Pub Date : 2024-03-16DOI: 10.1016/j.comtox.2024.100305
Christopher Barber, Crina Heghes, Laura Johnston
Advances in the development and application of in silico models in toxicology has been recognised by two OECD guidance documents (69: Guidance Document On The Validation Of (Quantitative) Structure-Activity Relationship [(Q)SAR] Models and 386: (Q)SAR Assessment Framework: Guidance for the regulatory assessment of (Q)SAR models, predictions, and results based on multiple predictions) published in 2007 and 2023 respectively. The former outlines criteria for appropriate model validation, whilst the latter provides guidance around assessing predictions derived from them. The concepts and criteria described within these guidelines have been used to establish a framework to support both model builders and those applying them to support regulatory decisions. Herein we demonstrate how to meet those criteria and propose where further guidance is essential for ensuring the consistent, confident, and safe application of in silico models in support of regulatory decisions.
{"title":"A framework to support the application of the OECD guidance documents on (Q)SAR model validation and prediction assessment for regulatory decisions","authors":"Christopher Barber, Crina Heghes, Laura Johnston","doi":"10.1016/j.comtox.2024.100305","DOIUrl":"https://doi.org/10.1016/j.comtox.2024.100305","url":null,"abstract":"<div><p>Advances in the development and application of in silico models in toxicology has been recognised by two OECD guidance documents (69: Guidance Document On The Validation Of (Quantitative) Structure-Activity Relationship [(Q)SAR] Models and 386: (Q)SAR Assessment Framework: Guidance for the regulatory assessment of (Q)SAR models, predictions, and results based on multiple predictions) published in 2007 and 2023 respectively. The former outlines criteria for appropriate model validation, whilst the latter provides guidance around assessing predictions derived from them. The concepts and criteria described within these guidelines have been used to establish a framework to support both model builders and those applying them to support regulatory decisions. Herein we demonstrate how to meet those criteria and propose where further guidance is essential for ensuring the consistent, confident, and safe application of in silico models in support of regulatory decisions.</p></div>","PeriodicalId":37651,"journal":{"name":"Computational Toxicology","volume":"30 ","pages":"Article 100305"},"PeriodicalIF":0.0,"publicationDate":"2024-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140190686","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}
Pub Date : 2024-03-15DOI: 10.1016/j.comtox.2024.100306
Alejandro Gómez, Andrés Alarcón, Wilson Acosta, Andrés Malagón
Glyphosate is a widely used herbicide known for its effectiveness in weed control; and it is an inhibitor of the plant enzyme 5-enolpyruvylshikimate-3-phosphate synthase. Currently, it is one of the most extensively used non-specific herbicides in agroindustry. However, toxic effects of glyphosate have recently been reported, including endocrine disruption, metabolic alterations, teratogenic, tumorigenic, and hepatorenal effects. Additionally, there are environmental concerns related to possible interactions with proteins from microorganisms, aquatic organisms, and mammals.
Research on the description of these interactions has gained interest, primarily with the aim of generating recommendations in terms of its use and possible regulations. On the other hand, computational methods have emerged to identify potential targets or unintended targets among numerous possible receptors. Several programs, online services, and databases are available for use in these methods.
In this study, we employed a set of online tools for computational target fishing to identify receptors of glyphosate. A set of thirteen targets were selected using six fishing tools. Furthermore, docking procedures were performed to investigate the expected interactions and binding energies. Certain associations with diseases are also reported.
{"title":"Identification of potential human targets of glyphosate using in silico target fishing","authors":"Alejandro Gómez, Andrés Alarcón, Wilson Acosta, Andrés Malagón","doi":"10.1016/j.comtox.2024.100306","DOIUrl":"https://doi.org/10.1016/j.comtox.2024.100306","url":null,"abstract":"<div><p>Glyphosate is a widely used herbicide known for its effectiveness in weed control; and it is an inhibitor of the plant enzyme 5-enolpyruvylshikimate-3-phosphate synthase. Currently, it is one of the most extensively used non-specific herbicides in agroindustry. However, toxic effects of glyphosate have recently been reported, including endocrine disruption, metabolic alterations, teratogenic, tumorigenic, and hepatorenal effects. Additionally, there are environmental concerns related to possible interactions with proteins from microorganisms, aquatic organisms, and mammals.</p><p>Research on the description of these interactions has gained interest, primarily with the aim of generating recommendations in terms of its use and possible regulations. On the other hand, computational methods have emerged to identify potential targets or unintended targets among numerous possible receptors. Several programs, online services, and databases are available for use in these methods.</p><p>In this study, we employed a set of online tools for computational target fishing to identify receptors of glyphosate. A set of thirteen targets were selected using six fishing tools. Furthermore, docking procedures were performed to investigate the expected interactions and binding energies. Certain associations with diseases are also reported.</p></div>","PeriodicalId":37651,"journal":{"name":"Computational Toxicology","volume":"30 ","pages":"Article 100306"},"PeriodicalIF":0.0,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140145179","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}
Pub Date : 2024-02-28DOI: 10.1016/j.comtox.2024.100304
G. Patlewicz , P. Karamertzanis , K. Paul Friedman , M. Sannicola , I. Shah
