Adverse Outcome Pathways: Moving from a Scientific Concept to an Internationally Accepted Framework

International legislative mandates require chemical safety assessments to increase consumer confidence and protect human health and wildlife. Many of these mandates necessitate that regulators evaluate large numbers of chemicals within short time frames to make informed regulatory decisions (e.g., the European Union's Registration, Evaluation, Authorisation and Restriction of Chemicals and the US Toxic Substances Control Act). To address this challenge and reduce the costs of toxicity testing, a new vision and strategy for toxicity testing has emerged, which aspires to transform testing by making greater use of recent scientific advances (over the past decade) in cell-based and computational methods. A key concept aligning with this vision is the adverse outcome pathway (AOP) framework (Ankley et al. 2010). In brief, AOPs organize available toxicological knowledge and describe the causal linkages between a molecular initiating event (MIE; the first interaction of a chemical with a biological macromolecule such as an enzyme or a receptor) and subsequent measurable responses (termed key events [KEs]) across biological levels of organization, which culminate in an adverse outcome (AO) of regulatory significance—typically at the individual or population level (Box 1). Over the past decade, the AOP framework has matured significantly and has increasingly been recognized as a powerful approach for organizing biological information into a format applicable for chemical safety evaluation in both human health and ecological contexts (Ankley et al. 2010). Further, critical advances in AOP development and technology, including the development of a Web-based AOP Knowledgebase (AOP-KB, https://aopkb.oecd.org/; Box 2), have provided the opportunity to engage stakeholders (users and developers of AOPs) from industry, government, and academia to both evaluate the state of the science and identify next steps in advancing the AOP framework and its uses. ADME = absorption, distribution, metabolism, and excretion; AOP = adverse outcome pathway; qAOP = quantitative AOP. The adverse outcome pathway knowledge base (AOP-KB; image source: https://aopkb.oecd.org/index.html) is the Web-based infrastructure that was created to support the collaborative development, distribution, visualization, and use of AOP knowledge, with the aspiration of serving as the search engine and integration point for the AOP community. The AOP-KB captures effects data from toxicity studies (i.e., integration with Organisation for Economic Co-operation and Development's [OECD's] Harmonized Template 201; http://www.oecd.org/ehs/templates/) and assembles the data to produce quantitative relationships between key events (i.e., through integration with Effectopedia; www.effectopedia.org). The ultimate goal of this KB is to form a comprehensive collection of accessible resources for disseminating AOP knowledge captured by internationally introduced standards. The AOP-KB consists of four separate AOP-related modules. The furthest developed and most widely used module is the AOP-Wiki (https://aopwiki.org/), developed initially by the US Environmental Protection Agency. The other 3 modules include Effectopedia, developed by the OECD and the European Commission Joint Research Centre; AOPXplorer (http://www.aopxplorer.org/), developed by the US Army; and the Intermediate Effects Data Base, which is still under development. Because each module was initially created by a different organization as a stand-alone tool, in various stages of development, to date a complete and well-integrated AOP-KB has not been fully realized. Recently, the OECD launched the e.AOP.Portal, which currently serves as a search engine to mine information from the AOP-Wiki and Effectopedia, bringing the integration of AOP modules a step closer. AOP-Wiki The AOP-Wiki captures manually entered AOP knowledge in a standardized format through the use of crowd sourcing. It constitutes the main source for AOPs to be accessed and evaluated, and it has been instrumental in capturing AOP knowledge and the associated weight of evidence over the past years. The AOP-Wiki has expanded significantly since its initial public release in 2014 with a total of 216 AOP entries, consisting of 6 AOPs that have been endorsed by the OECD after formal review. As the most advanced module of the AOP-KB, the AOP-Wiki was the primary focal point for discussions surrounding advances to the AOP framework throughout the Pellston Workshop. Particularly, work groups explored the strengths and weaknesses of the Wiki in its current state and made recommendations for future iterations as a means to better accommodate multiple AOP stakeholders, which include researchers, risk assessors, and risk managers, with diverse needs and uses for AOP knowledge. A general theme to these discussions included the desire to manipulate the level of detail displayed based on the intended use of the AOP knowledge to address the needs of the stakeholder. DB = database. This manuscript presents a summary and synthesis of