The Experts below are selected from a list of 150327 Experts worldwide ranked by ideXlab platform
Karine Audouze - One of the best experts on this subject based on the ideXlab platform.
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deciphering Adverse Outcome pathway network linked to bisphenol f using text mining and systems toxicology approaches
Toxicological Sciences, 2020Co-Authors: Marylene Rugard, Xavier Coumoul, Jeancharles Carvaillo, Robert Barouki, Karine AudouzeAbstract:Bisphenol F (BPF) is one of several Bisphenol A (BPA) substituents that is increasingly used in manufacturing industry leading to detectable human exposure. Whereas a large number of studies have been devoted to decipher BPA effects, much less is known about its substituents. To support decision making on BPF’s safety, we have developed a new computational approach to rapidly explore the available data on its toxicological effects, combining text mining and integrative systems biology, and aiming at connecting BPF to Adverse Outcome pathways (AOPs). We first extracted from different databases BPF-protein associations that were expanded to protein complexes using protein-protein interaction datasets. Over-representation analysis of the protein complexes allowed to identify the most relevant biological pathways putatively targeted by BPF. Then, automatic screening of scientific abstracts from literature using the text mining tool, AOP-helpFinder, combined with data integration from various sources (AOP-wiki, CompTox, etc.) and manual curation allowed us to link BPF to AOP events. Finally, we combined all the information gathered through those analyses and built a comprehensive complex framework linking BPF to an AOP network including, as Adverse Outcomes, various types of cancers such as breast and thyroid malignancies. These results which integrate different types of data can support regulatory assessment of the BPA substituent, BPF, and trigger new epidemiological and experimental studies.
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deciphering Adverse Outcome pathway network linked to bisphenol f using text mining and systems toxicology approaches
Toxicological Sciences, 2020Co-Authors: Marylene Rugard, Xavier Coumoul, Jeancharles Carvaillo, Robert Barouki, Karine AudouzeAbstract:: Bisphenol F (BPF) is one of several Bisphenol A (BPA) substituents that is increasingly used in manufacturing industry leading to detectable human exposure. Whereas a large number of studies have been devoted to decipher BPA effects, much less is known about its substituents. In order to support decision making on BPF's safety, we have developed a new computational approach to rapidly explore the available data on its toxicological effects, combining text mining and integrative systems biology, and aiming at connecting BPF to Adverse Outcome pathways (AOPs). We first extracted from different databases BPF-protein associations that were expanded to protein complexes using protein-protein interaction datasets. Overrepresentation analysis of the protein complexes allowed to identify the most relevant biological pathways putatively targeted by BPF. Then, automatic screening of scientific abstracts from literature using the text mining tool, AOP-helpFinder, combined with data integration from various sources (AOP-wiki, CompTox, etc.) and manual curation allowed us to link BPF to AOP events. Finally, we combined all the information gathered through those analyses and built a comprehensive complex framework linking BPF to an AOP network including, as Adverse Outcomes, various types of cancers such as breast and thyroid malignancies. These results which integrate different types of data can support regulatory assessment of the BPA substituent, BPF and trigger new epidemiological and experimental studies.