Read-across is a well-established data-gap filling technique used within analogue or category approaches. Acceptance remains an issue, mainly due to the difficulties of addressing residual uncertainties associated with a read-across prediction and because assessments are expert-driven. Frameworks to develop, assess and document read-across may help reduce variability in read-across results. Data-driven read-across approaches such as Generalised Read-Across (GenRA) include quantification of uncertainties and performance. GenRA also offers opportunities on how New Approach Method (NAM) data can be systematically incorporated to support the read-across hypothesis. Herein, a systematic investigation of differences in expert-driven read-across with data-driven approaches was pursued in terms of building scientific confidence in the use of read-across. A dataset of expert-driven read-across assessments that made use of registration data as disseminated in the public International Uniform Chemical Information Database (IUCLID) (version 6) of Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) Study Results were compiled. A dataset of ∼5000 read-across cases pertaining to repeated dose and developmental toxicity was extracted and mapped to content within EPA’s Distributed Structure Searchable Toxicity database (DSSTox) to retrieve chemical name and structural identification information. Content could be mapped to ∼3600 cases which when filtered for unique cases with curated quantitative structure–activity relationship-ready SMILES resulted in 389 target-source analogue pairs. The similarity between target and the source analogues on the basis of different contexts – from structural similarity using chemical fingerprints to metabolic similarity using predicted metabolic information was evaluated. An attempt was also made to quantify the relative contribution each similarity context played relative to the target-source analogue pairs by deriving a model which predicted known analogue pairs. Finally, point of departure values (PODs) were predicted using the GenRA approach underpinned by data extracted from the EPA’s Toxicity Values Database (ToxValDB). The GenRA predicted PODs were compared with those reported within the REACH dossiers themselves. This study offers generalisable insights on how read-across is already applied for regulatory submissions and expectations on the levels of similarity necessary to make decisions.
{"title":"A systematic analysis of read-across within REACH registration dossiers","authors":"G. Patlewicz , P. Karamertzanis , K. Paul Friedman , M. Sannicola , I. Shah","doi":"10.1016/j.comtox.2024.100304","DOIUrl":"https://doi.org/10.1016/j.comtox.2024.100304","url":null,"abstract":"<div><p>Read-across is a well-established data-gap filling technique used within analogue or category approaches. Acceptance remains an issue, mainly due to the difficulties of addressing residual uncertainties associated with a read-across prediction and because assessments are expert-driven. Frameworks to develop, assess and document read-across may help reduce variability in read-across results. Data-driven read-across approaches such as Generalised Read-Across (GenRA) include quantification of uncertainties and performance. GenRA also offers opportunities on how New Approach Method (NAM) data can be systematically incorporated to support the read-across hypothesis. Herein, a systematic investigation of differences in expert-driven read-across with data-driven approaches was pursued in terms of building scientific confidence in the use of read-across. A dataset of expert-driven read-across assessments that made use of registration data as disseminated in the public International Uniform Chemical Information Database (IUCLID) (version 6) of Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) Study Results were compiled. A dataset of ∼5000 read-across cases pertaining to repeated dose and developmental toxicity was extracted and mapped to content within EPA’s Distributed Structure Searchable Toxicity database (DSSTox) to retrieve chemical name and structural identification information. Content could be mapped to ∼3600 cases which when filtered for unique cases with curated quantitative structure–activity relationship-ready SMILES resulted in 389 target-source analogue pairs. The similarity between target and the source analogues on the basis of different contexts – from structural similarity using chemical fingerprints to metabolic similarity using predicted metabolic information was evaluated. An attempt was also made to quantify the relative contribution each similarity context played relative to the target-source analogue pairs by deriving a model which predicted known analogue pairs. Finally, point of departure values (PODs) were predicted using the GenRA approach underpinned by data extracted from the EPA’s Toxicity Values Database (ToxValDB). The GenRA predicted PODs were compared with those reported within the REACH dossiers themselves. This study offers generalisable insights on how read-across is already applied for regulatory submissions and expectations on the levels of similarity necessary to make decisions.</p></div>","PeriodicalId":37651,"journal":{"name":"Computational Toxicology","volume":"30 ","pages":"Article 100304"},"PeriodicalIF":0.0,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140063323","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}
Pub Date : 2024-02-13DOI: 10.1016/j.comtox.2024.100302
Shweta Singh Chauhan , E. Azra Thaseen , Ramakrishnan Parthasarathi
Bacterial infections caused by resistant strains, especially those conferring multi-drug resistance (MDR), have become a severe health problem worldwide. Novobiocin (NB) is a widely used antibiotic that inhibits the action of DNA gyrase in Escherichia coli (E. coli). The drug's efficiency is hindered by its strong binding with the resistance causing efflux pump AcrAB-TolC on recurrent exposure. Consequently, the discovery of alternate/substitute analogue compounds for the parent drug with higher selectivity could counter drug resistance. In this work, we identified potent analogues of drug NB against the gyrase B enzyme by performing high throughput virtual screening of forty analogues that includes drug-likeness properties, pharmacokinetic parameters analysis, molecular docking, and molecular dynamics (MD) simulations. Our comprehensive pharmacological profiling with intrinsic analysis of selectivity and safety resulted in the identification of four potential compounds, C4 (ZINC218812366), C6 (ZINC221968665), C8 (ZINC49783724) and C10 (ZINC49783727), have better inhibitory and binding capacity against the primary target gyrase B subunit and reduced interaction with the counterpart of resistant target AcrB. These findings provide proof of concept for developing lead compounds targeting gyrase B and help in combatting AcrB-mediated drug resistance.