the discussions and outcomes from a Society of Environmental Toxicology and Chemistry (SETAC) PellstonTM Workshop, “Advancing the Adverse Outcome Pathway Concept—An International Horizon Scanning Approach,” that was held in Cornwall, Ontario, Canada, between April 2 and 6, 2017 (Box 3). The main purpose of this workshop was to begin addressing recognized issues relevant to the development and application of AOPs for chemical risk assessment for both human and ecological health. In preparation for the workshop we engaged the international scientific community via a horizon-scanning effort “to solicit questions concerning the challenges or limitations that must be addressed to realize the full potential of the AOP framework in research and regulatory decision-making,” which has been described by LaLone et al. (2017). The questions received during the horizon-scanning stage were subjected to an expert ranking exercise, which identified 4 main themes that were addressed during the workshop by 4 working groups: 1) AOP networks and their applications; 2) quantitative AOPs (qAOPs) and their applications; 3) regulatory use of the AOP framework; and 4) expanding awareness of, involvement in, and acceptance of AOPs to support aspects of predictive toxicology and regulatory decision-making. The present article reports on the outcomes of the actual Pellston Workshop that built on the key questions and associated themes that from the horizon-scanning to and recommendations to address current challenges and identify critical next steps in the full potential of the AOP it on 1) the and themes of this Pellston Workshop, which have in a of the and outcomes of the 4 (i.e., et al. et al. et al. et al. US Research and et al. a on current limitations and with future for the AOP framework to into scientific A or approach was used to the stage for the 2017 Pellston Workshop, to scientific and regulatory et al. an was developed to questions that key challenges or limitations that must be addressed to realize the full potential of the adverse outcome pathway questions were from in and across diverse et al. were subjected to an expert ranking and used to the themes and questions to be addressed at the Pellston Workshop et al. The Pellston Workshop discussions were 4 themes from this horizon-scanning work consisting of to were to address each of the 4 themes and associated In international in the Pellston Workshop were from with in academia and AOP = adverse outcome pathway; = qAOP = quantitative AOP. were to the state of the science of their theme and to on the application of AOPs in a research and regulatory questions were provided from the questions during and the expert ranking to by LaLone et al. these it was through 3 use studies to the current state of AOP science and relevant for AOP development and evaluation be were to current available for and the AOP-KB (Box through 3 were to challenges associated with collaborative development, and of the AOP framework with was to to greater involvement in, and acceptance of AOPs by the international scientific and The horizon-scanning effort that the Pellston Workshop the international in the AOP framework and its for chemical research and et al. addressed the themes from a and international collaborative discussions with across to that issues to and were risk from the other discussions the use of in regulatory decision-making. In that different (e.g., Canada, the the were included in discussions of the regulatory use of AOPs and regulatory significantly from to were to application of the AOP during the Pellston Workshop. It was recognized that studies the of AOP science to address key questions that from the horizon-scanning Further, studies the evaluation of a AOP or AOP is (i.e., for use based on a in addressing regulatory challenges or research were to and recommendations for future to the AOP framework such that it the needs of a community (Box 3). with the of each identified AOP studies which in of development and 1). of the such as or of were used by multiple diverse and challenges associated with the development of AOP networks and as as the application of AOPs in different regulatory contexts et al. et al. et al. such as to in were used to make (e.g., the application of AOPs to and support ecological risk et al. on a of studies were used from individual AOPs the application to questions (e.g., to to the application of AOPs to support chemical or ecological risk assessment of in et al. to the AOP-Wiki as a for of for of by an AOP (e.g., et al. et al. the application and of the studies used by the different the of the AOP-KB in diverse from chemical (i.e., the of chemicals with to and and development to ecological risk assessments of It was recognized that studies powerful for stakeholders, is a for development of that to the needs of a including in risk and et al. of relevant studies is to an acceptance of this To the of with to AOPs have on their development of the AOP-KB was the first step in the for regulatory with population of the AOP-KB (Box 2), this initial has application of the AOP framework in a regulatory both to support from current