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Dehydroacetic acid hydrazones as potent enzyme inhibitors: design, synthesis and computational studies 脱氢乙酸腙作为有效的酶抑制剂:设计、合成和计算研究
Q2 TOXICOLOGY Pub Date : 2022-11-01 DOI: 10.1016/j.comtox.2022.100239
Raman Lakhia , Neera Raghav , Rashmi Pundeer

The present study offers the work on the hydrazone derivatives of dehydroacetic acid to be considered for computational and synthetic studies. The hydrazone derivatives of dehydroacetic acid were designed with different electron-withdrawing and electron-releasing substituents. The hydrazones and the parent compound (dehydroacetic acid) were subjected to computational studies to evaluate their pharmacological properties. The compounds were assessed by applying Lipinski’s rule followed by ADMET predictions. Among all the derivatives under studies, 4-hydroxy-6-methyl-3-(1-(2-(2-nitrophenyl) hydrazineylidene) ethyl)-2H-pyran-2-one was found to be the most effective derivative which was further evaluated against BSA, trypsin, amylase, lipase and cathepsins (B and H) by using docking studies. The computational results were also verified experimentally by synthesizing the derivative as well as performing enzyme inhibition studies on the synthesized hydrazone and the parent compound.

本研究为脱氢乙酸的腙衍生物的计算和合成研究提供了参考。采用不同的吸电子和放电子取代基设计了脱氢乙酸的腙衍生物。对腙和母体化合物(脱氢乙酸)进行了计算研究,以评估它们的药理学性质。通过应用Lipinski规则和ADMET预测来评估化合物。在所有研究的衍生物中,4-羟基-6-甲基-3-(1-(2-(2-硝基苯基)肼基)乙基)- 2h -吡喃-2- 1是最有效的衍生物,通过对接研究进一步对BSA、胰蛋白酶、淀粉酶、脂肪酶和组织蛋白酶(B和H)进行了评价。通过对衍生物的合成以及对合成的腙和母体化合物进行酶抑制研究,验证了计算结果。
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引用次数: 1
Evaluating structure-based activity in a high-throughput assay for steroid biosynthesis 在类固醇生物合成的高通量测定中评估基于结构的活性。
Q2 TOXICOLOGY Pub Date : 2022-11-01 DOI: 10.1016/j.comtox.2022.100245
Miran J Foster , Grace Patlewicz , Imran Shah , Derik E. Haggard , Richard S. Judson , Katie Paul Friedman

Data from a high-throughput human adrenocortical carcinoma assay (HT-H295R) for steroid hormone biosynthesis are available for > 2000 chemicals in single concentration and 654 chemicals in multi-concentration (mc). Previously, a metric describing the effect size of a chemical on the biosynthesis of 11 hormones was derived using mc data referred to as the maximum mean Mahalanobis distance (maxmMd). However, mc HT-H295R assay data remain unavailable for many chemicals. This work leverages existing HT-H295R assay data by constructing structure–activity relationships to make predictions for data-poor chemicals, including: (1) identification of individual structural descriptors, known as ToxPrint chemotypes, associated with increased odds of affecting estrogen or androgen synthesis; (2) a random forest (RF) classifier using physicochemical property descriptors to predict HT-H295R maxmMd binary (positive or negative) outcomes; and, (3) a local approach to predict maxmMd binary outcomes using nearest neighbors (NNs) based on two types of chemical fingerprints (chemotype or Morgan). Individual chemotypes demonstrated high specificity (85–98 %) for modulators of estrogen and androgen synthesis but with low sensitivity. The best RF model for maxmMd classification included 13 predicted physicochemical descriptors, yielding a balanced accuracy (BA) of 71 % with only modest improvement when hundreds of structural features were added. The best two NN models for binary maxmMd prediction demonstrated BAs of 85 and 81 % using chemotype and Morgan fingerprints, respectively. Using an external test set of 6302 chemicals (lacking HT-H295R data), 1241 were identified as putative estrogen and androgen modulators. Combined results across the three classification models (global RF model and two local NN models) predict that 1033 of the 6302 chemicals would be more likely to affect HT-H295R bioactivity. Together, these in silico approaches can efficiently prioritize thousands of untested chemicals for screening to further evaluate their effects on steroid biosynthesis.

