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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, C. Smith, X. Zhang, AND Dan Villeneuve. Adverse outcome pathway networks: Development, analytics, and applications. SETAC North America, Minneapolis, MN, November 12 - 16, 2017.
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:
Product 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. Abstract: The adverse outcome pathway (AOP) framework was developed with a recognition that individual AOPs are a pragmatic unit for development and evaluation, but that application of AOPs in real-world exposure and assessment scenarios requires the ability to consider both interactions among multiple AOPs as well as convergent and/or divergent effects of chemical exposures depending on target organ, life-stage, taxa, etc. considered. AOP networks, defined as an assembly of two or more AOPs that share one or more key events, address these more multi-faceted applications of the framework. This presentation briefly outlines critical concepts concerning the development/derivation of AOP networks, how they may be analyzed, and illustrates how information derived from them can be applied. Network development focuses on querying and filtering the AOP knowledgebase to extract an AOP network appropriate for a given research question or problem formulation. Once an AOP network is derived, analytics based on graph theory and/or data layers superimposed on the network diagram may be applied to identify important features or attributes. These and other considerations can aid in the identification of critical pathways through the network that may either dominate observed empirical outcomes or may be most important to a given assessment or application. These concepts are illustrated through a number of application case studies, additionally recommendations for ways to further enhance the utility of AOP networks are provided. The contents of this presentation neither constitute nor necessarily reflect US EPA policy.