stakeholders and to to new This is in the of recent that have explored the AOP concept be to regulatory by et al. and Society for the of Adverse Outcome and identified a of challenges that to be these initial or for have been made with to and to address of these including in support of qAOP development (e.g., et al. et al. recommendations for the AOP-Wiki to of AOP networks et al. et al. and (e.g., the US Environmental Protection to to The development and application of this expanding for AOP development and have been the work of a of and from government, industry, and in and with the needs of chemical risk assessment in the AOP framework to its it must be by a including risk and other This development of that and address the needs of, diverse groups across et al. et al. the of the 2017 Pellston Workshop were not to make in addressing challenges in the development and application of the AOP framework in regulatory and research contexts to to address the needs and greater acceptance of the framework by a international community that risk and in the individual AOPs a for development and AOP networks of multiple AOPs be the for of pathway International to the AOP-Wiki have to the of 216 AOPs between 2014 and the to begin and the AOP The of were to 1) evaluate the state of the science concerning AOP and 2) to future development to use in research and regulatory decision-making. surrounding these to the development of 3 The first by et al. AOP development including new recommendations for and to used in on intended application to in networks and to relevant information on the This work used studies (e.g., of and to these and of networks be under described in this for including greater biological detail in AOP networks that be for that require quantitative pathway it be to include greater detail in of the or in a biological or the as a means to and for (e.g., or that the In or AOP be for the the use of and that on information captured in the AOP-KB as a to the level of detail for of the based on data needs for The on to the of AOP which a means to evaluate the and of the to information on pathway for In critical a on a pathway of the research or regulatory was introduced with for of AOP were expanded on by et al. on the of the AOP to identify or that the or of AOPs for a this work discussions of which of biological be to AOPs and identify of et al. This in detail and through or development in that at a (i.e., or separate after a (i.e., In of critical (i.e., of the most for a be used in the of the relevant for risk assessment and between AOP networks be for of or responses were The manuscript on from the first 2 and the of and the AOP-Wiki as a for large AOP networks and individual AOPs that of the et al. in their article the an evaluation of the and as as of and of the AOP-KB since its a of its current state that be used to future of the the work in the of developed from the discussions at the Pellston Workshop addressed questions to the horizon-scanning and expanded the to and evaluate AOP networks of the of questions during the horizon-scanning that were addressed during the Pellston workshop and main themes associated with questions to be addressed by future a The was by a diverse of from application of the adverse outcome pathway framework to address toxicity to the framework be used to support or A of questions be in AOP = adverse outcome pathway; qAOP = quantitative = its most an AOP is a of measurable biological and the relationships between for such as a challenge for risk assessment the potential risk of chemicals be from the AOP. quantitative of chemical risk be data events within an AOP (i.e., a in an in a in a or the This quantitative of the biological pathway be used to support decision-making. The of 2 was to the AOP framework and KB be used to to and and of chemicals or in support of regulatory decision-making. The manuscript by 2 et al. on for qAOP and the for and comprehensive to confidence in the use of qAOP of quantitative relationships in a qAOP were including and relationships (i.e., between an and a relationships be captured by or based computational that other such as responses or with other biological or et al. explored chemical qAOP be with or that describe chemicals and through the (e.g., which by provided that qAOP with other to the of chemical an must to have an adverse from adverse effects in (i.e., in to in In the manuscript and application of these by a qAOP for (e.g., of et al. It was that networks for of AOPs and integration of multiple data from cell-based or The manuscript the diverse of from qAOP networks that for (e.g., to identify and chemicals for to in support of questions and decisions (e.g., the potential of chemical The by 2 the potential of qAOP to support regulatory risk assessment through predictive assessments based on available knowledge. of qAOP to and is an to and diverse studies that have a and to regulatory risk it be to the of qAOP to potential and regulatory that confidence and application of such The of AOPs to regulatory has been the of recent in et al. these that the AOP framework a and approach for this is for of to the current for