耐药菌株,尤其是具有多重耐药性(MDR)的耐药菌株引起的细菌感染已成为全球严重的健康问题。新生物素(NB)是一种广泛使用的抗生素,可抑制大肠杆菌(E. coli)中 DNA 回旋酶的作用。该药物在反复接触时会与导致耐药性的外排泵 AcrAB-TolC 发生强结合,从而影响其疗效。因此,发现具有更高选择性的母药替代/替代类似化合物可以对抗耐药性。在这项工作中,我们通过对 40 种类似物进行高通量虚拟筛选,包括药物相似性、药动学参数分析、分子对接和分子动力学(MD)模拟,确定了 NB 药物对回旋酶 B 的强效类似物。我们通过对选择性和安全性的内在分析进行了全面的药理学分析,最终确定了 C4(ZINC218812366)、C6(ZINC221968665)、C8(ZINC49783724)和 C10(ZINC49783727)这四种潜在化合物,它们对主要靶标回旋酶 B 亚基具有更好的抑制和结合能力,并减少了与抗性靶标 AcrB 的相互作用。这些发现为开发靶向回旋酶 B 的先导化合物提供了概念证明,有助于对抗 AcrB 介导的耐药性。
{"title":"Computational discovery of potent Escherichia coli DNA gyrase inhibitor: Selective and safer novobiocin analogues","authors":"Shweta Singh Chauhan , E. Azra Thaseen , Ramakrishnan Parthasarathi","doi":"10.1016/j.comtox.2024.100302","DOIUrl":"10.1016/j.comtox.2024.100302","url":null,"abstract":"<div><p>Bacterial infections caused by resistant strains, especially those conferring multi-drug resistance (MDR), have become a severe health problem worldwide. Novobiocin (NB) is a widely used antibiotic that inhibits the action of DNA gyrase in <em>Escherichia coli (E. coli).</em> The drug's efficiency is hindered by its strong binding with the resistance causing efflux pump AcrAB-TolC on recurrent exposure. Consequently, the discovery of alternate/substitute analogue compounds for the parent drug with higher selectivity could counter drug resistance. In this work, we identified potent analogues of drug NB against the gyrase B enzyme by performing high throughput virtual screening of forty analogues that includes drug-likeness properties, pharmacokinetic parameters analysis, molecular docking, and molecular dynamics (MD) simulations. Our comprehensive pharmacological profiling with intrinsic analysis of selectivity and safety resulted in the identification of four potential compounds, C4 (ZINC218812366), C6 (ZINC221968665), C8 (ZINC49783724) and C10 (ZINC49783727), have better inhibitory and binding capacity against the primary target gyrase B subunit and reduced interaction with the counterpart of resistant target AcrB. These findings provide proof of concept for developing lead compounds targeting gyrase B and help in combatting AcrB-mediated drug resistance.</p></div>","PeriodicalId":37651,"journal":{"name":"Computational Toxicology","volume":"29 ","pages":"Article 100302"},"PeriodicalIF":0.0,"publicationDate":"2024-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139892597","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}
Pub Date : 2024-02-09DOI: 10.1016/j.comtox.2024.100301
Tia Tate, Grace Patlewicz, Imran Shah
Animal toxicity testing is time and resource intensive, making it difficult to keep pace with the number of substances requiring assessment. Machine learning (ML) models that use chemical structure information and high-throughput experimental data can be helpful in predicting potential toxicity. However, much of the toxicity data used to train ML models is biased with an unequal balance of positives and negatives primarily since substances selected for in vivo testing are expected to elicit some toxicity effect. To investigate the impact this bias had on predictive performance, various sampling approaches were used to balance in vivo toxicity data as part of a supervised ML workflow to predict hepatotoxicity outcomes from chemical structure and/or targeted transcriptomic data. From the chronic, subchronic, developmental, multigenerational reproductive, and subacute repeat-dose testing toxicity outcomes with a minimum of 50 positive and 50 negative substances, 18 different study-toxicity outcome combinations were evaluated in up to 7 ML models. These included Artificial Neural Networks, Random Forests, Bernouilli Naïve Bayes, Gradient Boosting, and Support Vector classification algorithms which were compared with a local approach, Generalised Read-Across (GenRA), a similarity-weighted k-Nearest Neighbour (k-NN) method. The mean CV F1 performance for unbalanced data across all classifiers and descriptors for chronic liver effects was 0.735 (0.0395 SD). Mean CV F1 performance dropped to 0.639 (0.073 SD) with over-sampling approaches though the poorer performance of KNN approaches in some cases contributed to the observed decrease (mean CV F1 performance excluding KNN was 0.697 (0.072 SD)). With under-sampling approaches, the mean CV F1 was 0.523 (0.083 SD). For developmental liver effects, the mean CV F1 performance was much lower with 0.089 (0.111 SD) for unbalanced approaches and 0.149 (0.084 SD) for under-sampling. Over-sampling approaches led to an increase in mean CV F1 performance (0.234, (0.107 SD)) for developmental liver toxicity. Model performance was found to be dependent on dataset, model type, balancing approach and feature selection. Accordingly tailoring ML workflows for predicting toxicity should consider class imbalance and rely on simple classifiers first.