类固醇激素生物合成的高通量人类肾上腺皮质癌测定(HT-H295R)数据可用于单浓度>2000种化学物质和多浓度654种化学物质(mc)。以前,描述一种化学物质对11种激素生物合成的影响大小的指标是使用称为最大平均马氏距离(maxmMd)的mc数据得出的。然而,许多化学品的mc-HHT-H295R测定数据仍然不可用。这项工作利用现有的HT-H295R测定数据,通过构建结构-活性关系来预测缺乏数据的化学物质,包括:(1)识别与影响雌激素或雄激素合成的几率增加相关的单个结构描述符,即ToxPrint化学型;(2) 随机森林(RF)分类器,其使用物理化学性质描述符来预测HT-H295R maxmMd二元(阳性或阴性)结果;以及,(3)基于两种类型的化学指纹(化学型或Morgan),使用最近邻(NN)预测maxmMd二元结果的局部方法。个体化学型对雌激素和雄激素合成调节剂表现出高特异性(85-98%),但敏感性低。maxmMd分类的最佳RF模型包括13个预测的物理化学描述符,当添加数百个结构特征时,产生71%的平衡准确度(BA),只有适度的改进。二元maxmMd预测的最佳两个NN模型使用化学型和Morgan指纹分别显示出85%和81%的BA。使用6302种化学物质的外部测试集(缺乏HT-H295R数据),1241种被鉴定为推定的雌激素和雄激素调节剂。三个分类模型(全局RF模型和两个局部NN模型)的综合结果预测,6302种化学物质中的1033种更有可能影响HT-H295R的生物活性。总之,这些计算机方法可以有效地优先筛选数千种未经测试的化学物质,以进一步评估它们对类固醇生物合成的影响。
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引用次数: 1
Principles and procedures for assessment of acute toxicity incorporating in silico methods 硅方法急性毒性评估的原则和程序。
Q2 TOXICOLOGY Pub Date : 2022-11-01 DOI: 10.1016/j.comtox.2022.100237
Craig M. Zwickl , Jessica C. Graham , Robert A. Jolly , Arianna Bassan , Ernst Ahlberg , Alexander Amberg , Lennart T. Anger , Lisa Beilke , Phillip Bellion , Alessandro Brigo , Heather Burleigh-Flayer , Mark T.D. Cronin , Amy A. Devlin , Trevor Fish , Susanne Glowienke , Kamila Gromek , Agnes L. Karmaus , Ray Kemper , Sunil Kulkarni , Elena Lo Piparo , Glenn J. Myatt

Acute toxicity in silico models are being used to support an increasing number of application areas including (1) product research and development, (2) product approval and registration as well as (3) the transport, storage and handling of chemicals. The adoption of such models is being hindered, in part, because of a lack of guidance describing how to perform and document an in silico analysis. To address this issue, a framework for an acute toxicity hazard assessment is proposed. This framework combines results from different sources including in silico methods and in vitro or in vivo experiments. In silico methods that can assist the prediction of in vivo outcomes (i.e., LD50) are analyzed concluding that predictions obtained using in silico approaches are now well-suited for reliably supporting assessment of LD50-based acute toxicity for the purpose of the Globally Harmonized System (GHS) classification. A general overview is provided of the endpoints from in vitro studies commonly evaluated for predicting acute toxicity (e.g., cytotoxicity/cytolethality as well as assays targeting specific mechanisms). The increased understanding of pathways and key triggering mechanisms underlying toxicity and the increased availability of in vitro data allow for a shift away from assessments solely based on endpoints such as LD50, to mechanism-based endpoints that can be accurately assessed in vitro or by using in silico prediction models. This paper also highlights the importance of an expert review of all available information using weight-of-evidence considerations and illustrates, using a series of diverse practical use cases, how in silico approaches support the assessment of acute toxicity.