regulatory contexts such as application to testing and quantitative risk assessment of chemicals for the of Adverse Outcome In of these the of 3 were to 1) the regulatory to which the AOP framework be 2) for in and an AOP is and 3) identify regulatory needs future AOP development. et al. on the needs of different groups including both the community and in regulatory in with chemical safety The various stages of chemical (e.g., research and development, chemical for and and to the of the AOP framework across different chemical assessment 3 explored the of a from a pathway to a quantitative be to regulatory different levels of detail and that during the different stages of chemical both groups and chemical research and development is by the chemical and both the and the regulatory for AOPs in these different were identified that the of an AOP on the intended application et al. a of confidence and weight of evidence for regulatory be AOPs were to be used in including chemical or In during stages of research and development with new or for and to which AOPs be include and development, as described in the of the US by et al. which is to use testing to identify and evaluate the potential of chemicals to the of including In each AOP use has with to of and confidence in the AOPs or AOP networks of on these discussions 3 developed for the of an AOP. studies were used to AOPs have or used in support of regulatory 1). It was that the AOP framework a in chemical across the different stages of chemical that on the purpose of the safety et al. identified including 1) the for an of the AOP framework regulatory 2) a for of application of AOPs in regulatory and chemical testing, and 3) the development of that the biological or effects aligning with relevant in support of chemical and The AOP framework has been developed by a of and regulatory with the needs of the chemical and research in the within the AOP it during the horizon-scanning that was awareness of the AOP framework throughout the scientific and regulatory or In of the themes by was the to better the AOP framework the currently recognized groups as a means to acceptance and use of the framework across multiple groups including risk assessors, risk managers, researchers, and chemical The main of 4 were to 1) the AOP framework is to a 2) to the AOP framework to diverse and 3) identify be and by which current challenges the of the AOP framework and the associated be et al. identified and of the AOP framework that make it to a community. In the the for in of the AOP with and the of such knowledge in the AOP-KB, the and of the knowledge, and the potential for this knowledge. In support of these a of stakeholders were or from development of the AOP framework and its stakeholders included regulatory and chemical risk assessors, risk managers, the chemical industry, and and et al. et al. to describe a of key challenges in advancing the AOP include 1) of for and AOPs in the AOP-KB by (e.g., and the scientific 2) by risk and to support and use (i.e., the AOP for which has not been and which to and to and 3) the challenge in of the AOP in the of the The of 4 with a of recommendations the steps that to be to were for a of with and to the needs and of to and the and for AOPs were identified as for to of the AOP framework as a that the of next testing such as and of on testing to make decisions the use of The Pellston Workshop, “Advancing the Adverse Outcome Pathway Concept—An International Horizon Scanning Approach,” provided the opportunity to address key challenges and identify and to the AOP To that discussions that during the workshop and addressed key questions during an international horizon-scanning that the stage for the Pellston Workshop et al. the questions that were were addressed by and in the 1). was the of 4 et al. in addressing science to public and that through science The that a of questions from the horizon-scanning into this the of expanding the discussions to science to and in the AOP framework et al. It was that the AOP framework a that be to a of and questions different levels of AOP development, and In to the associated with AOPs to regulatory to the that application have in this complete development and for the application of AOPs to a of AOPs during stages of development that have not information to the research and development of new chemicals or the initial stages in development et al. In AOPs (e.g., AOP to toxicity in have been to evidence that or be of outcomes of regulatory applicable to the risk assessment of In the of quantitative is to the between the by and the stage in with knowledge the quantitative between the and the et al. this AOP has risk assessment of of the with to and main that was made across was that the of a approach to toxicity assessment has been by both the human and the ecological risk assessment Toxicology et al. 2010). the AOP framework has in a in that human toxicology and This is in to the that biological at the molecular groups (e.g., or is in current regulatory including the US Environmental Protection which has to in to evaluate chemicals for their potential to both and et al. it is that