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Is read-across for chemicals comparable to medical device equivalence and where to use it for conformity assessment? 化学品的 "可读性 "是否可与医疗器械的 "等效性 "相媲美?
IF 3.4 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-04-06 DOI: 10.1016/j.yrtph.2024.105622
Jan Sündermann , Annette Bitsch , Rupert Kellner , Theodor Doll

Novel medical devices must conform to medical device regulation (MDR) for European market entry. Likewise, chemicals must comply with the Registration, Evaluation, Authorization and Restriction of Chemicals (REACh) regulation. Both pose regulatory challenges for manufacturers, but concordantly provide an approach for transferring data from an already registered device or compound to the one undergoing accreditation. This is called equivalence for medical devices and read-across for chemicals.

Although read-across is not explicitly prohibited in the process of medical device accreditation, it is usually not performed due to a lack of guidance and acceptance criteria from the authorities. Nonetheless, a scientifically justified read-across of material-based endpoints, as well as toxicological assessment of chemical aspects, such as extractables and leachables, can prevent failure of MDR device equivalence if data is lacking. Further, read-across, if applied correctly can facilitate the standard MDR conformity assessment.

The need for read-across within medical device registration should let authorities to reconsider device accreditation and the formulation of respective guidance documents. Acceptance criteria like in the European Chemicals Agency (ECHA) read-across assessment framework (RAAF) are needed. This can reduce the impact of the MDR and help with keeping high European innovation device rate, beneficial for medical device patients.

新型医疗器械必须符合医疗器械法规 (MDR) 才能进入欧洲市场。同样,化学品也必须符合《化学品注册、评估、许可和限制》(REACh)法规。这两项法规都给制造商带来了监管方面的挑战,但同时也提供了一种将数据从已注册设备或化合物转移到正在接受认证的设备或化合物的方法。虽然在医疗器械认证过程中并没有明令禁止 "数据转换",但由于缺乏主管部门的指导和接受标准,通常不会进行 "数据转换"。尽管如此,如果缺乏数据,对基于材料的终点进行有科学依据的重新交叉,以及对可萃取物和可浸出物等化学物质进行毒理学评估,可以防止 MDR 设备等效性失败。此外,如果应用得当,"可读性交叉 "还能促进标准的 MDR 符合性评估。"可读性交叉 "在医疗器械注册中的必要性应促使相关机构重新考虑器械认证和相应指导文件的制定。需要像欧洲化学品管理局 (ECHA) 的 "可读性评估框架"(RAAF) 一样的验收标准。这可以减少 MDR 的影响,并有助于保持较高的欧洲创新器械率,使医疗器械患者受益。
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引用次数: 0
Letter to the Editors regarding “Using historical control data in bioassays for regulatory toxicology” by Kluxen et al. (2021) 致编辑的信,内容涉及 Kluxen 等人撰写的《在监管毒理学生物测定中使用历史对照数据》(2021 年)
IF 3.4 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-04-06 DOI: 10.1016/j.yrtph.2024.105624
Jürg A. Zarn, H. Christoph Geiser, Sebastian L.B. König, Holly V. Shaw, Ursina A. Zürcher
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引用次数: 0
Biomonitoring Equivalents for ethylene thiourea 乙烯硫脲的生物监测当量
IF 3.4 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-04-05 DOI: 10.1016/j.yrtph.2024.105618
Sean M. Hays , Christopher R. Kirman , Jennifer Flippin , Theresa Lopez

Ethylene thiourea, or ETU, is used in the rubber industry and is a degradation product and impurity in some fungicides. The general public may be exposed to low concentrations of residues of ETU in a variety of ways, including food treated with ethylene bis-dithiocarbamate (EBDC) fungicides or migration from rubber products. Biomonitoring of ETU in urine is useful for an assessment of integrated exposures to ETU across different sources and routes of exposure. In this evaluation, we review available health-based risk assessments and toxicological reference values (TRVs) for ETU and derive Biomonitoring Equivalent (BE) values for interpretation of population biomonitoring data. BEs were derived based on existing TRVs derived by Health Canada, yielding a BE of 27 μg of total ETU/L in urine associated with the Acceptable Daily Intake (ADI) and 6.7 μg/L associated with a 1e-6 cancer risk. These BEs are based on an analytical method that involves a digestion step to liberate conjugated ETU, thus producing ‘total’ ETU in urine. The BE values derived in this manuscript can serve as a guide to help public health officials and regulators interpret population based ETU biomonitoring data in a public health risk context.