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Linking Bisphenol S to Adverse Outcome Pathways Using a Combined Text Mining and Systems Biology Approach
Environmental Health Perspectives, 2019Co-Authors: Jeancharles Carvaillo, Xavier Coumoul, Robert Barouki, Karine AudouzeAbstract:Background:Available toxicity data can be optimally interpreted if they are integrated using computational approaches such as systems biology modeling. Such approaches are particularly warranted in cases where regulatory decisions have to be made rapidly.Objectives:The study aims at developing and applying a new integrative computational strategy to identify associations between bisphenol S (BPS), a substitute for bisphenol A (BPA), and components of Adverse Outcome pathways (AOPs). Methods: The proposed approach combines a text mining (TM) procedure and integrative systems biology to comprehensively analyze the scientific literature to enrich AOPs related to environmental stressors. First, to identify relevant associations between BPS and different AOP components, a list of abstracts was screened using the developed text-mining tool AOP-helpFinder, which calculates scores based on the graph theory to prioritize the findings. Then, to fill gaps between BPS, biological events, and Adverse Outcomes (AOs), a systems biology approach was used to integrate information from the AOP-Wiki and ToxCast databases, followed by manual curation of the relevant publications. Results: Links between BPS and 48 AOP key events (KEs) were identified and scored via 31 references. The main Outcomes were related to reproductive health, endocrine disruption, impairments of metabolism, and obesity. We then explicitly analyzed co-mention of the terms BPS and obesity by data integration and manual curation of the full text of the publications. Several molecular and cellular pathways were identified, which allowed the proposal of a biological explanation for the association between BPS and obesity. Conclusions: By analyzing dispersed information from the literature and databases, our novel approach can identify links between stressors and AOP KEs. The findings associating BPS and obesity illustrate the use of computational tools in predictive toxicology and highlight the relevance of the approach to decision makers assessing substituents to toxic chemicals. https://doi.org/10.1289/EHP4200
Jeancharles Carvaillo - One of the best experts on this subject based on the ideXlab platform.
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deciphering Adverse Outcome pathway network linked to bisphenol f using text mining and systems toxicology approaches
Toxicological Sciences, 2020Co-Authors: Marylene Rugard, Xavier Coumoul, Jeancharles Carvaillo, Robert Barouki, Karine AudouzeAbstract:Bisphenol F (BPF) is one of several Bisphenol A (BPA) substituents that is increasingly used in manufacturing industry leading to detectable human exposure. Whereas a large number of studies have been devoted to decipher BPA effects, much less is known about its substituents. To support decision making on BPF’s safety, we have developed a new computational approach to rapidly explore the available data on its toxicological effects, combining text mining and integrative systems biology, and aiming at connecting BPF to Adverse Outcome pathways (AOPs). We first extracted from different databases BPF-protein associations that were expanded to protein complexes using protein-protein interaction datasets. Over-representation analysis of the protein complexes allowed to identify the most relevant biological pathways putatively targeted by BPF. Then, automatic screening of scientific abstracts from literature using the text mining tool, AOP-helpFinder, combined with data integration from various sources (AOP-wiki, CompTox, etc.) and manual curation allowed us to link BPF to AOP events. Finally, we combined all the information gathered through those analyses and built a comprehensive complex framework linking BPF to an AOP network including, as Adverse Outcomes, various types of cancers such as breast and thyroid malignancies. These results which integrate different types of data can support regulatory assessment of the BPA substituent, BPF, and trigger new epidemiological and experimental studies.
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deciphering Adverse Outcome pathway network linked to bisphenol f using text mining and systems toxicology approaches
Toxicological Sciences, 2020Co-Authors: Marylene Rugard, Xavier Coumoul, Jeancharles Carvaillo, Robert Barouki, Karine AudouzeAbstract:: Bisphenol F (BPF) is one of several Bisphenol A (BPA) substituents that is increasingly used in manufacturing industry leading to detectable human exposure. Whereas a large number of studies have been devoted to decipher BPA effects, much less is known about its substituents. In order to support decision making on BPF's safety, we have developed a new computational approach to rapidly explore the available data on its toxicological effects, combining text mining and integrative systems biology, and aiming at connecting BPF to Adverse Outcome pathways (AOPs). We first extracted from different databases BPF-protein associations that were expanded to protein complexes using protein-protein interaction datasets. Overrepresentation analysis of the protein complexes allowed to identify the most relevant biological pathways putatively targeted by BPF. Then, automatic screening of scientific abstracts from literature using the text mining tool, AOP-helpFinder, combined with data integration from various sources (AOP-wiki, CompTox, etc.) and manual curation allowed us to link BPF to AOP events. Finally, we combined all the information gathered through those analyses and built a comprehensive complex framework linking BPF to an AOP network including, as Adverse Outcomes, various types of cancers such as breast and thyroid malignancies. These results which integrate different types of data can support regulatory assessment of the BPA substituent, BPF and trigger new epidemiological and experimental studies.
