Regulatory Toxicology and Pharmacology最新文献_第10页

A framework enabling LLMs into regulatory environment for transparency and trustworthiness and its application to drug labeling document 使法律文件管理者融入监管环境以提高透明度和可信度的框架及其在药品标签文件中的应用

IF 3.4 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-04-02 DOI: 10.1016/j.yrtph.2024.105613

Leihong Wu , Joshua Xu , Shraddha Thakkar , Magnus Gray , Yanyan Qu , Dongying Li , Weida Tong

{"title":"A framework enabling LLMs into regulatory environment for transparency and trustworthiness and its application to drug labeling document","authors":"Leihong Wu , Joshua Xu , Shraddha Thakkar , Magnus Gray , Yanyan Qu , Dongying Li , Weida Tong","doi":"10.1016/j.yrtph.2024.105613","DOIUrl":"https://doi.org/10.1016/j.yrtph.2024.105613","url":null,"abstract":"<div><p>Regulatory agencies consistently deal with extensive document reviews, ranging from product submissions to both internal and external communications. Large Language Models (LLMs) like ChatGPT can be invaluable tools for these tasks, however present several challenges, particularly the proprietary information, combining customized function with specific review needs, and transparency and explainability of the model's output. Hence, a localized and customized solution is imperative.</p><p>To tackle these challenges, we formulated a framework named askFDALabel on FDA drug labeling documents that is a crucial resource in the FDA drug review process. AskFDALabel operates within a secure IT environment and comprises two key modules: a semantic search and a Q&A/text-generation module. The Module S built on word embeddings to enable comprehensive semantic queries within labeling documents. The Module T utilizes a tuned LLM to generate responses based on references from Module S. As the result, our framework enabled small LLMs to perform comparably to ChatGPT with as a computationally inexpensive solution for regulatory application.</p><p>To conclude, through AskFDALabel, we have showcased a pathway that harnesses LLMs to support agency operations within a secure environment, offering tailored functions for the needs of regulatory research.</p></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"149 ","pages":"Article 105613"},"PeriodicalIF":3.4,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0273230024000540/pdfft?md5=89cb7ecd4deb810548df92ba2e8afb7e&pid=1-s2.0-S0273230024000540-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140343774","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

Evaluation of in silico model predictions for mammalian acute oral toxicity and regulatory application in pesticide hazard and risk assessment 评估哺乳动物急性口服毒性的硅学模型预测以及在农药危害和风险评估中的监管应用

IF 3.4 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-04-02 DOI: 10.1016/j.yrtph.2024.105614

Patricia L. Bishop , Kamel Mansouri , William P. Eckel , Michael B. Lowit , David Allen , Amy Blankinship , Anna B. Lowit , D. Ethan Harwood , Tamara Johnson , Nicole C. Kleinstreuer

{"title":"Evaluation of in silico model predictions for mammalian acute oral toxicity and regulatory application in pesticide hazard and risk assessment","authors":"Patricia L. Bishop , Kamel Mansouri , William P. Eckel , Michael B. Lowit , David Allen , Amy Blankinship , Anna B. Lowit , D. Ethan Harwood , Tamara Johnson , Nicole C. Kleinstreuer","doi":"10.1016/j.yrtph.2024.105614","DOIUrl":"https://doi.org/10.1016/j.yrtph.2024.105614","url":null,"abstract":"<div><p>The United States Environmental Protection Agency (USEPA) uses the lethal dose 50% (LD<sub>50</sub>) value from <em>in vivo</em> rat acute oral toxicity studies for pesticide product label precautionary statements and environmental risk assessment (RA). The Collaborative Acute Toxicity Modeling Suite (CATMoS) is a quantitative structure-activity relationship (QSAR)-based <em>in silico</em> approach to predict rat acute oral toxicity that has the potential to reduce animal use when registering a new pesticide technical grade active ingredient (TGAI). This analysis compared LD<sub>50</sub> values predicted by CATMoS to empirical values from <em>in vivo</em> studies for the TGAIs of 177 conventional pesticides. The accuracy and reliability of the model predictions were assessed relative to the empirical data in terms of USEPA acute oral toxicity categories and discrete LD<sub>50</sub> values for each chemical. CATMoS was most reliable at placing pesticide TGAIs in acute toxicity categories III (>500–5000 mg/kg) and IV (>5000 mg/kg), with 88% categorical concordance for 165 chemicals with empirical <em>in vivo</em> LD<sub>50</sub> values ≥ 500 mg/kg. When considering an LD<sub>50</sub> for RA, CATMoS predictions of 2000 mg/kg and higher were found to agree with empirical values from limit tests (<em>i.e.</em>, single, high-dose tests) or definitive results over 2000 mg/kg with few exceptions.</p></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"149 ","pages":"Article 105614"},"PeriodicalIF":3.4,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0273230024000552/pdfft?md5=e53f0126e17a2f2ed07733d7e189b4e1&pid=1-s2.0-S0273230024000552-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140547140","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

