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Adverse outcome pathway networks II: Network analytics.

ABSTRACT: Toxicological responses to stressors are more complex than the simple one-biological-perturbation to one-adverse-outcome model portrayed by individual adverse outcome pathways (AOPs). Consequently, the AOP framework was designed to facilitate de facto development of AOP networks that can aid in the understanding and prediction of pleiotropic and interactive effects more common to environmentally realistic, complex exposure scenarios. The present study introduces nascent concepts related to the qualitative analysis of AOP networks. First, graph theory-based approaches for identifying important topological features are illustrated using 2 example AOP networks derived from existing AOP descriptions. Second, considerations for identifying the most significant path(s) through an AOP network from either a biological or risk assessment perspective are described. Finally, approaches for identifying interactions among AOPs that may result in additive, synergistic, or antagonistic responses (or previously undefined emergent patterns of response) are introduced. Along with a companion article (part I), these concepts set the stage for the development of tools and case studies that will facilitate more rigorous analysis of AOP networks, and the utility of AOP network-based predictions, for use in research and regulatory decision-making. The present study addresses one of the major themes identified through a Society of Environmental Toxicology and Chemistry Horizon Scanning effort focused on advancing the AOP framework. Environ Toxicol Chem 2018;37:1734-1748. © 2018 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.

SUBMITTER: Villeneuve DL

PROVIDER: S-EPMC6010347 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Adverse outcome pathway networks II: Network analytics.

Villeneuve Daniel L DL Angrish Michelle M MM Fortin Marie C MC Katsiadaki Ioanna I Leonard Marc M Margiotta-Casaluci Luigi L Munn Sharon S O'Brien Jason M JM Pollesch Nathan L NL Smith L Cody LC Zhang Xiaowei X Knapen Dries D

Environmental toxicology and chemistry 20180507 6

Toxicological responses to stressors are more complex than the simple one-biological-perturbation to one-adverse-outcome model portrayed by individual adverse outcome pathways (AOPs). Consequently, the AOP framework was designed to facilitate de facto development of AOP networks that can aid in the understanding and prediction of pleiotropic and interactive effects more common to environmentally realistic, complex exposure scenarios. The present study introduces nascent concepts related to the q ...[more]

PMID: 29492998

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Project description:The adverse outcome pathway (AOP) framework has gained international recognition as a systematic approach linking mechanistic processes to toxicity endpoints. Nevertheless, successful implementation into risk assessments is still limited by the lack of quantitative AOP models (qAOPs) and assessment of uncertainties. The few published qAOP models so far are typically based on data-demanding systems biology models. Here, we propose a less data-demanding approach for quantification of AOPs and AOP networks, based on regression modeling and Bayesian networks (BNs). We demonstrate this approach with the proposed AOP #245, "Uncoupling of photophosphorylation leading to reduced ATP production associated growth inhibition," using a small experimental data set from exposure of Lemna minor to the pesticide 3,5-dichlorophenol. The AOP-BN reflects the network structure of AOP #245 containing 2 molecular initiating events (MIEs), 3 key events (KEs), and 1 adverse outcome (AO). First, for each dose-response and response-response (KE) relationship, we quantify the causal relationship by Bayesian regression modeling. The regression models correspond to dose-response functions commonly applied in ecotoxicology. Secondly, we apply the fitted regression models with associated uncertainty to simulate 10 000 response values along the predictor gradient. Thirdly, we use the simulated values to parameterize the conditional probability tables of the BN model. The quantified AOP-BN model can be run in several directions: 1) prognostic inference, run forward from the stressor node to predict the AO level; 2) diagnostic inference, run backward from the AO node; and 3) omnidirectionally, run from the intermediate MIEs and/or KEs. Internal validation shows that the AOP-BN can obtain a high accuracy rate, when run is from intermediate nodes and when a low resolution is acceptable for the AO. Although the performance of this AOP-BN is limited by the small data set, our study demonstrates a proof-of-concept: the combined use of Bayesian regression modeling and Bayesian network modeling for quantifying AOPs. Integr Environ Assess Manag 2021;17:147-164. © 2020 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

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Adverse outcome pathway networks II: Network analytics.

Publications

Adverse outcome pathway networks II: Network analytics.

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