动物毒性测试需要大量时间和资源,因此很难跟上需要评估的物质数量。使用化学结构信息和高通量实验数据的机器学习(ML)模型有助于预测潜在毒性。然而,用于训练 ML 模型的大部分毒性数据都存在偏差,阳性和阴性数据不平衡,这主要是因为被选中进行体内测试的物质预计会引起一些毒性效应。为了研究这种偏差对预测性能的影响,我们采用了各种取样方法来平衡体内毒性数据,作为监督式 ML 工作流程的一部分,以便从化学结构和/或靶向转录组数据中预测肝毒性结果。从至少 50 种阳性物质和 50 种阴性物质的慢性、亚慢性、发育、多代生殖和亚急性重复剂量测试毒性结果中,在多达 7 个 ML 模型中评估了 18 种不同的研究-毒性结果组合。这些模型包括人工神经网络、随机森林、Bernouilli Naïve Bayes、梯度提升和支持向量分类算法,并与一种本地方法--广义读数交叉(GenRA)--相似性加权 k-近邻(k-NN)方法进行了比较。在所有分类器和描述符的非平衡数据中,慢性肝脏效应的平均 CV F1 性能为 0.735(0.0395 SD)。过度取样方法的平均 CV F1 性能降至 0.639(0.073 标差),尽管在某些情况下 KNN 方法的性能较差也导致了观察到的性能下降(不包括 KNN 的平均 CV F1 性能为 0.697(0.072 标差))。采用取样不足法时,平均 CV F1 为 0.523(0.083 标差)。在发育肝效应方面,不平衡方法的平均 CV F1 性能更低,为 0.089(0.111 标差),而采样不足方法的平均 CV F1 性能为 0.149(0.084 标差)。过度取样方法导致发育期肝脏毒性的平均 CV F1 性能提高(0.234,(0.107 标差))。研究发现,模型性能取决于数据集、模型类型、平衡方法和特征选择。因此,在定制预测毒性的 ML 工作流程时应考虑类的不平衡性,并首先依赖简单的分类器。
{"title":"A comparison of machine learning approaches for predicting hepatotoxicity potential using chemical structure and targeted transcriptomic data","authors":"Tia Tate, Grace Patlewicz, Imran Shah","doi":"10.1016/j.comtox.2024.100301","DOIUrl":"https://doi.org/10.1016/j.comtox.2024.100301","url":null,"abstract":"<div><p>Animal toxicity testing is time and resource intensive, making it difficult to keep pace with the number of substances requiring assessment. Machine learning (ML) models that use chemical structure information and high-throughput experimental data can be helpful in predicting potential toxicity. However, much of the toxicity data used to train ML models is biased with an unequal balance of positives and negatives primarily since substances selected for <em>in vivo</em> testing are expected to elicit some toxicity effect. To investigate the impact this bias had on predictive performance, various sampling approaches were used to balance <em>in vivo</em> toxicity data as part of a supervised ML workflow to predict hepatotoxicity outcomes from chemical structure and/or targeted transcriptomic data. From the chronic, subchronic, developmental, multigenerational reproductive, and subacute repeat-dose testing toxicity outcomes with a minimum of 50 positive and 50 negative substances, 18 different study-toxicity outcome combinations were evaluated in up to 7 ML models. These included Artificial Neural Networks, Random Forests, Bernouilli Naïve Bayes, Gradient Boosting, and Support Vector classification algorithms which were compared with a local approach, Generalised Read-Across (GenRA), a similarity-weighted k-Nearest Neighbour (k-NN) method. The mean CV F1 performance for unbalanced data across all classifiers and descriptors for chronic liver effects was 0.735 (0.0395 SD). Mean CV F1 performance dropped to 0.639 (0.073 SD) with over-sampling approaches though the poorer performance of KNN approaches in some cases contributed to the observed decrease (mean CV F1 performance excluding KNN was 0.697 (0.072 SD)). With under-sampling approaches, the mean CV F1 was 0.523 (0.083 SD). For developmental liver effects, the mean CV F1 performance was much lower with 0.089 (0.111 SD) for unbalanced approaches and 0.149 (0.084 SD) for under-sampling. Over-sampling approaches led to an increase in mean CV F1 performance (0.234, (0.107 SD)) for developmental liver toxicity. Model performance was found to be dependent on dataset, model type, balancing approach and feature selection. Accordingly tailoring ML workflows for predicting toxicity should consider class imbalance and rely on simple classifiers first.</p></div>","PeriodicalId":37651,"journal":{"name":"Computational Toxicology","volume":"29 ","pages":"Article 100301"},"PeriodicalIF":0.0,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139743839","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}
Pub Date : 2024-01-29DOI: 10.1016/j.comtox.2024.100300
Steven Kane, Dan Newman, David J. Ponting, Edward Rosser, Robert Thomas, Jonathan D. Vessey, Samuel J. Webb, William H.J. Wood
To reach conclusions during chemical safety assessments, risk assessors need to ensure sufficient information is present to satisfy the decision criteria. This often requires data to be generated and, in some cases, insufficient knowledge is present, or it is not feasible to generate new data through experiments. Read-across is a powerful technique to fill such data gaps, however the expert-driven process can be time intensive and subjective in nature resulting in variation of approach. To overcome these barriers a prototype software application has been developed by Lhasa Limited to support decision making about the toxicity and potency of chemicals using a read-across approach. The application supports a workflow which allows the user to gather data and knowledge about a chemical of interest and possible read-across candidates. Relevant information is then presented that enables the user to decide if read-across can be performed and, if so, which analogue or category can be considered the most appropriate. Data and knowledge about the toxicity of a compound and potential analogues include assay and metabolism data, toxicophore identification and its local similarity, physico-chemical and pharmacokinetic properties and observed and predicted metabolic profile. The utility of the approach is demonstrated with case studies using N-nitrosamine compounds, where the conclusions from using the workflow supported by the software are concordant with the evidence base. The components of the workflow have been further validated by demonstrating that conclusions are significantly better than would be expect from the distribution of data in test sets. The approach taken demonstrates how software implementing intuitive workflows that guide experts during read-across can support decisions and how validation of the methods can increase confidence in the overall approach.