乙烯硫脲(ETU)用于橡胶工业,是某些杀菌剂的降解产物和杂质。公众可能会通过多种途径接触到低浓度的 ETU 残留物,包括用乙烯双二硫代氨基甲酸酯(EBDC)杀真菌剂处理过的食物或从橡胶制品中迁移。对尿液中的 ETU 进行生物监测有助于评估不同来源和接触途径的 ETU 综合接触情况。在本评估中,我们回顾了现有的基于健康的 ETU 风险评估和毒理学参考值 (TRV),并得出了生物监测等效值 (BE),用于解释人口生物监测数据。生物监测等效值是根据加拿大卫生部现有的 TRV 得出的,得出的生物监测等效值为尿液中总 ETU 含量为 27 μg/L 与每日允许摄入量 (ADI) 相关,6.7 μg/L 与 1e-6 癌症风险相关。这些 BE 值是根据一种分析方法得出的,该方法包括一个消化步骤,以释放共轭 ETU,从而产生尿液中的 "总 "ETU。本手稿中得出的 BE 值可作为指南,帮助公共卫生官员和监管人员在公共卫生风险背景下解释基于人群的 ETU 生物监测数据。
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引用次数: 0
Implications of variability on medical device chemical equivalence assessment 变异性对医疗器械化学等效性评估的影响
IF 3.4 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-04-02 DOI: 10.1016/j.yrtph.2024.105612
David M. Saylor, Joshua A. Young

Chemical equivalence testing can be used to assess the biocompatibility implications of a materials or manufacturing change for a medical device. This testing can provide a relatively facile means to evaluate whether the change may result in additional or different toxicological concerns. However, one of the major challenges in the interpretation of chemical equivalence data is the lack established criteria for determining if two sets of extractables data are effectively equivalent. To address this gap, we propose a two–part approach based upon a relatively simple statistical model. First, the probability of a false positive conclusion, wherein there is an incorrectly perceived increase for a given analyte in the comparator relative to the baseline device, can be reduced to a prescribed level by establishing an appropriate acceptance criterion for the ratio of the observed means. Second, the probability of a false negative conclusion, where an actual increase in a given analyte cannot be discerned from the test results, can be minimized by specifying a limiting value of applicability based on the margin of safety (MoS) of the analyte. This approach provides a quantitative, statistically motivated method to interpret chemical equivalence data, despite the relatively high intrinsic variability and small number of replicates typically associated with a chemical characterization evaluation.

化学等效性测试可用于评估医疗器械材料或制造工艺改变对生物相容性的影响。这种测试可以提供一种相对简便的方法,以评估变化是否会导致额外或不同的毒理学问题。然而,解释化学等效数据的主要挑战之一是缺乏确定两组萃取物数据是否有效等效的既定标准。为了弥补这一缺陷,我们提出了一种基于相对简单的统计模型的两部分方法。首先,通过为观察到的平均值之比制定适当的接受标准,可以将假阳性结论的概率降低到规定的水平。其次,根据被分析物的安全系数 (MoS),规定一个适用性的极限值,可以最大限度地降低假阴性结论的概率,即无法从测试结果中发现特定被分析物的实际增加。这种方法提供了一种定量的统计方法来解释化学等效数据,尽管化学特性评估通常具有相对较高的内在变异性和较少的重复次数。
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引用次数: 0
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 Q1 MEDICINE, LEGAL 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

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.

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.

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.