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Linking Bisphenol S to Adverse Outcome Pathways Using a Combined Text Mining and Systems Biology Approach
Environmental Health Perspectives, 2019Co-Authors: Jeancharles Carvaillo, Xavier Coumoul, Robert Barouki, Karine AudouzeAbstract:Background:Available toxicity data can be optimally interpreted if they are integrated using computational approaches such as systems biology modeling. Such approaches are particularly warranted in cases where regulatory decisions have to be made rapidly.Objectives:The study aims at developing and applying a new integrative computational strategy to identify associations between bisphenol S (BPS), a substitute for bisphenol A (BPA), and components of Adverse Outcome pathways (AOPs). Methods: The proposed approach combines a text mining (TM) procedure and integrative systems biology to comprehensively analyze the scientific literature to enrich AOPs related to environmental stressors. First, to identify relevant associations between BPS and different AOP components, a list of abstracts was screened using the developed text-mining tool AOP-helpFinder, which calculates scores based on the graph theory to prioritize the findings. Then, to fill gaps between BPS, biological events, and Adverse Outcomes (AOs), a systems biology approach was used to integrate information from the AOP-Wiki and ToxCast databases, followed by manual curation of the relevant publications. Results: Links between BPS and 48 AOP key events (KEs) were identified and scored via 31 references. The main Outcomes were related to reproductive health, endocrine disruption, impairments of metabolism, and obesity. We then explicitly analyzed co-mention of the terms BPS and obesity by data integration and manual curation of the full text of the publications. Several molecular and cellular pathways were identified, which allowed the proposal of a biological explanation for the association between BPS and obesity. Conclusions: By analyzing dispersed information from the literature and databases, our novel approach can identify links between stressors and AOP KEs. The findings associating BPS and obesity illustrate the use of computational tools in predictive toxicology and highlight the relevance of the approach to decision makers assessing substituents to toxic chemicals. https://doi.org/10.1289/EHP4200
Daniel L Villeneuve - One of the best experts on this subject based on the ideXlab platform.
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Representing the Process of Inflammation as Key Events in Adverse Outcome Pathways
TOXICOLOGICAL SCIENCES, 2018Co-Authors: Daniel L Villeneuve, Brigitte Landesmann, Anna Bal-price, Paola Allavena, Noah Ashley, Emanuela Corsini, Sabina Halappanavar, Tracy Hussell, Debra Laskin, Toby LawrenceAbstract:Inflammation is an important biological process involved in many target organ toxicities. However, there has been little consensus on how to represent inflammatory processes using the Adverse Outcome pathway (AOP) framework. In particular, there were concerns that inflammation was not being represented in a way that it would be recognized as a highly connected, central node within the global AOP network. The consideration of salient features common to the inflammatory process across tissues was used as a basis to propose 3 hub key events (KEs) for use in AOP network development. Each event, ``tissue resident cell activation'', ``increased pro-inflammatory mediators'', and ``leukocyte recruitment/activation,'' is viewed as a hallmark of inflammation, independent of tissue, and can be independently measured. Using these proposed hub KEs, it was possible to link together a series of AOPs that previously had no shared KEs. Significant challenges remain with regard to accurate prediction of inflammation-related toxicological Outcomes even if a broader and more connected network of inflammation-centered AOPs is developed. Nonetheless, the current proposal addresses one of the major hurdles associated with representation of inflammation in AOPs and may aid fit-for-purpose evaluations of other AOPs operating in a network context.