硅模型中的急性毒性正被用于支持越来越多的应用领域,包括(1)产品研发,(2)产品批准和注册,以及(3)化学品的运输、储存和处理。这种模型的采用受到阻碍,部分原因是缺乏描述如何执行和记录计算机分析的指导。为了解决这个问题,提出了一个急性毒性危害评估框架。该框架结合了来自不同来源的结果,包括计算机方法和体外或体内实验。对有助于预测体内结果(即LD50)的计算机内方法进行了分析,得出的结论是,使用计算机内方法获得的预测现在非常适合可靠地支持基于LD50的急性毒性评估,用于GHS分类。概述了体外研究的终点,这些终点通常用于预测急性毒性(例如细胞毒性/细胞致死性以及针对特定机制的测定)。对潜在毒性的途径和关键触发机制的了解增加,以及体外数据的可用性增加,使得从仅基于LD50等终点的评估转变为可以在体外或通过使用计算机预测模型准确评估的基于机制的终点。本文还强调了使用证据权重考虑因素对所有可用信息进行专家审查的重要性,并通过一系列不同的实际用例说明了计算机方法如何支持急性毒性评估。
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引用次数: 2
A strategy to define applicability domains for read-across 定义跨读适用域的策略
Q2 TOXICOLOGY Pub Date : 2022-05-01 DOI: 10.1016/j.comtox.2022.100220
Cynthia Pestana , Steven J. Enoch , James W. Firman , Judith C. Madden , Nicoleta Spînu , Mark T.D. Cronin

The definition, characterisation and assessment of the similarity between target and source molecules are cornerstones of the acceptance of a read-across prediction to fill a data gap for a toxicological endpoint. There is much guidance and many frameworks which are applicable in a regulatory context, but as yet no formalised process exists by which to determine whether or not the properties of an analogue (or chemicals within a category) fall within an appropriate domain from which a reliable read-across prediction can be made. This investigation has synthesised much of the existing knowledge in this area into a practical strategy to enable the domain of a read-across prediction to be defined, in terms of chemistry (structure and properties), toxicodynamics and toxicokinetics. The strategy is robust, comprehensive, flexible, and can be implemented readily. It enables the relative similarity and dissimilarity, between target and source molecules, for both the analogue and category approaches, to be analysed and provides a basis for alternative scenarios such as read-across based on formation of a common metabolite or biological profile to be defiend. Herein, the read-across domains for the repeated dose toxicity of a group of triazoles and imidazoles have been evaluated. The most challenging aspect to this approach will continue to be determining what is an “acceptable” degree of similarity when performing read-across for a specific purpose.

靶分子和源分子之间相似性的定义、表征和评估是接受跨读预测以填补毒理学终点数据空白的基石。有许多指导和许多框架适用于监管环境,但目前还没有正式的过程来确定类似物(或类别内的化学品)的性质是否属于可以进行可靠读取预测的适当领域。这项研究综合了该领域的许多现有知识,形成了一种实用的策略,可以从化学(结构和性质)、毒性动力学和毒性动力学的角度来定义跨读预测领域。该战略稳健、全面、灵活,易于实施。它可以分析靶分子和源分子之间的相对相似性和不相似性,用于模拟和分类方法,并为替代方案提供基础,例如基于共同代谢物或生物概况的形成进行解读。本文对一组三唑和咪唑的重复剂量毒性进行了跨域读取评价。这种方法最具挑战性的方面仍然是,在为特定目的执行读取时,确定什么是“可接受的”相似性程度。
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引用次数: 1
Estimating the reliability of simulated metabolism using documented data and theoretical knowledge. QSAR application 使用记录的数据和理论知识评估模拟代谢的可靠性。QSAR应用
Q2 TOXICOLOGY Pub Date : 2022-05-01 DOI: 10.1016/j.comtox.2022.100218
Irina A. Dermen , Hristiana I. Ivanova , Elena K. Kaloyanova , Nadezhda H. Dimitrova , Antonia D. Kesova , Todor S. Pavlov , Terry W. Schultz , Ovanes G. Mekenyan

Establishing the reliability of simulated metabolism continues to be pivotal in accepting predictions of both fate and toxicological endpoints, especially when metabolic activation of a parent chemical is deemed crucial. A quintessential way of estimating the reliability of simulated metabolism is by comparing a simulated metabolic map with an appropriate documented metabolic map. The approach is constructed on two core parts - experimental and theoretical corroboration. Specifically, the three-layer algorithm is used to support experimentally the adequacy of the simulated maps. The first layer defines similarity boundaries between the parent chemical or metabolite starting the sequence, the root of the simulated series of biotransformations, and the corresponding initial structure of the analogue from the database with documented maps. Different criteria (e.g., the commonality between organic functional groups) are used for this rationale. The second layer delineates the metabolic transformation sequences applied to the target chemical or the initial metabolite of the transformation sequence. The last layer establishes the similarity between the final transformation product in the simulated and documented sequences. To support the adequacy of the simulated molecular transformations, a library of theoretical knowledge is used, providing mechanistic justification on applied transformations. The results of applications of the above procedure are shown using two examples.