{"title":"Developing and validating read-across workflows that enable decision making for toxicity and potency: Case studies with N-nitrosamines","authors":"Steven Kane, Dan Newman, David J. Ponting, Edward Rosser, Robert Thomas, Jonathan D. Vessey, Samuel J. Webb, William H.J. Wood","doi":"10.1016/j.comtox.2024.100300","DOIUrl":"https://doi.org/10.1016/j.comtox.2024.100300","url":null,"abstract":"<div><p>To reach conclusions during chemical safety assessments, risk assessors need to ensure sufficient information is present to satisfy the decision criteria. This often requires data to be generated and, in some cases, insufficient knowledge is present, or it is not feasible to generate new data through experiments. Read-across is a powerful technique to fill such data gaps, however the expert-driven process can be time intensive and subjective in nature resulting in variation of approach. To overcome these barriers a prototype software application has been developed by Lhasa Limited to support decision making about the toxicity and potency of chemicals using a read-across approach. The application supports a workflow which allows the user to gather data and knowledge about a chemical of interest and possible read-across candidates. Relevant information is then presented that enables the user to decide if read-across can be performed and, if so, which analogue or category can be considered the most appropriate. Data and knowledge about the toxicity of a compound and potential analogues include assay and metabolism data, toxicophore identification and its local similarity, physico-chemical and pharmacokinetic properties and observed and predicted metabolic profile. The utility of the approach is demonstrated with case studies using <em>N</em>-nitrosamine compounds, where the conclusions from using the workflow supported by the software are concordant with the evidence base. The components of the workflow have been further validated by demonstrating that conclusions are significantly better than would be expect from the distribution of data in test sets. The approach taken demonstrates how software implementing intuitive workflows that guide experts during read-across can support decisions and how validation of the methods can increase confidence in the overall approach.</p></div>","PeriodicalId":37651,"journal":{"name":"Computational Toxicology","volume":"29 ","pages":"Article 100300"},"PeriodicalIF":0.0,"publicationDate":"2024-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139731861","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}
Pub Date : 2024-01-23DOI: 10.1016/j.comtox.2024.100299
L.M. Bilinsky
This paper presents an ordinary differential equation (ODE) model of endogenous H2O2 metabolism in hepatocytes that is unique, at the time of writing, in its ability to accurately compute intracellular H2O2 concentration during incidents of oxidative stress and in its usefulness for constructing PBPK/PD models for ROS-generating xenobiotics. Versions of the model are presented for rat hepatocytes in vitro and mouse liver in vivo. A generic method is given for using the model to create PBPK/PD models which predict intracellular H2O2 concentration and oxidative-stress-induced hepatocyte death; these are identifiable from in vitro data sets reporting cell mortality following xenobiotic exposure at various levels. The procedure is demonstrated for the trivalent arsenical dimethylarsinous acid (DMAIII), which is produced in liver as part of the arsenic elimination pathway. This is the first model of H2O2 metabolism in hepatocytes to feature values for the endogenous rates of H2O2 production by mitochondria and other organelles which are inferred from the physiology literature, and to feature a detailed, realistic treatment of GSH metabolism; the latter is achieved by incorporating a minimal version of Reed and coworkers’ pioneering model of GSH metabolism in liver. Model simulations indicate that critical GSH depletion is the immediate trigger for intracellular H2O2 rising to concentrations associated with apoptosis (), that this may only occur hours after the xenobiotic concentration peaks (“delay effect”), that when critical GSH depletion does occur, H2O2 concentration rises rapidly in a sequence of two boundary layers, characterized by the kinetics of glutathione peroxidase (first boundary layer) and catalase (second boundary layer), and that intracellular H2O2 concentration implies critical GSH depletion. There has been speculation that ROS levels in the range associated with apoptosis simply indicate, rather than cause, an apoptotic milieu. Model simulations are consistent with this view. In a result of interest to the wider physiology community, the delay effect is shown to provide a GSH-based mechanism by which cells can distinguish transient elevations in H2O2 concentration, of use in intracellular signaling, from persistent ones indicative of either pathology or the presence of toxins, the second state of affairs eventually triggering apoptosis.