is still for of research into the of toxicity across groups and recent advances in and increasingly across of recent advances and the development of the opportunity for a approach to human health and ecological risk assessment that is by the AOP in to the large of questions that were addressed by the 4 a of during the and discussions that require that were the of the themes during the workshop In questions to themes the use or of AOPs in support of the use or of in the of AOPs to support in to in the application of AOPs to and risk and aspects of AOP development. of the questions were not applicable to and were not during the Pellston Workshop. A of have been that begin to address of these issues including and the application of AOPs to risk assessment and an Pellston workshop is held in that on the of in the of the AOP framework and regulatory As the horizon-scanning has identified a of greater that advanced by different groups that the to that science The surrounding AOPs have from over the framework be to discussions its is recognized the is The 2 most critical aspects in the of the AOP framework 1) the to and a to and support to and or the AOP-KB and the associated and and 2) the community to engage in both the development and use of To a of and have been with the development and of the AOP which has through standardized development and and a knowledge base This knowledge base the key infrastructure for the development, and use of Because of the resources available to this AOP the organization, and of the AOP-KB have been based on the of a have been with the and development of the AOP framework since its As in the AOP framework across scientific and regulatory and a and was which is by the on and of the Organisation for Economic Co-operation and with the of the AOP current infrastructure and limitations with to and the AOP-KB, and the and and through the is an to a This require of and across the scientific that and resources in support of this scientific the AOP framework is to into scientific and it must with from a of this is currently by of which were in detail by 4 et al. the most concerning 1) the of and to and AOPs to the AOP-KB and the and 2) the and of the AOP-KB, in for key stakeholders such as risk and 3) the of studies that have use of AOPs in decision-making. the the of the AOP framework as a to support regulatory has been of with and AOPs to the In AOPs have been to the AOP-Wiki to date of of which have with the OECD by = = = the AOPs as This is concerning that the AOP-KB was developed as a for the collaborative development of AOPs and a between the of the of the AOP framework in the and science and the actual and to the knowledge As by et al. of the main for this is the of to for and AOPs in the AOP-KB by (e.g., and the scientific community. the and for AOPs through the OECD is and which is by 6 AOPs been endorsed to the AOP-KB to be an and the must be and the significantly the for AOPs to be to or for for the AOP-KB to a scientific from and within was the to the of to the most information that be by the for the intended application et al. The AOP-Wiki was built by with the of and has as the for AOP development and AOP information is not in a that it to be in regulatory risk and to make informed decisions to be to risk managers, the AOP-KB must for and of information through an the of relevant information from the AOP-Wiki the AOPs associated with or the AOP-Wiki for or and AOPs a it is to identify and information from this large of AOP the AOP-KB, the needs to be to include advanced or search based on the and et al. et al. that stakeholders to through and information relevant to their In 3 of the 4 and 4) that of stakeholders is of that use of the AOP-KB in to the or human health. Further, information from AOPs is or as a of et al. et al. et al. is a of the to with stakeholders to that AOP development with current and future needs of regulators and This has been in the of chemical has been an desire for application of the AOP framework in a regulatory of the limitations of the framework in the of application is the of and the AOP framework has been in a regulatory a of in the of the AOP which was used to testing for in the European and in to the US AOPs to causal linkages from to It is recognized that use to to use and development. of AOP development in (e.g., industry, government, and on for development to of AOP knowledge and its acceptance as a future regulatory in risk The Data available on the at the Society of Environmental Toxicology and Chemistry (SETAC) in and provided support to the workshop and workshop and after the Pellston In we and for their of an of the the support from the US Environmental Protection the Research for and Toxicology of the European Commission Joint Research European the Society the Society of the the Toxicology and In we the groups from industry, and was by the Research The manuscript was in with the of the of Research and The in the present of the and not the or of the or the US of the of or or for This article The is not for the or of information by the be to the for the

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