison , Jillian Blubaugh , Sierra Engled , Mike Karb , Cathy Lester , Cindy Obringer , Kara Woeller","doi":"10.1016/j.yrtph.2025.105872","DOIUrl":"10.1016/j.yrtph.2025.105872","url":null,"abstract":"<div><div>Structure activity relationship (SAR) based read across uses existing toxicity data from an analog to predict the toxicity of a target chemical. An analog can be classified as suitable, suitable with interpretation, suitable with precondition or not suitable. Few have evaluated the scenario of “suitable with precondition”; thus, we present a case study where the systemic safety of L-menthyl D-lactate is established via suitable with precondition analogs, DL-menthol and D-lactic acid, which are predicted ester hydrolysis metabolites of the target chemical. In vitro metabolism assays demonstrated the ester hydrolysis pathway for L-menthyl D-lactate, indicating that the ester hydrolysis metabolites could be used as analogs. The rate and extent of L-menthyl D-lactate metabolism by human skin and liver S9 and plasma were determined and inputted into a human physiologically based pharmacokinetic (PBPK) model to estimate internal exposure to L-menthyl D-lactate following different exposure scenarios. Margins of internal and external exposure were determined by comparing scenario specific exposures to an internal threshold of toxicological concern or toxicity data from the metabolites. Additional analysis conducted with a rat PBPK model to prospectively estimate internal exposure to L-menthyl D-lactate that would occur from an oral toxicity study demonstrated that it would be metabolized rapidly and extensively by rats and the predominate (99.8 %) systemic exposure would be to the ester hydrolysis metabolites with only a minor, transient exposure occurring to L-menthyl D-lactate. Reapplication of the current approach for human safety assessments holds promise for ensuring human health by using robust approaches for read across.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105872"},"PeriodicalIF":3.0,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199909","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