建立模拟代谢的可靠性仍然是接受命运和毒理学终点预测的关键,特别是当母体化学物质的代谢激活被认为是至关重要的。估计模拟代谢可靠性的一种典型方法是将模拟代谢图与适当的记录代谢图进行比较。该方法是建立在两个核心部分-实验和理论确证。具体来说,三层算法用于实验支持模拟地图的充分性。第一层定义了序列起始的母体化学物质或代谢物、模拟生物转化系列的根以及数据库中具有文档地图的模拟物的相应初始结构之间的相似性边界。不同的标准(例如,有机官能团之间的共性)用于这个基本原理。第二层描述应用于目标化学品或转化序列的初始代谢物的代谢转化序列。最后一层建立模拟序列和文档序列中最终转换产品之间的相似性。为了支持模拟分子转化的充分性,使用了理论知识库,为应用转化提供了机制证明。用两个实例说明了上述方法的应用结果。
{"title":"Estimating the reliability of simulated metabolism using documented data and theoretical knowledge. QSAR application","authors":"Irina A. Dermen ,&nbsp;Hristiana I. Ivanova ,&nbsp;Elena K. Kaloyanova ,&nbsp;Nadezhda H. Dimitrova ,&nbsp;Antonia D. Kesova ,&nbsp;Todor S. Pavlov ,&nbsp;Terry W. Schultz ,&nbsp;Ovanes G. Mekenyan","doi":"10.1016/j.comtox.2022.100218","DOIUrl":"10.1016/j.comtox.2022.100218","url":null,"abstract":"<div><p>Establishing the reliability of simulated metabolism continues to be pivotal in accepting predictions of both fate and toxicological endpoints, especially when metabolic activation of a parent chemical is deemed crucial. A quintessential way of estimating the reliability of simulated metabolism is by comparing a simulated metabolic map with an appropriate documented metabolic map. The approach is constructed on two core parts - experimental and theoretical corroboration. Specifically, the three-layer algorithm is used to support experimentally the adequacy of the simulated maps. The first layer defines similarity boundaries between the parent chemical or metabolite starting the sequence, the root of the simulated series of biotransformations, and the corresponding initial structure of the analogue from the database with documented maps. Different criteria (e.g., the commonality between organic functional groups) are used for this rationale. The second layer delineates the metabolic transformation sequences applied to the target chemical or the initial metabolite of the transformation sequence. The last layer establishes the similarity between the final transformation product in the simulated and documented sequences. To support the adequacy of the simulated molecular transformations, a library of theoretical knowledge is used, providing mechanistic justification on applied transformations. The results of applications of the above procedure are shown using two examples.</p></div>","PeriodicalId":37651,"journal":{"name":"Computational Toxicology","volume":"22 ","pages":"Article 100218"},"PeriodicalIF":0.0,"publicationDate":"2022-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45295400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Development of an in silico consensus model for the prediction of the phospholipigenic potential of small molecules 一种预测小分子磷脂生成潜能的硅共识模型的发展
Q2 TOXICOLOGY Pub Date : 2022-05-01 DOI: 10.1016/j.comtox.2022.100226
Sebastian Schieferdecker, Andreas Eberlein, Esther Vock, Mario Beilmann

Phospholipidosis (PL) describes the accumulation of phospholipids in lysosomes of cells of various tissues after prolonged exposure with drug like compounds. These cellular findings can result in a delay of drug development, cause increased costs in affected projects and potentially may halt a drug development program. The early detection of compounds which potentially cause phospholipidosis therefore is desirable for risk mitigation. Here we describe an in silico consensus model for the detection of phospholipigenic potential of small molecules. The model was trained on in house in vitro data yielding an accuracy of 94%. By employing model agnostic explainability methods, we could show that the model learns reasonable molecular properties. The consensus model showed good performance on underrepresented PL-active compounds in clusters of similar molecules of the test dataset and on external in vitro and in vivo validation data of highly structural dissimilarity to the training data. Using the external in vitro data, an applicability domain of the model was deduced.

