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Adverse outcome pathway networks: Development, analytics and applications
Citation:
Knapen, D., M. Angrish, M. Fortin, I. Katsiadaki, M. Leonard, L. Margiotta-Casaluci, S. Munn, J. O'Brien, N. Pollesch, L. Smith, X. Zhang, AND Dan Villeneuve. Adverse outcome pathway networks: Development, analytics and applications. SETAC Europe, Rome, ITALY, May 13 - 17, 2018.
Impact/Purpose:
The US EPA is developing more cost effective and efficient ways to evaluate chemical safety using high throughput and computationally based testing strategies. An important component of this approach is the ability to translate chemical effects on fundamental biological processes like enzyme activities, gene expression, and basic cellular functions into what those effects mean to human health or ecosystem sustainability. The adverse outcome pathway framework was developed to facilitate that translation. The current presentation focuses on how to apply that framework to predict more complex interactions resulting from exposure to chemicals that cause multiple biological effects in an organism or exposures to mixtures of chemicals. It summarizes results and an expert workshop and lays out fundamental concepts that are expected to guide the derivation and application of AOP networks in research, risk assessment, and regulatory decision-making. This is foundational research aimed at addressing the challenges to predictive risk assessment that are posed by exposure to multiple chemicals, pleiotropic effects of single chemical exposures, and the diversity of effects chemicals may cause in different taxa, life-stages, or sexes of organisms. This research directly supports Task 2.3 under CSS Project 17.01.
Description:
The US EPA is developing more cost effective and efficient ways to evaluate chemical safety using high throughput and computationally based testing strategies. An important component of this approach is the ability to translate chemical effects on fundamental biological processes like enzyme activities, gene expression, and basic cellular functions into what those effects mean to human health or ecosystem sustainability. The adverse outcome pathway framework was developed to facilitate that translation. The current work focuses on how to apply that framework to predict more complex interactions resulting from exposure to chemicals that cause multiple biological effects in an organism or exposures to mixtures of chemicals. This is critical work, as most real-world exposures to chemicals involve these more complex scenarios. Adverse outcome pathways (AOPs) are an important framework that can help support more effective use of mechanistic, pathway-based, data in risk assessment and regulatory decision-making. AOPs have rapidly evolved from a conceptual paradigm into a formalized framework for organizing biological and toxicological knowledge according to a set of generally accepted principles and guidelines. In response to the recognized need to continue advancing the framework, SETAC sponsored a global horizon scanning exercise to identify major outstanding topics and challenges related to the AOP framework and its application. The development of guidance related to AOP network development and analysis was identified as a critical need. This not only included questions focusing directly on AOP networks, but also on related topics such as mixture toxicity assessment and the implementation of feedback loops within the AOP framework. This presentation briefly outlines critical concepts concerning the development of AOP networks, how they may be analyzed, and illustrates how information derived from them can be applied. First, derivation of AOP networks is considered in the context of how it differs from development of individual AOP descriptions. Next, the application of filters and layers is discussed, which can be used to refine and enrich derived AOP networks so that they may be tailored to address specific questions of interest. We then introduce a number of analytical and computational approaches that may be used to characterize and analyze the structure of AOP networks to derive information that can guide research and regulatory decision-making. A number of application case studies is used to illustrate concepts underlying development and analysis of AOP networks, and how those concepts tie in with ultimate application. The contents of this presentation represent the personal opinions of the authors and neither constitute, nor necessarily reflect the policies or viewpoints of their employers or institutes.