You are here:
Adverse outcome pathway networks I: Development and applications
Citation:
Knapen, D., M. Angrish, M. Fortin, I. Katsiadaki, M. Leonard, L. Mariotta-Casaluci, S. Munn, J. O'Brien, N. Pollesch, L. Smith, X. Zhang, AND Dan Villeneuve. Adverse outcome pathway networks I: Development and applications. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY. Society of Environmental Toxicology and Chemistry, Pensacola, FL, 37(6):1723-1733, (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. Based on the results of a SETAC-sponsored horizon scanning exercise focused on advancing the AOP framework, the development of guidance related to AOP network development 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. A set of two papers has been developed to begin exploring these concepts. In the present paper (part I), derivation of AOP networks is considered in the context of how it differs from development of individual AOPs. We then propose the use of filters and layers to tailor AOP networks to suit the needs of a given research question or application. We briefly introduce a number of analytical approaches that may be used to characterize the structure of AOP networks. These analytical concepts are further described in a dedicated, complementary paper (part II). Finally, we present a number of case studies that illustrate concepts underlying development, analysis and application of AOP networks. The concepts described in this paper, and in its companion paper focused on AOP network analytics, are intended to serve as a starting point for further development of the AOP network concept, but also to catalyze AOP network development and application by the different stakeholder communities.