磷脂沉着症(PL)描述了长时间暴露于类药物化合物后,各种组织细胞溶酶体中磷脂的积累。这些细胞发现可能会导致药物开发的延迟,导致受影响项目的成本增加,并可能导致药物开发计划的中断。因此,早期发现可能导致磷脂病的化合物对于降低风险是可取的。在这里,我们描述了一个硅共识模型,用于检测小分子的磷脂生成潜力。该模型是在室内体外数据上训练的,准确度为94%。通过采用与模型无关的可解释性方法,我们可以证明模型学习了合理的分子性质。共识模型在测试数据集中相似分子簇中代表性不足的pl活性化合物以及与训练数据结构高度不同的外部体外和体内验证数据上表现良好。利用体外实验数据,推导出模型的适用范围。
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引用次数: 1
Physiologically based kinetic model for assessing intermittent chronic internal exposure to chemicals: Application for disinfection by-products in swimming pool water 基于生理学的评估间歇性慢性内部化学品暴露的动力学模型:游泳池水消毒副产物的应用
Q2 TOXICOLOGY Pub Date : 2022-05-01 DOI: 10.1016/j.comtox.2022.100227
Zijian Li , Jie Xiong , Yuan Guo

Chronic exposure to disinfection by-products (DBPs) via swimming in chlorinated pools can damage the genetic material and even cause cancers in humans. To assess the intermittent chronic internal exposure to DBPs in swimming pool water, a physiologically based kinetic (PBK) modeling framework was introduced to simulate daily average internal exposure doses of DBPs that can be linked to the corresponding daily average external doses. Biotransfer factor (BTF), i.e., the steady-state concentration ratio between human bodies and swimming pool water, was applied to measure the bioaccumulation potential of chemicals in organs and tissues. The results simulated for the four selected trihalomethanes (THMs) (i.e., chloroform, bromoform, dibromochloromethane, and bromodichloromethane) showed that lungs had the highest simulated BTF among human organs and tissues, with the inhalation route showing the maximum contribution to the overall external dose. In addition, route-specific analysis indicated that chronic internal exposure doses of THMs via oral and dermal routes were negligible compared to the inhalation route. Theoretical simulation using the dissipation coefficient of THMs in the air can help optimize the design and operation of swimming pools to substantially reduce chronic internal exposure doses of THMs. The simulated results for time-dependent chloroform concentration in human blood agreed with the reported data and can be further improved once more information about the THM concentrations in breathing zones of swimmers is obtained, indicating that the proposed model can be used as a practical tool to assess intermittent chronic internal exposure of THMs in swimming pool water. In future studies, human exposure to THMs via other pathways (e.g., drinking water, showering, and bathing) can be incorporated into the proposed model to comprehensively evaluate the internal exposure doses of THMs in humans.

通过在氯化池中游泳而长期暴露于消毒副产物(DBPs)会破坏遗传物质,甚至导致人类癌症。为了评估游泳池水中DBPs的间歇性慢性内暴露,引入了一个基于生理学的动力学(PBK)建模框架来模拟DBPs的每日平均内暴露剂量,该剂量可以与相应的每日平均外暴露剂量相关联。生物传递因子(Biotransfer factor, BTF),即人体与泳池水之间的稳态浓度比,用于测量化学物质在器官和组织中的生物蓄积势。对四种选定的三卤甲烷(即氯仿、溴仿、二溴氯甲烷和溴二氯甲烷)的模拟结果表明,肺在人体器官和组织中具有最高的模拟BTF,吸入途径对总外剂量的贡献最大。此外,特定途径的分析表明,与吸入途径相比,经口服和皮肤途径的THMs慢性内暴露剂量可以忽略不计。利用空气中THMs的耗散系数进行理论模拟,有助于优化游泳池的设计和运行,从而大幅降低THMs的慢性内暴露剂量。人体血液中随时间变化的氯仿浓度的模拟结果与报道的数据一致,一旦获得更多关于游泳者呼吸区THM浓度的信息,可以进一步改进,表明所提出的模型可以用作评估游泳池水中THM间歇性慢性内暴露的实用工具。在未来的研究中,可以将人体通过其他途径(如饮用水、淋浴和沐浴)暴露于THMs纳入所提出的模型中,以全面评估人体THMs的内暴露剂量。
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引用次数: 4
Differences between in vitro and in vivo genotoxicity due to metabolism: The role of kinetics 代谢引起的体外和体内遗传毒性的差异:动力学的作用
Q2 TOXICOLOGY Pub Date : 2022-05-01 DOI: 10.1016/j.comtox.2022.100222
P.I. Petkov , H. Ivanova , M. Honma , T. Yamada , T. Morita , A. Furuhama , S. Kotov , E. Kaloyanova , G. Dimitrova , O. Mekenyan