{"title":"A computational model of endogenous hydrogen peroxide metabolism in hepatocytes, featuring a critical role for GSH","authors":"L.M. Bilinsky","doi":"10.1016/j.comtox.2024.100299","DOIUrl":"10.1016/j.comtox.2024.100299","url":null,"abstract":"<div><p>This paper presents an ordinary differential equation (ODE) model of endogenous H<sub>2</sub>O<sub>2</sub> <!-->metabolism in hepatocytes that is unique, at the time of writing, in its ability to accurately compute intracellular H<sub>2</sub>O<sub>2</sub> <!-->concentration during incidents of oxidative stress and in its usefulness for constructing PBPK/PD models for ROS-generating xenobiotics. Versions of the model are presented for rat hepatocytes <em>in vitro</em> and mouse liver <em>in vivo</em>. A generic method is given for using the model to create PBPK/PD models which predict intracellular H<sub>2</sub>O<sub>2</sub> <!-->concentration and oxidative-stress-induced hepatocyte death; these are identifiable from <em>in vitro</em> data sets reporting cell mortality following xenobiotic exposure at various levels. The procedure is demonstrated for the trivalent arsenical dimethylarsinous acid (DMA<sup><em>III</em></sup>), which is produced in liver as part of the arsenic elimination pathway. This is the first model of H<sub>2</sub>O<sub>2</sub> <!-->metabolism in hepatocytes to feature values for the endogenous rates of H<sub>2</sub>O<sub>2</sub> <!-->production by mitochondria and other organelles which are inferred from the physiology literature, and to feature a detailed, realistic treatment of GSH metabolism; the latter is achieved by incorporating a minimal version of Reed and coworkers’ pioneering model of GSH metabolism in liver. Model simulations indicate that critical GSH depletion is the immediate trigger for intracellular H<sub>2</sub>O<sub>2</sub> <!-->rising to concentrations associated with apoptosis (<span><math><mrow><mo>></mo><mn>1</mn><mi>μ</mi><mi>M</mi></mrow></math></span>), that this may only occur hours after the xenobiotic concentration peaks (“delay effect”), that when critical GSH depletion does occur, H<sub>2</sub>O<sub>2</sub> <!-->concentration rises rapidly in a sequence of two boundary layers, characterized by the kinetics of glutathione peroxidase (first boundary layer) and catalase (second boundary layer), and that intracellular H<sub>2</sub>O<sub>2</sub> <!-->concentration <span><math><mrow><mo>></mo><mn>1</mn><mi>μ</mi><mi>M</mi></mrow></math></span> implies critical GSH depletion. There has been speculation that ROS levels in the range associated with apoptosis simply indicate, rather than cause, an apoptotic milieu. Model simulations are consistent with this view. In a result of interest to the wider physiology community, the delay effect is shown to provide a GSH-based mechanism by which cells can distinguish transient elevations in H<sub>2</sub>O<sub>2</sub> <!-->concentration, of use in intracellular signaling, from persistent ones indicative of either pathology or the presence of toxins, the second state of affairs eventually triggering apoptosis.</p></div>","PeriodicalId":37651,"journal":{"name":"Computational Toxicology","volume":"29 ","pages":"Article 100299"},"PeriodicalIF":0.0,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139640107","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}
Pub Date : 2023-12-29DOI: 10.1016/j.comtox.2023.100298
Suman Chakravarti, Roustem D. Saiakhov, Mounika Girireddy
We present a method for computing confidence in the Carcinogenic Potency Categorization Approach (CPCA) based predictions for N-nitrosamines. Our method relies on capturing local structural variations surrounding the nitrosamine core, which can significantly influence potency and may introduce uncertainty into predictions relying on these features.
We use continuous-valued fingerprints to conduct a specialized neighborhood analysis, grouping nitrosamines with similar local features. Using a reference dataset of 7679 potential Nitrosamine Drug Substance Related Impurities (NDSRIs) with pre-computed CPCA-derived Acceptable Intake (AI) limits, we gauge the prediction confidence for a given query N-nitrosamine by evaluating the distances and CPCA derived potency category distribution among neighboring NDSRIs. Our methodology allows for a nuanced assessment of CPCA's discrete four-level outcomes (i.e. 18/26.5, 100, 400, and 1500 ng AI limits). It enables the differentiation of robust predictions from potentially uncertain ones, for instance, cases where low confidence arises from rare structural features in the query nitrosamine, helpful in regulatory decision-making.
In our analysis of 30 nitrosamines with animal carcinogenicity data, we often observed lower confidence scores when experimental TD50 values significantly disagreed with CPCA-calculated potency. Moreover, lower confidence scores were associated with greater variability in the predicted α-carbon hydroxylation potential of neighboring compounds. In a list of 265 NDSRIs with established regulatory AI limits, approximately 68% received strong confidence scores for accurate CPCA potency class predictions. However, 8% received poor confidence in potency class predictions, as well as lacked sufficient neighbor support due to uncommon structural features.