False positive findings associated with adenoviral vector-based vaccine underscore the regulatory necessity to eliminate abnormal toxicity test 与基于腺病毒载体的疫苗相关的假阳性结果凸显了监管部门消除异常毒性测试的必要性

IF 3.4 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-03-30 DOI: 10.1016/j.yrtph.2024.105617

Ryan Meng , Mark van Ooij , Yali Li , Yunhai Zhang , Jianxun Xie

{"title":"False positive findings associated with adenoviral vector-based vaccine underscore the regulatory necessity to eliminate abnormal toxicity test","authors":"Ryan Meng , Mark van Ooij , Yali Li , Yunhai Zhang , Jianxun Xie","doi":"10.1016/j.yrtph.2024.105617","DOIUrl":"https://doi.org/10.1016/j.yrtph.2024.105617","url":null,"abstract":"<div><p>Accumulating evidence has shown that the abnormal toxicity test (ATT) is not suitable as a quality control batch release test for biologics and vaccines. The purpose of the current study was to explore the optimal ATT experimental design for an adenoviral vector-based vaccine product to avoid false positive results following the standard test conditions stipulated in the Pharmacopoeias. ATT were conducted in both mice and guinea pigs based on methods in Pharmacopeias, with modifications to assess effects of dose volume and amount of virus particles (VPs). The results showed intraperitoneal (IP) dosing at human relevant dose and volume (i.e., VPs), as required by pharmacopeia study design, resulted in false positive findings not associated with extraneous contaminants of a product. Considering many gene therapy products use adeno associated virus as the platform for transgene delivery, data from this study are highly relevant in providing convincing evidence to show the ATT is inappropriate as batch release test for biologics, vaccine and gene therapy products. In conclusion, ATT, which requires unnecessary animal usage and competes for resources which otherwise can be spent on innovative medicine research, should be deleted permanently as batch release test by regulatory authorities around the world.</p></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"149 ","pages":"Article 105617"},"PeriodicalIF":3.4,"publicationDate":"2024-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140332906","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

Pharmacokinetic models for first-in-human dose selection of immune-activating products in oncology 用于肿瘤免疫激活产品首次人体剂量选择的药代动力学模型。

IF 3.4 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-03-30 DOI: 10.1016/j.yrtph.2024.105616

Haleh Saber, Matthew D. Thompson, John K. Leighton

{"title":"Pharmacokinetic models for first-in-human dose selection of immune-activating products in oncology","authors":"Haleh Saber, Matthew D. Thompson, John K. Leighton","doi":"10.1016/j.yrtph.2024.105616","DOIUrl":"10.1016/j.yrtph.2024.105616","url":null,"abstract":"<div><p>Pharmacokinetic (PK) models are increasingly submitted to the FDA to support first-in-human (FIH) dose selection of immune-oncology products. To examine whether a simple PK modeling (SPM) using clearance for scaling was acceptable for dose estimation, FIH<sub>(SPM)</sub> doses were computed and compared to doses that were safely administered to patients. We concluded that the SPM approach is acceptable in FIH dose estimation, but the variables should be carefully selected for CD3 constructs. For CD3 constructs, use of 60 kg BW<sub>h</sub>, a clearance exponent of 0.75, and a targeted plasma concentration based on relevant and/or sensitive activity assays was an acceptable approach for FIH dose selection; use of 0.85 as the scaling factor is questionable at this time as it resulted in a FIH dose that was too close to the AHD for one product (7%). Immune activating mAbs were not sensitive to changes in the clearance exponent (0.75–0.85) or body weight (60–70 kg). For PD-1/PD-L1 mAbs, using products’ in vitro EC50 in the model resulted in suboptimal FIH doses and clinical data of closely related products informed FIH dose selection. PK models submitted by sponsors were diverse in methods, assumptions, and variables, and the resulting FIH doses were not always optimal.</p></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"149 ","pages":"Article 105616"},"PeriodicalIF":3.4,"publicationDate":"2024-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140336699","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

