Building and Applying Quantitative Adverse Outcome Pathway Models for Chemical Hazard and Risk Assessment.

Edward J Perkins,Stefan Scholz,Brigitte Landesmann,Anze Zupanic,Cameron Mackay,Rory Conolly,James R Wheeler,Lyle Burgoon,Nathan Pollesch,Roman Ashauer,Cheryl A Murphy

doi:10.1002/etc.4505

Abstract

An important goal in toxicology is the development of new ways to increase the speed, accuracy, and applicability of chemical hazard and risk assessment approaches. A promising route is the integration of in vitro assays with biological pathway information. We examined how the adverse outcome pathway (AOP) framework can be used to develop pathway‐based quantitative models useful for regulatory chemical safety assessment. By using AOPs as initial conceptual models and the AOP knowledge base as a source of data on key event relationships, different methods can be applied to develop computational quantitative AOP models (qAOPs) relevant for decision making. A qAOP model may not necessarily have the same structure as the AOP it is based on. Useful AOP modeling methods range from statistical, Bayesian networks, regression, and ordinary differential equations to individual‐based models and should be chosen according to the questions being asked and the data available. We discuss the need for toxicokinetic models to provide linkages between exposure and qAOPs, to extrapolate from in vitro to in vivo, and to extrapolate across species. Finally, we identify best practices for modeling and model building and the necessity for transparent and comprehensive documentation to gain confidence in the use of qAOP models and ultimately their use in regulatory applications. Environ Toxicol Chem 2019;38:1850–1865. © 2019 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.

Highlights

The hazard and risk assessment of chemicals has relied heavily on animal testing
In the adverse outcome pathway (AOP) framework (Figure 1), the initiation of a molecular initiating event starts a cascade of key events causally linked by key event relationships (KERs) that lead to an adverse outcome (Ankley et al 2010)
Quantitative AOP models can provide a bridge from descriptive knowledge to the prediction of an adverse outcome in hazard and risk assessments

Summary

Introduction

The hazard and risk assessment of chemicals has relied heavily on animal testing. Frameworks that support the plausibility and causal understanding of how chemical exposures lead to toxicity/adverse outcomes include the mode of action framework (Sonich‐Mullin et al 2001; Meek et al 2003; US Environmental Protection Agency 2005; Boobis et al 2009; Meek et al 2013) and, more recently, the adverse outcome pathway (AOP) concept (Ankley et al 2010). The AOP framework has emerged as one potential way of integrating evidence from in vitro assays in the context of a pathway that leads to an adverse outcome. In the AOP framework (Figure 1), the initiation of a molecular initiating event starts a cascade of key events causally linked by key event relationships (KERs) that lead to an adverse outcome (Ankley et al 2010). The KERs represent the regulatory, mechanistic, structural, and/or functional relationship between 2 key events and are supported by empirical data that provide information on dose response and temporality (Meek et al 2014; Becker et al 2017)

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