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increasing scientific confidence in Adverse Outcome pathways application of tailored bradford hill considerations for evaluating weight of evidence
Regulatory Toxicology and Pharmacology, 2015Co-Authors: Richard A Becker, Magdalini Sachana, Stephen W. Edwards, Gerald T Ankley, Sean W Kennedy, Igor Linkov, Bette Meek, Helmut Segner, Bart Van Der Burg, Daniel L VilleneuveAbstract:Systematic consideration of scientific support is a critical element in developing and, ultimately, using Adverse Outcome pathways (AOPs) for various regulatory applications. Though weight of evidence (WoE) analysis has been proposed as a basis for assessment of the maturity and level of confidence in an AOP, methodologies and tools are still being formalized. The Organization for Economic Co-operation and Development (OECD) Users' Handbook Supplement to the Guidance Document for Developing and Assessing AOPs (OECD 2014a; hereafter referred to as the OECD AOP Handbook) provides tailored Bradford-Hill (BH) considerations for systematic assessment of confidence in a given AOP. These considerations include (1) biological plausibility and (2) empirical support (dose-response, temporality, and incidence) for Key Event Relationships (KERs), and (3) essentiality of key events (KEs). Here, we test the application of these tailored BH considerations and the guidance outlined in the OECD AOP Handbook using a number of case examples to increase experience in more transparently documenting rationales for assigned levels of confidence to KEs and KERs, and to promote consistency in evaluation within and across AOPs. The major lessons learned from experience are documented, and taken together with the case examples, should contribute to better common understanding of the nature and form of documentation required to increase confidence in the application of AOPs for specific uses. Based on the tailored BH considerations and defining questions, a prototype quantitative model for assessing the WoE of an AOP using tools of multi-criteria decision analysis (MCDA) is described. The applicability of the approach is also demonstrated using the case example aromatase inhibition leading to reproductive dysfunction in fish. Following the acquisition of additional experience in the development and assessment of AOPs, further refinement of parameterization of the model through expert elicitation is recommended. Overall, the application of quantitative WoE approaches hold promise to enhance the rigor, transparency and reproducibility for AOP WoE determinations and may play an important role in delineating areas where research would have the greatest impact on improving the overall confidence in the AOP.
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Adverse Outcome pathways organizing toxicological information to improve decision making
Journal of Pharmacology and Experimental Therapeutics, 2015Co-Authors: Stephen W. Edwards, M.e. Meek, Daniel L Villeneuve, Yumei Tan, Charlene A McqueenAbstract:The number of chemicals for which environmental regulatory decisions are required far exceeds the current capacity for toxicity testing. High-throughput screening commonly used for drug discovery has the potential to increase this capacity. The Adverse Outcome pathway (AOP) concept has emerged as a framework for connecting high-throughput toxicity testing (HTT) and other results to potential impacts on human and wildlife populations. As a result of international efforts, the AOP development process is now well-defined and efforts are underway to broaden the participation through outreach and training. One key principle is that AOPs represent the chemical-agnostic portions of pathways to increase the generalizability of their application from early key events to overt toxicity. The closely related mode of action framework extends the AOP as needed when evaluating the potential risk of a specific chemical. This in turn enables integrated approaches to testing and assessment (IATA), which incorporate results of assays at various levels of biologic organization such as in silico; HTT; chemical-specific aspects including absorption, distribution, metabolism, and excretion (ADME); and an AOP describing the biologic basis of toxicity. Thus, it is envisaged that provision of limited information regarding both the AOP for critical effects and the ADME for any chemical associated with any Adverse Outcome would allow for the development of IATA and permit more detailed AOP and ADME research, where higher precision is needed based on the decision context.