Traditional QSAR models predict mutagenicity solely based on structural alerts for the interaction of parent chemicals or their metabolites with target macromolecules. In the present work, it is demonstrated that the presence of an alert is necessary to identify damage but it is not always sufficient to assess mutagenic potential. This is addressed by accounting for the kinetics of simulating metabolism and formation of adducts with macromolecules. The mutagenic potential of chemicals is related to the degree to which selected macromolecules are altered. This extent is estimated by the amount of formed DNA/protein adducts. Here the effect of modelling kinetic factors is investigated for chemicals having documented in vitro negative and in vivo positive data in mutagenicity and clastogenicity tests of similar capacity - in vitro Ames vs in vivo TGR and in vitro CA vs in vivo MN tests. Two factors justify the conflict in mutagenicity data: the differences in enzyme expression in the in vitro vs in vivo metabolism and the difference in exposure time for in vitro and in vivo tests. Addressing these factors required simulating the formation of DNA/protein adducts and introducing empirically-defined thresholds for the amounts of the adducts leading to mutagenic potential.

传统的QSAR模型仅基于母体化学物质或其代谢物与目标大分子相互作用的结构警报来预测突变性。在目前的工作中,它证明了警报的存在是必要的,以确定损害,但它并不总是足以评估致突变的潜力。这是通过计算模拟代谢和形成加合物与大分子的动力学来解决。化学物质的致突变潜能与所选择的大分子被改变的程度有关。这个程度是通过形成的DNA/蛋白质加合物的数量来估计的。在这里,对在类似容量的致突变性和致裂性试验(体外Ames与体内TGR试验和体外CA与体内MN试验)中记录了体外阴性和体内阳性数据的化学物质,研究了建模动力学因素的影响。两个因素证明了致突变性数据的冲突:体外和体内代谢中酶表达的差异以及体外和体内试验暴露时间的差异。解决这些因素需要模拟DNA/蛋白质加合物的形成,并引入经验定义的导致突变潜力的加合物数量的阈值。
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引用次数: 2
Assessment of uncertainty and credibility of predictions by the OECD QSAR Toolbox automated read-across workflow for predicting acute oral toxicity 经合组织QSAR工具箱预测急性口服毒性的不确定性和可信度评估
Q2 TOXICOLOGY Pub Date : 2022-05-01 DOI: 10.1016/j.comtox.2022.100219
Terry W. Schultz , Atanas Chapkanov , Stela Kutsarova , Ovanes G. Mekenyan

The platform of OECD Toolbox version 4.5 was used for building an automated decision tree for filling data gaps for rat acute oral toxicity (AOT) by read-across (RA). Our previous publications have described the workflow of the AOT tree and conducted verification and validation studies on it. The overall uncertainty in the AOT workflow is low as the similarity in mechanistic probability, metabolism and 2D structure are maximized in the RA analogue selection process. The endpoint, rat oral LD50, is well-defined and has universal regulatory acceptance. Since OECD test guidelines are followed in generating the database, the data are widely recognized to be of the highest quality. The credibility of the workflow is high as it meets the critical factors of being based on confirmed assumptions, having demonstrated concordance and consistency, permitting the ability to explain AOT-related mechanisms and modes of action, and being simple in design. Additionally, the Z-score and probability distribution methods of assessing the uncertainty of a particular RA are discussed. Two examples of numerical and classification uncertainty are presented. These cases represent the extremes observed in a series of target chemical-based predictions that the authors observed when testing the workflow. The reliability and relevance associated with the workflow are high. However, the completeness and weights-of-evidence varied markedly among possible RA scenarios and particular target substances.

