Alex N Cayley, Robert S Foster, Emma Hill, Steven Kane, Grace Kocks, Alun Myden, Daniel Newman, Susanne A Stalford, Jonathan D Vessey, Reza Zarei, Antonio Anax F De Oliveira
{"title":"致癌性不良后果途径网络的建立及其作为安全性评估的证据框架","authors":"Alex N Cayley, Robert S Foster, Emma Hill, Steven Kane, Grace Kocks, Alun Myden, Daniel Newman, Susanne A Stalford, Jonathan D Vessey, Reza Zarei, Antonio Anax F De Oliveira","doi":"10.14573/altex.2201311","DOIUrl":null,"url":null,"abstract":"<p><p>The traditional paradigm for safety assessment of chemicals for their carcinogenic potential to humans relies heavily on a battery of well-established genotoxicity tests, usually followed up by long-term, high-dose rodent studies. There are a variety of problems with this approach, not least that the rodent may not always be the best model to predict toxicity in humans. Consequently, new approach methodologies (NAMs) are being developed to replace or enhance predictions coming from the existing assays. However, a combination of the data arising from NAMs is likely to be required to improve upon the current paradigm, and consequently a framework is needed to combine evidence in a meaningful way. Adverse outcome pathways (AOPs) represent an ideal construct on which to organize this evidence. In this work, a data structure outlined previously was used to capture AOPs and evidence relating to carcinogenicity. Knowledge held within the predictive system Derek Nexus was extracted, built upon, and arranged into a coherent network containing 37 AOPs. 60 assays and 351 in silico alerts were then associated with KEs in this network, and it was brought to life by associating data and contextualizing evidence and predictions for over 13,400 compounds. Initial investigations into using the network to view knowledge and reason between evidence in different ways were made. Organizing knowledge and evidence in this way provides a flexible framework on which to carry out more consistent and meaningful carcinogenicity safety assessments in many different contexts.</p>","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":null,"pages":null},"PeriodicalIF":4.5000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"4","resultStr":"{\"title\":\"Development of a network of carcinogenicity adverse outcome pathways and its employment as an evidence framework for safety assessment\",\"authors\":\"Alex N Cayley, Robert S Foster, Emma Hill, Steven Kane, Grace Kocks, Alun Myden, Daniel Newman, Susanne A Stalford, Jonathan D Vessey, Reza Zarei, Antonio Anax F De Oliveira\",\"doi\":\"10.14573/altex.2201311\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The traditional paradigm for safety assessment of chemicals for their carcinogenic potential to humans relies heavily on a battery of well-established genotoxicity tests, usually followed up by long-term, high-dose rodent studies. There are a variety of problems with this approach, not least that the rodent may not always be the best model to predict toxicity in humans. Consequently, new approach methodologies (NAMs) are being developed to replace or enhance predictions coming from the existing assays. However, a combination of the data arising from NAMs is likely to be required to improve upon the current paradigm, and consequently a framework is needed to combine evidence in a meaningful way. Adverse outcome pathways (AOPs) represent an ideal construct on which to organize this evidence. In this work, a data structure outlined previously was used to capture AOPs and evidence relating to carcinogenicity. Knowledge held within the predictive system Derek Nexus was extracted, built upon, and arranged into a coherent network containing 37 AOPs. 60 assays and 351 in silico alerts were then associated with KEs in this network, and it was brought to life by associating data and contextualizing evidence and predictions for over 13,400 compounds. Initial investigations into using the network to view knowledge and reason between evidence in different ways were made. Organizing knowledge and evidence in this way provides a flexible framework on which to carry out more consistent and meaningful carcinogenicity safety assessments in many different contexts.</p>\",\"PeriodicalId\":51231,\"journal\":{\"name\":\"Altex-Alternatives To Animal Experimentation\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.5000,\"publicationDate\":\"2023-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"4\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Altex-Alternatives To Animal Experimentation\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.14573/altex.2201311\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Altex-Alternatives To Animal Experimentation","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.14573/altex.2201311","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
Development of a network of carcinogenicity adverse outcome pathways and its employment as an evidence framework for safety assessment
The traditional paradigm for safety assessment of chemicals for their carcinogenic potential to humans relies heavily on a battery of well-established genotoxicity tests, usually followed up by long-term, high-dose rodent studies. There are a variety of problems with this approach, not least that the rodent may not always be the best model to predict toxicity in humans. Consequently, new approach methodologies (NAMs) are being developed to replace or enhance predictions coming from the existing assays. However, a combination of the data arising from NAMs is likely to be required to improve upon the current paradigm, and consequently a framework is needed to combine evidence in a meaningful way. Adverse outcome pathways (AOPs) represent an ideal construct on which to organize this evidence. In this work, a data structure outlined previously was used to capture AOPs and evidence relating to carcinogenicity. Knowledge held within the predictive system Derek Nexus was extracted, built upon, and arranged into a coherent network containing 37 AOPs. 60 assays and 351 in silico alerts were then associated with KEs in this network, and it was brought to life by associating data and contextualizing evidence and predictions for over 13,400 compounds. Initial investigations into using the network to view knowledge and reason between evidence in different ways were made. Organizing knowledge and evidence in this way provides a flexible framework on which to carry out more consistent and meaningful carcinogenicity safety assessments in many different contexts.
期刊介绍:
ALTEX publishes original articles, short communications, reviews, as well as news and comments and meeting reports. Manuscripts submitted to ALTEX are evaluated by two expert reviewers. The evaluation takes into account the scientific merit of a manuscript and its contribution to animal welfare and the 3R principle.