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Adverse Outcome pathway development ii best practices
Toxicological Sciences, 2014Co-Authors: Daniel L Villeneuve, Doug Crump, Natalia Garciareyero, Markus Hecker, Thomas H HutchinsonAbstract:Organization of existing and emerging toxicological knowledge into Adverse Outcome pathway (AOP) descriptions can facilitate greater application of mechanistic data, including those derived through high-throughput in vitro, high content omics and imaging, and biomarker approaches, in risk-based decision making. The previously ad hoc process of AOP development is being formalized through development of internationally harmonized guidance and principles. The goal of this article was to outline the information content desired for formal AOP description and some rules of thumb and best practices intended to facilitate reuse and connectivity of elements of an AOP description in a knowledgebase and network context. For example, key events (KEs) are measurements of change in biological state that are indicative of progression of a perturbation toward a specified Adverse Outcome. Best practices for KE description suggest that each KE should be defined as an independent measurement made at a particular level of biological organization. The concept of “functional equivalence” can help guide both decisions about how many KEs to include in an AOP and the specificity with which they are defined. Likewise, in describing both KEs and evidence that supports a causal linkage or statistical association between them (ie, a key event relationship; KER), best practice is to build from and contribute to existing KE or KER descriptions in the AOP knowledgebase rather than creating redundant descriptions. The best practices proposed address many of the challenges and uncertainties related to AOP development and help promote a consistent and reliable, yet flexible approach.
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Adverse Outcome pathway aop development i strategies and principles
Toxicological Sciences, 2014Co-Authors: Daniel L Villeneuve, Doug Crump, Natalia Garciareyero, Markus Hecker, Thomas H HutchinsonAbstract:An Adverse Outcome pathway (AOP) is a conceptual framework that organizes existing knowledge concerning biologically plausible, and empirically supported, links between molecular-level perturbation of a biological system and an Adverse Outcome at a level of biological organization of regulatory relevance. Systematic organization of information into AOP frameworks has potential to improve regulatory decision-making through greater integration and more meaningful use of mechanistic data. However, for the scientific community to collectively develop a useful AOP knowledgebase that encompasses toxicological contexts of concern to human health and ecological risk assessment, it is critical that AOPs be developed in accordance with a consistent set of core principles. Based on the experiences and scientific discourse among a group of AOP practitioners, we propose a set of five fundamental principles that guide AOP development: (1) AOPs are not chemical specific; (2) AOPs are modular and composed of reusable components—notably key events (KEs) and key event relationships (KERs); (3) an individual AOP, composed of a single sequence of KEs and KERs, is a pragmatic unit of AOP development and evaluation; (4) networks composed of multiple AOPs that share common KEs and KERs are likely to be the functional unit of prediction for most real-world scenarios; and (5) AOPs are living documents that will evolve over time as new knowledge is generated. The goal of the present article was to introduce some strategies for AOP development and detail the rationale behind these 5 key principles. Consideration of these principles addresses many of the current uncertainties regarding the AOP framework and its application and is intended to foster greater consistency in AOP development.
Menno V Huisman - One of the best experts on this subject based on the ideXlab platform.
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brain type natriuretic peptide levels in the prediction of Adverse Outcome in patients with pulmonary embolism a systematic review and meta analysis
American Journal of Respiratory and Critical Care Medicine, 2008Co-Authors: Frederikus A Klok, Menno V HuismanAbstract:Rationale: The potential role of elevated brain-type natriuretic peptides (BNP) in the differentiation of patients suffering from acute pulmonary embolism at risk for Adverse clinical Outcome has not been fully established.Objectives: We evaluated the relation between elevated BNP or N-terminal–pro-BNP (NT–pro-BNP) levels and clinical Outcome in patients with pulmonary embolism.Methods: Articles reporting on studies that evaluated the risk of Adverse Outcome in patients with pulmonary embolism and elevated BNP or NT–pro-BNP levels were abstracted from Medline and EMBASE. Information on study design, patient and assay characteristics, and clinical Outcome was extracted. Primary endpoints were overall mortality and predefined composite Outcome of Adverse clinical events.Measurements and Main Results: Data from 13 studies were included. In 51% (576/1,132) of the patients, BNP or NT–pro-BNP levels were increased. The different analyses were performed in subpopulations. Elevated levels of BNP or NT–pro-BNP wer...