监管机构一直在处理大量的文件审查工作,从产品提交到内部和外部沟通,不一而足。像 ChatGPT 这样的大型语言模型(LLM)是完成这些任务的宝贵工具,但也面临着一些挑战,尤其是专有信息、将定制功能与特定审查需求相结合以及模型输出的透明度和可解释性。为了应对这些挑战,我们针对 FDA 药品审查过程中的重要资源--FDA 药品标签文件,制定了一个名为 AskFDALabel 的框架。AskFDALabel 在安全的 IT 环境下运行,由两个关键模块组成:语义搜索和问答模块。S 模块建立在词嵌入的基础上,可以在标签文档中进行全面的语义查询。最后,我们通过 AskFDALabel 展示了一种利用 LLM 在安全环境中支持机构运作的途径,为监管研究的需求提供了量身定制的功能。
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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 Q1 MEDICINE, LEGAL 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

The United States Environmental Protection Agency (USEPA) uses the lethal dose 50% (LD50) value from in vivo 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 in silico 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 LD50 values predicted by CATMoS to empirical values from in vivo 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 LD50 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 in vivo LD50 values ≥ 500 mg/kg. When considering an LD50 for RA, CATMoS predictions of 2000 mg/kg and higher were found to agree with empirical values from limit tests (i.e., single, high-dose tests) or definitive results over 2000 mg/kg with few exceptions.

美国环境保护局 (USEPA) 在农药产品标签防范说明和环境风险评估 (RA) 中使用体内大鼠急性经口毒性研究得出的致死剂量 50% (LD50) 值。急性毒性合作建模套件 (CATMoS) 是一种基于定量结构-活性关系 (QSAR) 的硅学方法,用于预测大鼠急性经口毒性,有可能在登记新农药技术级活性成分 (TGAI) 时减少动物用量。这项分析比较了 CATMoS 预测的 LD50 值和 177 种常规农药技术级活性成分的体内研究经验值。根据 USEPA 急性经口毒性类别和每种化学品的离散 LD50 值,评估了模型预测与经验数据相比的准确性和可靠性。CATMoS 在将农药 TGAI 列入急性毒性类别 III(500-5000 毫克/千克)和 IV(5000 毫克/千克)方面最为可靠,对于体内 LD50 经验值≥ 500 毫克/千克的 165 种化学品,分类一致性达到 88%。在考虑 RA 的半数致死剂量时,CATMoS 预测的 2000 mg/kg 或更高值与极限试验(即单次高剂量试验)的经验值或超过 2000 mg/kg 的确定结果一致,只有少数例外。
{"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 ,&nbsp;Kamel Mansouri ,&nbsp;William P. Eckel ,&nbsp;Michael B. Lowit ,&nbsp;David Allen ,&nbsp;Amy Blankinship ,&nbsp;Anna B. Lowit ,&nbsp;D. Ethan Harwood ,&nbsp;Tamara Johnson ,&nbsp;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 (&gt;500–5000 mg/kg) and IV (&gt;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 Q1 MEDICINE, LEGAL Pub Date : 2024-03-30 DOI: 10.1016/j.yrtph.2024.105617
Ryan Meng , Mark van Ooij , Yali Li , Yunhai Zhang , Jianxun Xie

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.

越来越多的证据表明,异常毒性试验(ATT)不适合作为生物制品和疫苗的质量控制批次释放试验。本研究的目的是探索基于腺病毒载体的疫苗产品的最佳 ATT 实验设计,以避免按照药典规定的标准试验条件出现假阳性结果。根据药典中的方法在小鼠和豚鼠身上进行了ATT实验,并对剂量和病毒颗粒(VPs)数量的影响进行了评估。结果表明,按照药典研究设计的要求,以与人体相关的剂量和体积(即 VPs)进行腹腔注射(IP)会导致假阳性结果,而与产品的外来污染物无关。考虑到许多基因治疗产品使用腺相关病毒作为转基因递送平台,本研究的数据具有很强的相关性,可提供令人信服的证据表明 ATT 不适合作为生物制品、疫苗和基因治疗产品的批次释放检验。总之,ATT 需要不必要地使用动物,并占用了本可用于创新药物研究的资源,因此世界各地的监管机构应永久取消将其作为批量放行测试的做法。
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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 Q1 MEDICINE, LEGAL Pub Date : 2024-03-30 DOI: 10.1016/j.yrtph.2024.105616
Haleh Saber, Matthew D. Thompson, John K. Leighton

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(SPM) 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 BWh, 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.

