Adverse Outcome Pathways: Moving from a Scientific Concept to an Internationally Accepted Framework

Hecker, Markus; LaLone, Carlie A.

doi:10.1002/etc.4385

Cited by 25 publications

(14 citation statements)

References 12 publications

(58 reference statements)

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“…The development and quantification of AOP networks are emergent topics in predictive toxicology and safety assessment. The Pellston Workshop (Hecker and LaLone 2019) addressed key challenges, approaches and solutions to progress the AOP framework, emphasising the need for more examples of where and how AOPs can fit in a regulatory context. Currently, three approaches have been proposed for modelling qAOPs: semiquantitative/quantitative weight of evidence (WoE) of qAOPs, probabilistic qAOP and qAOP networks, and mechanistic qAOPs (Perkins et al 2019).…”

Section: Types Of Modelling Approaches For Qaopsmentioning

confidence: 99%

Development and analysis of an adverse outcome pathway network for human neurotoxicity

et al. 2019

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An adverse outcome pathway (AOP) network is an attempt to represent the complexity of systems toxicology. This study illustrates how an AOP network can be derived and analysed in terms of its topological features to guide research and support chemical risk assessment. A four-step workflow describing general design principles and applied design principles was established and implemented. An AOP network linking nine linear AOPs was mapped and made available in AOPXplorer. The resultant AOP network was modelled and analysed in terms of its topological features, including level of degree, eccentricity and betweenness centrality. Several well-connected KEs were identified, and cell injury/death was established as the most hyperlinked KE across the network. The derived network expands the utility of linear AOPs to better understand signalling pathways involved in developmental and adult/ageing neurotoxicity. The results provide a solid basis to guide the development of in vitro test method batteries, as well as further quantitative modelling of key events (KEs) and key event relationships (KERs) in the AOP network, with an eventual aim to support hazard characterisation and chemical risk assessment.

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Section: Types Of Modelling Approaches For Qaopsmentioning

confidence: 99%

Development and analysis of an adverse outcome pathway network for human neurotoxicity

et al. 2019

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“…While providing a greater mechanistic understanding of contaminant toxicity, it is not clear how the approach informs regulatory decision making in the context of threshold levels or risk‐based discharge limits for permitting purposes, remediation, and target clean‐up goals, and design of risk‐based remedial strategies. Applying AOPs to regulatory decisions remains challenging (Coady et al., 2019; Hecker & LaLone, 2019), and there are no examples of using AOPs to satisfy the regulatory requirements of risk assessment such as remediation goals or cleanup levels.…”

Section: Novel Risk Assessment Methods and Toolsmentioning

confidence: 99%

Evolving Science and Practice of Risk Assessment

Stackelberg

Williams²

2020

Risk Analysis

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Managing public health risks from environmental contaminants has historically relied on a risk assessment process defined by the regulatory context in which these risks are assessed. Risk assessment guidance follows a straightforward, chemical‐by‐chemical approach to inform regulatory decisions around the question “what is the risk‐based concentration protective of human and ecological health outcomes?” Here we briefly summarize regulatory risk assessment in the context of innovative risk assessment approaches based on an evolving understanding of the underlying scientific disciplines that support risk analysis more broadly. We discuss scientific versus regulatory tensions in the application of these approaches for future risk assessments, and challenges in translating our improved understanding of the underlying scientific complexity to the regulatory landscape to better inform decision making that extends beyond conventional regulatory mandates.

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“…Unless dedicated funds and sustainable human resources are available, this process can take more than a couple of years and in most cases, lack of sustainable resources force authors to abandon the efforts. The AOP knowledgebase lists more than 200 AOPs that are at different stages of development and less than 10 AOPs are fully assembled and endorsed [162]. Once endorsed, readiness of an AOP for a specific purpose (e.g., informing research gaps, regulatory decisions) has to be verified and will depend on the type of data used for building AOP modules (KEs, KERs) [8].…”

Section: Challenges To Implementing the Aop Framework For Nanomateriamentioning

confidence: 99%

Adverse outcome pathways as a tool for the design of testing strategies to support the safety assessment of emerging advanced materials at the nanoscale

et al. 2020

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Toxicity testing and regulation of advanced materials at the nanoscale, i.e. nanosafety, is challenged by the growing number of nanomaterials and their property variants requiring assessment for potential human health impacts. The existing animal-reliant toxicity testing tools are onerous in terms of time and resources and are less and less in line with the international effort to reduce animal experiments. Thus, there is a need for faster, cheaper, sensitive and effective animal alternatives that are supported by mechanistic evidence. More importantly, there is an urgency for developing alternative testing strategies that help justify the strategic prioritization of testing or targeting the most apparent adverse outcomes, selection of specific endpoints and assays and identifying nanomaterials of high concern. The Adverse Outcome Pathway (AOP) framework is a systematic process that uses the available mechanistic information concerning a toxicological response and describes causal or mechanistic linkages between a molecular initiating event, a series of intermediate key events and the adverse outcome. The AOP framework provides pragmatic insights to promote the development of alternative testing strategies. This review will detail a brief overview of the AOP framework and its application to nanotoxicology, tools for developing AOPs and the role of toxicogenomics, and summarize various AOPs of relevance to inhalation toxicity of nanomaterials that are currently under various stages of development. The review also presents a network of AOPs derived from connecting all AOPs, which shows that several adverse outcomes induced by nanomaterials originate from a molecular initiating event that describes the interaction of nanomaterials with lung cells and involve similar intermediate key events. Finally, using the example of an established AOP for lung fibrosis, the review will discuss various in vitro tests available for assessing lung fibrosis and how the information can be used to support a tiered testing strategy for lung fibrosis. The AOPs and AOP network enable deeper understanding of mechanisms involved in inhalation toxicity of nanomaterials and provide a strategy for the development of alternative test

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Adverse Outcome Pathways: Moving from a Scientific Concept to an Internationally Accepted Framework

Abstract: Focus articles are part of a regular series intended to sharpen understanding of current and emerging topics of interest to the scientific community.

Cited by 25 publications

References 12 publications

Development and analysis of an adverse outcome pathway network for human neurotoxicity

Development and analysis of an adverse outcome pathway network for human neurotoxicity

Evolving Science and Practice of Risk Assessment

Adverse outcome pathways as a tool for the design of testing strategies to support the safety assessment of emerging advanced materials at the nanoscale

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