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brain type natriuretic peptide levels in the prediction of Adverse Outcome in patients with pulmonary embolism a systematic review and meta analysis
American Journal of Respiratory and Critical Care Medicine, 2008Co-Authors: Frederikus A Klok, Inge C M Mos, Menno V HuismanAbstract:Rationale: The potential role of elevated brain-type natriuretic peptides (BNP) in the differentiation of patients suffering from acute pulmonary embolism at risk for Adverse clinical Outcome has not been fully established.Objectives: We evaluated the relation between elevated BNP or N-terminal–pro-BNP (NT–pro-BNP) levels and clinical Outcome in patients with pulmonary embolism.Methods: Articles reporting on studies that evaluated the risk of Adverse Outcome in patients with pulmonary embolism and elevated BNP or NT–pro-BNP levels were abstracted from Medline and EMBASE. Information on study design, patient and assay characteristics, and clinical Outcome was extracted. Primary endpoints were overall mortality and predefined composite Outcome of Adverse clinical events.Measurements and Main Results: Data from 13 studies were included. In 51% (576/1,132) of the patients, BNP or NT–pro-BNP levels were increased. The different analyses were performed in subpopulations. Elevated levels of BNP or NT–pro-BNP wer...
Mathieu Vinken - One of the best experts on this subject based on the ideXlab platform.
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Liver Adverse Outcome Pathways: What's in for the Hepatologist?
Journal of gastrointestinal and liver diseases : JGLD, 2020Co-Authors: Mathieu VinkenAbstract:Adverse Outcome pathways are tools to capture and visualize mechanisms underlying Adverse effects, and are currently emerging in the areas of toxicology and chemical risk assessment. Less attention has yet been paid to potential clinical applications of Adverse Outcome pathways, including in the hepatology field. Liver Adverse Outcome pathways can serve the development and optimization of the clinically relevant animal models of liver diseases for fundamental and translational research as well as for testing new liver therapeutics. They also can aid the characterization of novel and more specific diagnostic and prognostic biomarkers of liver disease. Full clinical exploitation in these directions requires further technical optimization of Adverse Outcome pathways as well as intensive interdisciplinary and intersectoral collaboration.
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Robustness testing and optimization of an Adverse Outcome pathway on cholestatic liver injury
Archives of Toxicology, 2020Co-Authors: Eva Gijbels, Vânia Vilas‐boas, Pieter Annaert, Tamara Vanhaecke, Lindsey Devisscher, Mathieu VinkenAbstract:Adverse Outcome pathways (AOPs) have been recently introduced as tools to map the mechanisms underlying toxic events relevant for chemical risk assessment. AOPs particularly depict the linkage between a molecular initiating event and an Adverse Outcome through a number of intermediate key events. An AOP has been previously introduced for cholestatic liver injury. The objective of this study was to test the robustness of this AOP for different types of cholestatic insult and the in vitro to in vivo extrapolation. For this purpose, in vitro samples from human hepatoma HepaRG cell cultures were exposed to cholestatic drugs (i.e. intrahepatic cholestasis), while in vivo samples were obtained from livers of cholestatic mice (i.e. extrahepatic cholestasis). The occurrence of cholestasis in vitro was confirmed through analysis of bile transporter functionality and bile acid analysis. Transcriptomic analysis revealed inflammation and oxidative stress as key events in both types of cholestatic liver injury. Major transcriptional differences between intrahepatic and extrahepatic cholestatic liver insults were observed at the level of cell death and metabolism. Novel key events identified by pathway analysis included endoplasmic reticulum stress in intrahepatic cholestasis, and autophagy and necroptosis in both intrahepatic as extrahepatic cholestasis. This study demonstrates that AOPs constitute dynamic tools that should be frequently updated with new input information.
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The use of Adverse Outcome pathways in the safety evaluation of food additives
Archives of Toxicology, 2020Co-Authors: Mathieu Vinken, Nynke Kramer, Timothy E. H. Allen, Yvette Hoffmans, Natalie Thatcher, Sara Levorato, Heinz Traussnig, Stefan Schulte, Alan Boobis, Anette ThielAbstract:In the last decade, Adverse Outcome pathways have been introduced in the fields of toxicology and risk assessment of chemicals as pragmatic tools with broad application potential. While their use in the pharmaceutical and cosmetics sectors has been well documented, their application in the food area remains largely unexplored. In this respect, an expert group of the International Life Sciences Institute Europe has recently explored the use of Adverse Outcome pathways in the safety evaluation of food additives. A key activity was the organization of a workshop, gathering delegates from the regulatory, industrial and academic areas, to discuss the potentials and challenges related to the application of Adverse Outcome pathways in the safety assessment of food additives. The present paper describes the Outcome of this workshop followed by a number of critical considerations and perspectives defined by the International Life Sciences Institute Europe expert group.