New Approach Methodologies (NAMs) for ad hoc human health risk assessment of food and non-food products - Proceedings of a workshop 对食品和非食品产品进行特别人类健康风险评估的新方法（NAMs）--研讨会记录。

IF 3.4 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-03-28 DOI: 10.1016/j.yrtph.2024.105615

Lianne de Wit , Hester Hendriks , Jacqueline van Engelen , Harm Heusinkveld , Anne Kienhuis , Emiel Rorije , Marjolijn Woutersen , Margriet van der Zee , Suzanne Jeurissen

{"title":"New Approach Methodologies (NAMs) for ad hoc human health risk assessment of food and non-food products - Proceedings of a workshop","authors":"Lianne de Wit , Hester Hendriks , Jacqueline van Engelen , Harm Heusinkveld , Anne Kienhuis , Emiel Rorije , Marjolijn Woutersen , Margriet van der Zee , Suzanne Jeurissen","doi":"10.1016/j.yrtph.2024.105615","DOIUrl":"10.1016/j.yrtph.2024.105615","url":null,"abstract":"<div><p>RIVM convened a workshop on the use of New Approach Methodologies (NAMs) for the ad hoc human health risk assessment of food and non-food products. Central to the workshop were two case studies of marketed products with a potential health concern: the botanical <em>Tabernanthe iboga</em> which is used to facilitate mental or spiritual insight or to (illegally) treat drug addiction and is associated with cardiotoxicity, and dermal creams containing female sex hormones, intended for use by perimenopausal women to reduce menopause symptoms without medical supervision. The workshop participants recognized that data from NAM approaches added valuable information for the ad hoc risk assessment of these products, although the available approaches were inadequate to derive health-based guidance values. Recommendations were provided on how to further enhance and implement NAM approaches in regulatory risk assessment, specifying both scientific and technical aspects as well as stakeholder engagement aspects.</p></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"149 ","pages":"Article 105615"},"PeriodicalIF":3.4,"publicationDate":"2024-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0273230024000564/pdfft?md5=0ac95f66a6a6e14cf1beb757443c4ed5&pid=1-s2.0-S0273230024000564-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140330102","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

Commentary: Value of information case study strongly supports use of the Threshold of Toxicological Concern (TTC) 评论：案例研究的信息价值有力地支持了毒理学关注阈值 (TTC) 的使用。

IF 3.4 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-03-28 DOI: 10.1016/j.yrtph.2024.105594

Ted W. Simon , Jessica Ryman , Richard A. Becker

{"title":"Commentary: Value of information case study strongly supports use of the Threshold of Toxicological Concern (TTC)","authors":"Ted W. Simon , Jessica Ryman , Richard A. Becker","doi":"10.1016/j.yrtph.2024.105594","DOIUrl":"10.1016/j.yrtph.2024.105594","url":null,"abstract":"<div><p>A Value of Information (VOI) analysis can play a key role in decision-making for adopting new approach methodologies (NAMs). We applied EPA's recently developed VOI framework to the Threshold of Toxicological Concern (TTC). Obtaining/deriving a TTC value for use as a toxicity reference value (TRV) for substances with limited toxicity data was shown to provide equivalent or greater health protection, immense return on investment (ROI), greater net benefit, and substantially lower costs of delay (CoD) compared with TRVs derived from either traditional human health assessment (THHA) chronic toxicity testing in lab animals or the 5-day <em>in vivo</em> EPA Transcriptomic Assessment Product (ETAP). For all nine exposure scenarios examined, the TTC was more economical terms of CoD and ROI than the ETAP or the THHA; expected net benefit was similar for the TTC and ETAP with both of these more economical than the THHA The TTC ROI was immensely greater (5,000,000-fold on average) than the ROI for THHA and the ETAP ROI (100,000-fold on average). These results support the use of the TTC for substances within its domain of applicability to waive requiring certain <em>in vivo</em> tests, or at a minimum, as an initial screening step before conducting either the ETAP or THHA <em>in vivo</em> studies.</p></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"149 ","pages":"Article 105594"},"PeriodicalIF":3.4,"publicationDate":"2024-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140330101","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

Species differences in specific ligand-binding affinity and activation of AHR: The biological basis for calculation of relative effective potencies and toxic equivalence factors 特异配体结合亲和力和激活 AHR 的物种差异：计算相对有效药效和毒性当量因子的生物学基础。

