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

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.

Gene co-regulation and co-expression in the aryl hydrocarbon receptor-mediated transcriptional regulatory network in the mouse liver

“…Specifically, statistical and visualization tools were used to establish a relationship between gene co-regulation by multiple TFs and gene co-expression, and link groups of co-regulated genes to distinct downstream functional outcomes. Such reconstructed networks can form the basis of a new generation of quantitative adverse outcome pathways (Conolly et al 2017;Perkins et al 2019). Our focus here is on the early stages of hepatic response to TCDD exposure-longer term exposure may lead to a different suite of adaptive responses at the cellular and tissue level.…”

The use of adverse outcome pathways in the safety evaluation of food additives

“…the adverse outcome). This would require the development and use of quantitative, not only qualitative, AOPs for systemic toxic endpoints, as described recently by Perkins et al (2019), Zgheib et al (2019), and Battistoni et al (2019). Moreover, points-of-departure derived from in vitro bioassays reflecting KEs in an AOP cannot directly be converted into health-based reference values.…”

Application of Biomarker Tools Using Bivalve Models Toward the Development of Adverse Outcome Pathways for Contaminants of Emerging Concern

“…Such linkages define causal relationships between events at different levels of biological organization, supported by documented empirical evidence, and contribute to the development of qualitative AOPs based on OECD guidelines (Organsiation for Economic Co-operation and Development 2013). Further development of quantitative linkages between key events helps in identifying response relationships that add precision to the performance of risk assessment and regulatory decision-making (Perkins et al 2019). Development of AOPs and their use at each phase must be guided by a research question and its relevance in predicting an adverse outcome.…”

“…include developing quantitative relationships between causal events in the AOP framework and evaluating the magnitude or probability of an AO. Application of quantitative AOP approaches and mathematical modeling that identifies dose-response and/or response-response relationships will contribute toward better hazard predictions (Perkins et al 2019). For ERA purposes, it is valuable to identify the chemical concentration required to trigger the molecular initiating event in an AOP.…”

“…Such identification of the effective internal dose is dependent on toxicokinetic differences. Linkages that examine relationships between external hazardous exposure concentrations and internal dose therefore enhance AOP applicability in risk characterization of chemical exposures (Perkins et al 2013(Perkins et al , 2019. Coupling quantitative AOP development with toxicokinetic models to consider chemical absorption and metabolism will allow us to characterize internal dose at the molecular initiating event.…”