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Adverse Outcome pathways: opportunities, limitations and open questions
Archives of Toxicology, 2017Co-Authors: Marcel Leist, Ahmed Ghallab, Susanne Hougaard Bennekou, Alice Limonciel, Stefan Schildknecht, Reham Hassan, Rosemarie Marchan, Mathieu Vinken, Rabea Graepel, Tanja WaldmannAbstract:Adverse Outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory purposes. AOP links a molecular initiating event (MIE) to the Adverse Outcome (AO) via key events (KE), in a way specified by key event relationships (KER). Although this approach to formalize mechanistic toxicological information only started in 2010, over 200 AOPs have already been established. At this stage, new requirements arise, such as the need for harmonization and re-assessment, for continuous updating, as well as for alerting about pitfalls, misuses and limits of applicability. In this review, the history of the AOP concept and its most prominent strengths are discussed, including the advantages of a formalized approach, the systematic collection of weight of evidence, the linkage of mechanisms to apical end points, the examination of the plausibility of epidemiological data, the identification of critical knowledge gaps and the design of mechanistic test methods. To prepare the ground for a broadened and appropriate use of AOPs, some widespread misconceptions are explained. Moreover, potential weaknesses and shortcomings of the current AOP rule set are addressed (1) to facilitate the discussion on its further evolution and (2) to better define appropriate vs. less suitable application areas. Exemplary toxicological studies are presented to discuss the linearity assumptions of AOP, the management of event modifiers and compensatory mechanisms, and whether a separation of toxicodynamics from toxicokinetics including metabolism is possible in the framework of pathway plasticity. Suggestions on how to compromise between different needs of AOP stakeholders have been added. A clear definition of open questions and limitations is provided to encourage further progress in the field.
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Adverse Outcome pathways: opportunities, limitations and open questions
Archives of Toxicology, 2017Co-Authors: Marcel Leist, Ahmed Ghallab, Susanne Hougaard Bennekou, Alice Limonciel, Stefan Schildknecht, Reham Hassan, Rosemarie Marchan, Mathieu Vinken, Rabea Graepel, Tanja WaldmannAbstract:Adverse Outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory purposes. AOP links a molecular initiating event (MIE) to the Adverse Outcome (AO) via key events (KE), in a way specified by key event relationships (KER). Although this approach to formalize mechanistic toxicological information only started in 2010, over 200 AOPs have already been established. At this stage, new requirements arise, such as the need for harmonization and re-assessment, for continuous updating, as well as for alerting about pitfalls, misuses and limits of applicability. In this review, the history of the AOP concept and its most prominent strengths are discussed, including the advantages of a formalized approach, the systematic collection of weight of evidence, the linkage of mechanisms to apical end points, the examination of the plausibility of epidemiological data, the identification of critical knowledge gaps and the design of mechanistic test methods. To prepare the ground for a broadened and appropriate use of AOPs, some widespread misconceptions are explained. Moreover, potential weaknesses and shortcomings of the current AOP rule set are addressed (1) to facilitate the discussion on its further evolution and (2) to better define appropriate vs. less suitable application areas. Exemplary toxicological studies are presented to discuss the linearity assumptions of AOP, the management of event modifiers and compensatory mechanisms, and whether a separation of toxicodynamics from toxicokinetics including metabolism is possible in the framework of pathway plasticity. Suggestions on how to compromise between different needs of AOP stakeholders have been added. A clear definition of open questions and limitations is provided to encourage further progress in the field.