{"title":"Confidence score calculation for the carcinogenic potency categorization approach (CPCA) predictions for N-nitrosamines","authors":"Suman Chakravarti, Roustem D. Saiakhov, Mounika Girireddy","doi":"10.1016/j.comtox.2023.100298","DOIUrl":"https://doi.org/10.1016/j.comtox.2023.100298","url":null,"abstract":"<div><p>We present a method for computing confidence in the Carcinogenic Potency Categorization Approach (CPCA) based predictions for N-nitrosamines. Our method relies on capturing local structural variations surrounding the nitrosamine core, which can significantly influence potency and may introduce uncertainty into predictions relying on these features.</p><p>We use continuous-valued fingerprints to conduct a specialized neighborhood analysis, grouping nitrosamines with similar local features. Using a reference dataset of 7679 potential Nitrosamine Drug Substance Related Impurities (NDSRIs) with pre-computed CPCA-derived Acceptable Intake (AI) limits, we gauge the prediction confidence for a given query N-nitrosamine by evaluating the distances and CPCA derived potency category distribution among neighboring NDSRIs. Our methodology allows for a nuanced assessment of CPCA's discrete four-level outcomes (i.e. 18/26.5, 100, 400, and 1500 ng AI limits). It enables the differentiation of robust predictions from potentially uncertain ones, for instance, cases where low confidence arises from rare structural features in the query nitrosamine, helpful in regulatory decision-making.</p><p>In our analysis of 30 nitrosamines with animal carcinogenicity data, we often observed lower confidence scores when experimental TD<sub>50</sub> values significantly disagreed with CPCA-calculated potency. Moreover, lower confidence scores were associated with greater variability in the predicted α-carbon hydroxylation potential of neighboring compounds. In a list of 265 NDSRIs with established regulatory AI limits, approximately 68% received strong confidence scores for accurate CPCA potency class predictions. However, 8% received poor confidence in potency class predictions, as well as lacked sufficient neighbor support due to uncommon structural features.</p></div>","PeriodicalId":37651,"journal":{"name":"Computational Toxicology","volume":"29 ","pages":"Article 100298"},"PeriodicalIF":0.0,"publicationDate":"2023-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139100547","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}
Pub Date : 2023-12-23DOI: 10.1016/j.comtox.2023.100297
Ramez Labib, Ripal Amin, Chris Bartlett, Lisa Hoffman
Cannabidiol (CBD) is increasingly being used as an ingredient in cosmetics, but to date no pre-clinical studies have been published to address the skin sensitization end point. This case study investigated its skin sensitization potential for use in a face cream application at 0.3 % using Next Generation Risk Assessment (NGRA) framework. Based on chemical structure and in-silico prediction using Derek Nexus, CBD was predicted to be weak sensitizer with a resorcinol alert moiety. In vitro testing was conducted confirming it to be sensitizer, but the New Approach Methodologies (NAM) data could not provide sufficient confidence to determine a point of departure (PoD). Integrated testing strategy (ITS)v1 Defined Approach (DA), adopted in OECD Guideline No. 497, was used for skin sensitization potency categorization. However, ITSv1 DA alone is not used for further refinement of the potency prediction based on EC3 (the estimated concentration that produces a stimulation index of 3 in murine local lymph node assay) values. Therefore, the application of read-across using Derek Nexus derived a PoD derived from the LLNA EC3 of 42 %. This led to a favorable NGRA conclusion and to support use of CBD at 0.3 % in face cream application.
{"title":"Utilizing integrated testing strategy (ITSv1) defined approach and read across to predict skin sensitization of cannabidiol","authors":"Ramez Labib, Ripal Amin, Chris Bartlett, Lisa Hoffman","doi":"10.1016/j.comtox.2023.100297","DOIUrl":"https://doi.org/10.1016/j.comtox.2023.100297","url":null,"abstract":"<div><p>Cannabidiol (CBD) is increasingly being used as an ingredient in cosmetics, but to date no pre-clinical studies have been published to address the skin sensitization end point. This case study investigated its skin sensitization potential for use in a face cream application at 0.3 % using Next Generation Risk Assessment (NGRA) framework. Based on chemical structure and <em>in-silico</em> prediction using Derek Nexus, CBD was predicted to be weak sensitizer with a resorcinol alert moiety. <em>In vitro</em> testing was conducted confirming it to be sensitizer, but the New Approach Methodologies (NAM) data could not provide sufficient confidence to determine a point of departure (PoD). Integrated testing strategy (ITS)v1 Defined Approach (DA), adopted in OECD Guideline No. 497, was used for skin sensitization potency categorization. However, ITSv1 DA alone is not used for further refinement of the potency prediction based on EC3 (the estimated concentration that produces a stimulation index of 3 in murine local lymph node assay) values. Therefore, the application of read-across using Derek Nexus derived a PoD derived from the LLNA EC3 of 42 %. This led to a favorable NGRA conclusion and to support use of CBD at 0.3 % in face cream application.</p></div>","PeriodicalId":37651,"journal":{"name":"Computational Toxicology","volume":"29 ","pages":"Article 100297"},"PeriodicalIF":0.0,"publicationDate":"2023-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139100704","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}