OECD工具箱4.5版平台用于构建一个自动化决策树,用于通过读取(RA)填补大鼠急性口服毒性(AOT)的数据空白。我们以前的出版物描述了AOT树的工作流程,并对其进行了验证和验证研究。由于在RA类似物选择过程中,机制概率、代谢和二维结构的相似性最大化,AOT工作流程中的整体不确定性较低。终点是大鼠口服LD50,定义明确,并得到普遍监管认可。由于在编制数据库时遵循经合发组织的测试准则,因此人们普遍认为这些数据具有最高质量。工作流的可信度很高,因为它满足以下关键因素:基于已确认的假设,已证明了一致性和一致性,允许解释aot相关机制和行为模式的能力,并且设计简单。此外,还讨论了评估特定RA不确定性的z分数和概率分布方法。给出了数值不确定性和分类不确定性的两个例子。这些案例代表了作者在测试工作流程时观察到的一系列基于目标化学物质的预测中观察到的极端情况。与工作流相关的可靠性和相关性很高。然而,证据的完整性和权重在可能的RA情景和特定目标物质之间存在显著差异。
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引用次数: 2
Non-linearity in cancer dose-response: The role of exposure duration 癌症剂量反应的非线性:暴露持续时间的作用
Q2 TOXICOLOGY Pub Date : 2022-05-01 DOI: 10.1016/j.comtox.2022.100217
Andrey A. Korchevskiy , Arseniy Korchevskiy

Context

An apparent deviation from nonlinearity in cancer dose-response was reported for various carcinogens. In particular, some studies hypothesized that in mesothelioma, the exposure-response relationship can be modelled as a power function with exponent from 0.6 to 1. However, various factors can affect the shape of the dose-response, producing the apparent supralinear trend.

Objective

To develop a mathematical model that would demonstrate a relationship of mesothelioma lifetime risk and exposure duration, with various assumptions about a hazard rate function.

Methods

Two different hazard rate functions – the Peto model and the two-stage clonal expansion (TSCE) model – were considered. The analytical formulas for lifetime risk were developed, with and without a lifetable correction. Standard calculus methods were applied to test the shape of the lifetime risk curve.

Results

For both Peto and TSCE models, it was shown that mesothelioma lifetime risk changes supralinearly with duration; the exponent of the power function was ranging from 0.68 to 0.89. However, the dose-response curve by cumulative exposure is close to linearity and is linear if the exposure duration would be constant. The model has been tested for chrysotile asbestos cohorts, with a good agreement demonstrated with published mesothelioma excess mortality (R=0.88, p<0.0041).

Conclusion

For mesothelioma, the observed deviation from linearity in the dose-response relationship can be potentially explained by the impact of a change in the duration of exposure. In a meta-analysis, this deviation can be eliminated by standardizing the mortality data for various cohorts by duration of exposure.

Short Abstract

An apparent deviation from nonlinearity in cancer dose-response was reported for various carcinogens. We applied two different hazard rate equations – the Peto model and the two-stage clonal expansion (TSCE) model – to pleural mesothelioma mortality. The analytical formulas for lifetime risk were developed. For both the Peto and TSCE models, it was shown that mesothelioma lifetime risk changes supralinearly with duration. However, the dose-response curve for cumulative exposure is close to linearity.

据报道,各种致癌物的剂量反应明显偏离非线性。特别是,一些研究假设在间皮瘤中,暴露-反应关系可以建模为指数从0.6到1的幂函数。然而,各种因素可以影响剂量反应的形状,产生明显的超线性趋势。目的建立间皮瘤终生风险与暴露时间关系的数学模型,并对危险率函数进行各种假设。方法采用Peto模型和两期克隆扩增(TSCE)模型进行风险率分析。开发了终生风险的分析公式,有或没有生命表校正。采用标准演算方法检验终身风险曲线的形状。结果Peto模型和TSCE模型均显示间皮瘤终生风险随病程呈超线性变化;幂函数的指数范围为0.68 ~ 0.89。然而,累积暴露的剂量-反应曲线接近线性,如果暴露时间一定,则是线性的。该模型已在温石棉队列中进行了测试,与已公布的间皮瘤超额死亡率(R=0.88, p<0.0041)有很好的一致性。结论对于间皮瘤,观察到的剂量-反应关系的线性偏差可以用暴露时间变化的影响来解释。在荟萃分析中,可以通过按暴露时间对不同队列的死亡率数据进行标准化来消除这种偏差。摘要据报道,各种致癌物的剂量反应明显偏离非线性。我们应用了两种不同的风险率方程——Peto模型和两期克隆扩张(TSCE)模型——来计算胸膜间皮瘤的死亡率。建立了终身风险的分析公式。Peto和TSCE模型均显示间皮瘤终生风险随病程呈超线性变化。然而,累积暴露的剂量-反应曲线接近线性。
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引用次数: 2
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Computational Toxicology
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