越来越多的药物代谢动力学(PK)模型被提交给美国食品与药物管理局(FDA),以支持免疫肿瘤产品的首次人体试验(FIH)剂量选择。为了检验使用清除率进行缩放的简单 PK 模型(SPM)是否可用于剂量估算,我们计算了 FIH(SPM)剂量,并与患者安全用药的剂量进行了比较。我们得出的结论是,SPM 方法在 FIH 剂量估算中是可以接受的,但对于 CD3 构合物而言,应谨慎选择变量。对于 CD3 构建药,使用 60 千克体重、0.75 的清除指数以及基于相关和/或敏感活性测定的目标血浆浓度是一种可接受的 FIH 剂量选择方法;使用 0.85 作为比例系数目前尚有疑问,因为它导致一种产品(7%)的 FIH 剂量过于接近 AHD。免疫激活 mAbs 对清除指数(0.75-0.85)或体重(60-70 千克)的变化不敏感。对于PD-1/PD-L1 mAbs来说,在模型中使用产品的体外EC50会导致FIH剂量的不理想,而密切相关产品的临床数据则为FIH剂量的选择提供了依据。申办者提交的 PK 模型在方法、假设和变量方面各不相同,因此得出的 FIH 剂量并不总是最佳的。
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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 Q1 MEDICINE, LEGAL 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

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 Tabernanthe iboga 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.

国际兽疫局召开了一次关于使用新方法(NAMs)对食品和非食品进行特别人类健康风险评估的研讨会。研讨会的中心议题是两个具有潜在健康问题的上市产品案例研究:植物药 Tabernanthe iboga,用于促进心理或精神洞察力或(非法)治疗毒瘾,并与心脏毒性有关;以及含有女性性激素的皮肤乳膏,用于围绝经期妇女在没有医疗监督的情况下减轻更年期症状。研讨会与会者认识到,虽然现有方法不足以得出基于健康的指导值,但从非杀伤人员地雷方法中获得的数据为这些产品的特别风险评估增加了宝贵的信息。与会者就如何在监管风险评估中进一步加强和实施非杀伤人员地雷方法提出了建议,具体说明了科学和技术方面以及利益相关者参与方面的问题。
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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 Q1 MEDICINE, LEGAL Pub Date : 2024-03-28 DOI: 10.1016/j.yrtph.2024.105594
Ted W. Simon , Jessica Ryman , Richard A. Becker

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 in vivo 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 in vivo tests, or at a minimum, as an initial screening step before conducting either the ETAP or THHA in vivo studies.

信息价值 (VOI) 分析可在采用新方法 (NAM) 的决策中发挥关键作用。我们将 EPA 最近开发的 VOI 框架应用于毒理学关注阈值 (TTC)。与通过传统人类健康评估 (THHA) 实验室动物慢性毒性测试或 5 天体内 EPA 转录组评估产品 (ETAP) 得出的毒性参考值相比,获得/得出 TTC 值作为毒性参考值 (TRV) 用于毒性数据有限的物质可提供同等或更大的健康保护、更高的投资回报率 (ROI)、更大的净效益以及更低的延迟成本 (CoD)。在所有九种暴露情况下,TTC 在 CoD 和投资回报率方面都比 ETAP 或 THHA 更经济;TTC 和 ETAP 的预期净效益相似,都比 THHA 更经济。这些结果支持将 TTC 用于其适用范围内的物质,以免除某些体内测试的要求,或至少作为进行 ETAP 或 THHA 体内研究之前的初步筛选步骤。
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引用次数: 0
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Regulatory Toxicology and Pharmacology
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