Pub Date : 2023-12-12DOI: 10.1016/j.comtox.2023.100296
Mo'tasem M. Alsmadi
Opioid use disorders (OUD) during pregnancy are related to neonatal opioid withdrawal syndrome (NOWS). R,S-methadone used to treat OUD and NOWS can penetrate the placenta. High neonatal brain extracellular fluid (bECF) levels of R,S-methadone can induce respiratory depression in newborns. The purpose of this work was to estimate neonatal bECF and saliva levels to establish the neonatal R,S-methadone salivary thresholds for respiratory depression after maternal oral dosing despite the sparse data in pregnancy and newborn populations. An adult physiologically-based pharmacokinetic (PBPK) model for R,S-methadone after intravenous and oral administration was constructed, vetted, and scaled to newborn and pregnancy populations. The pregnancy model predicted the R-methadone and S-methadone doses transplacentally transferred to newborns. Then, the newborn PBPK model was used to estimate newborn exposure after such doses. After maternal oral dosing of R,S-methadone (43.8 mg/day), the neonatal plasma levels were below the respiratory depression threshold. Further, the bECF levels were above the analgesia threshold for more than 96 h. The salivary thresholds for the analgesic effects of R-methadone, S-methadone, and R,S-methadone were estimated herein at 1.7, 43, and 16 ng/mL, respectively. Moreover, the salivary thresholds for the respiratory depression of R-methadone and R,S-methadone were estimated at 58 and 173 ng/mL, respectively. Using neonatal salivary monitoring of methadone can be useful in ensuring newborns' safety during maternal OUD treatment.
怀孕期间阿片类药物使用障碍(OUD)与新生儿阿片类药物戒断综合征(NOWS)有关。用于治疗OUD和NOWS的R、s -美沙酮可以穿透胎盘。高新生儿脑细胞外液(bECF)水平R, s -美沙酮可引起新生儿呼吸抑制。本研究的目的是评估新生儿bECF和唾液水平,以确定母亲口服给药后新生儿R、s -美沙酮唾液阈值对呼吸抑制的影响,尽管在妊娠和新生儿人群中数据较少。建立了R, s -美沙酮静脉和口服给药后的成人生理药代动力学(PBPK)模型,并对其进行了审查,并按比例扩展到新生儿和妊娠人群。妊娠模型预测经胎盘转移给新生儿的r -美沙酮和s -美沙酮剂量。然后,使用新生儿PBPK模型来估计这些剂量后的新生儿暴露。母亲口服R, s -美沙酮(43.8 mg/d)后,新生儿血浆水平低于呼吸抑制阈值。此外,bECF水平高于镇痛阈值的时间超过96小时。本文估计R-美沙酮、s -美沙酮和R, s -美沙酮的镇痛作用的唾液阈值分别为1.7、43和16 ng/mL。此外,R-美沙酮和R, s -美沙酮的呼吸抑制唾液阈值分别为58和173 ng/mL。使用新生儿唾液监测美沙酮可用于确保产妇OUD治疗期间新生儿的安全。
{"title":"Salivary therapeutic monitoring of methadone toxicity in neonates after transplacental transfer from parturient mothers treated with oral methadone guided by PBPK modeling","authors":"Mo'tasem M. Alsmadi","doi":"10.1016/j.comtox.2023.100296","DOIUrl":"https://doi.org/10.1016/j.comtox.2023.100296","url":null,"abstract":"<div><p>Opioid use disorders (OUD) during pregnancy are related to neonatal opioid withdrawal syndrome (NOWS). R,S-methadone used to treat OUD and NOWS can penetrate the placenta. High neonatal brain extracellular fluid (bECF) levels of R,S-methadone can induce respiratory depression in newborns. The purpose of this work was to estimate neonatal bECF and saliva levels to establish the neonatal R,S-methadone salivary thresholds for respiratory depression after maternal oral dosing despite the sparse data in pregnancy and newborn populations. An adult physiologically-based pharmacokinetic (PBPK) model for R,S-methadone after intravenous and oral administration was constructed, vetted, and scaled to newborn and pregnancy populations. The pregnancy model predicted the R-methadone and S-methadone doses transplacentally transferred to newborns. Then, the newborn PBPK model was used to estimate newborn exposure after such doses. After maternal oral dosing of R,S-methadone (43.8 mg/day), the neonatal plasma levels were below the respiratory depression threshold. Further, the bECF levels were above the analgesia threshold for more than 96 h. The salivary thresholds for the analgesic effects of R-methadone, S-methadone, and R,S-methadone were estimated herein at 1.7, 43, and 16 ng/mL, respectively. Moreover, the salivary thresholds for the respiratory depression of R-methadone and R,S-methadone were estimated at 58 and 173 ng/mL, respectively. Using neonatal salivary monitoring of methadone can be useful in ensuring newborns' safety during maternal OUD treatment.</p></div>","PeriodicalId":37651,"journal":{"name":"Computational Toxicology","volume":"29 ","pages":"Article 100296"},"PeriodicalIF":0.0,"publicationDate":"2023-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138656177","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}