IF 3.4 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-03-26 DOI: 10.1016/j.yrtph.2024.105598

David L. Eaton , Ted W. Simon , Norbert E. Kaminski , Gary H. Perdew , Daniel W. Nebert

{"title":"Species differences in specific ligand-binding affinity and activation of AHR: The biological basis for calculation of relative effective potencies and toxic equivalence factors","authors":"David L. Eaton , Ted W. Simon , Norbert E. Kaminski , Gary H. Perdew , Daniel W. Nebert","doi":"10.1016/j.yrtph.2024.105598","DOIUrl":"10.1016/j.yrtph.2024.105598","url":null,"abstract":"<div><p>In 2022 the World Health Organization (WHO) published updated ‘Toxic Equivalence Factors’ (TEFs) for a wide variety of chlorinated dioxins, dibenzofurans and PCBs [collectively referred to as ‘dioxin-like chemicals’; DLCs) that interact with the aryl hydrocarbon receptor (AHR)]. Their update used sophisticated statistical analysis of hundreds of published studies that reported estimation of ‘Relative Effective Potency’ (REP) values for individual DLC congeners. The weighting scheme used in their assessment of each study favored in vivo over in vitro studies and was based largely on rodent studies. In this Commentary, we highlight the large body of published studies that demonstrate large species differences in AHR-ligand activation and provide supporting evidence for our position that the WHO 2022 TEF values intended for use in human risk assessment of DLC mixtures will provide highly misleading overestimates of ‘Toxic Equivalent Quotients’ (TEQs), because of well-recognized striking differences in AHR ligand affinities between rodent (rat, mouse) and human. The data reviewed in our Commentary support the position that human tissue-derived estimates of REP/TEF values for individual DLC congeners, although uncertain, will provide much better, more realistic estimates of potential activation of the human AHR, when exposure to complex DLC mixtures occurs.</p></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"149 ","pages":"Article 105598"},"PeriodicalIF":3.4,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140319109","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

Editorial: 2024 - A promising start for regulatory toxicology and pharmacology 社论：2024 年--毒理学和药理学监管的良好开端。

IF 3.4 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-03-20 DOI: 10.1016/j.yrtph.2024.105601

Martin van den Berg (Editors-in-Chief), Lesa Aylward (Editors-in-Chief)

引用次数: 0

Selectively addressing total risk avoidance for certain chemicals while overlooking others: The case of per-and-poly-fluoroalkyls 选择性地解决某些化学品的全面风险规避问题，而忽略其他化学品：全氟烷基和多氟烷基的案例。

IF 3.4 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-03-17 DOI: 10.1016/j.yrtph.2024.105602

Alberto Boretti

引用次数: 0

Review of the standards of proof (of safety) for FDA regulated consumer products and how the generally recognized as safe criteria could be applied to cosmetics 审查 FDA 监管消费品的（安全）证明标准，以及如何将公认安全标准应用于化妆品。

IF 3.4 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-03-15 DOI: 10.1016/j.yrtph.2024.105603

George A. Burdock

{"title":"Review of the standards of proof (of safety) for FDA regulated consumer products and how the generally recognized as safe criteria could be applied to cosmetics","authors":"George A. Burdock","doi":"10.1016/j.yrtph.2024.105603","DOIUrl":"10.1016/j.yrtph.2024.105603","url":null,"abstract":"<div><p>The Modernization of Cosmetics Regulation Act of 2022 (MoCRA) amends the Food, Drug and Cosmetic Act (FDCA), elevating the standard of proof of safety (better known as a “safety standard”) for cosmetics to the standard of a “reasonable certainty … [of] … safe.”a standard equal to that of food ingredients. The standards of the proof of safety differ for various classes of FDA-regulated product categories <em>e.g</em>., cosmetics, dietary supplements, food ingredients and food itself. This manuscript describes the various standards of proof, the essential differences between the standards, key elements required to achieve a particular standard and, compares the standards to more familiar legal terms such as “a preponderance of the evidence” or “beyond reasonable doubt.” The standards of proof for these product categories are also ranked according to increasing threshold for achievement of “safe” status. Lastly, this manuscript suggests how the requirements for the high standard of a “reasonable certainty of safe” (or “reasonable certainty of no harm”) might be met.</p></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"149 ","pages":"Article 105603"},"PeriodicalIF":3.4,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140144009","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