Users' Handbook supplement to the Guidance Document for developing and assessing Adverse Outcome Pathways

doi:10.1787/5jlv1m9d1g32-en

Cited by 77 publications

(50 citation statements)

References 8 publications

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“…They should be supported by plausibility and evidence and, ideally, a quantitative understanding. The analytical construct of an AOP should include causally interconnected events that can generate deleterious health and/or eco-toxicological effects (OECD 2018).…”

Section: Use Of Adverse Outcome Pathways (Aops) To Structure Predictimentioning

confidence: 99%

Critical assessment and integration of separate lines of evidence for risk assessment of chemical mixtures

et al. 2019

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Humans are exposed to multiple chemicals on a daily basis instead of to just a single chemical, yet the majority of existing toxicity data comes from single-chemical exposure. Multiple factors must be considered such as the route, concentration, duration, and the timing of exposure when determining toxicity to the organism. The need for adequate model systems (in vivo, in vitro, in silico and mathematical) is paramount for better understanding of chemical mixture toxicity. Currently, shortcomings plague each model system as investigators struggle to find the appropriate balance of rigor, reproducibility and appropriateness in mixture toxicity studies. Significant questions exist when comparing single-to mixture-chemical toxicity concerning additivity, synergism, potentiation, or antagonism. Dose/concentration relevance is a major consideration and should be subthreshold for better accuracy in toxicity assessment. Previous work was limited by the technology and methodology of the time, but recent advances have resulted in significant progress in the study of mixture toxicology. Novel technologies have added insight to data obtained from in vivo studies for predictive toxicity testing. These include new in vitro models: omics-related tools, organs-on-a-chip and 3D cell culture, and in silico methods. Taken together, all these modern methodologies improve the understanding of the multiple toxicity pathways associated with adverse outcomes (e.g., adverse outcome pathways), thus allowing investigators to better predict risks linked to exposure to chemical mixtures. As technology and knowledge advance, our ability to harness and integrate separate streams of evidence regarding outcomes associated with chemical mixture exposure improves. As many national and international organizations are currently stressing, studies on chemical mixture toxicity are of primary importance.

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Section: Use Of Adverse Outcome Pathways (Aops) To Structure Predictimentioning

confidence: 99%

Critical assessment and integration of separate lines of evidence for risk assessment of chemical mixtures

et al. 2019

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“…An Adverse Outcome Pathway (AOP) wiki was developed based on Villeneuve et al, 2014 and the OECD guidelines (OECD, 2012a, 2012b, 2016, 2018). An AOP has a single starting point; the molecular initiation event and only one endpoint or adverse outcome.…”

Section: Approachmentioning

confidence: 99%

“…An AOP has a single starting point; the molecular initiation event and only one endpoint or adverse outcome. All AOPs follow the same format: a single molecular initiation event (MIE), progress through several key events and culminate in a single adverse outcome either in an individual or a population (OECD, 2012a, 2012b, 2016, 2018). For VOC induced irritation, the binding to sensory receptors was determined to be the molecular initiation event (MIE), and the adverse outcome (AO) is respiratory irritation.…”

Section: Approachmentioning

confidence: 99%

“…Evaluation of the AOP was based on the Bradford Hill criteria as described in the OECD AOP handbook (OECD, 2012, 2012a, 2016,2018) with the additional guidance provided in Becker et al (2015) and Vinken et al (2013). A box and linear flow diagram presented above was constructed to allow an easy determination of the sequence of biological events at the different levels of biological organization.…”

Section: Sensory Irritation Adverse Outcome Pathwaymentioning

confidence: 99%

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Activation of TRPA1 by volatile organic chemicals leading to sensory irritation

Martinez

Eling

2019

ALTEX

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Many volatile organic chemicals (VOCs) have not been tested for sensory pulmonary irritation. Development of in vitro non-animal sensory irritation assay suitable for large number of chemicals is needed to replace the mouse assay. An adverse outcome pathway (AOP) was developed to provide a clear description of the biochemical and cellular processes leading to toxicological effects or an adverse outcome. The AOP for chemical sensory pulmonary irritation was developed according to the Organization for Economic Co-operation and Development guidance including the Bradford Hill criteria for a weight of evidence to determine the confidence of the AOP. The proposed AOP is based on an in-depth review of the relevant scientific literature to identify the initial molecular event for respiratory irritation. The activation of TRPA1 receptor (transient receptor potential cation channel, subfamily A, member 1) is identified as the molecular initial event (MIE) leading to sensory irritation. A direct measure of TRPA1 activation in vitro should identify chemical sensory irritants and provide an estimate of potency. Fibroblasts expressing TRPA1 are used to determine TRPA1 activation and irritant potency. Based on preliminary analysis we report a apparent linear relationship between the in vivo RD50 and the in vitro pEC50 values to support this hypothesis. We propose that this in vitro assay after additional analysis and validation could serve as a suitable candidate to replace the mouse sensory irritation assay.

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“…Adverse outcome pathway (AOP) framework describing components and structure of a linear pathway. Adapted from the Organisation for Economic Co-operation and Development's AOP handbook[35].…”

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confidence: 99%

Advancing the adverse outcome pathway framework—An international horizon scanning approach

LaLone

Ankley

Belanger

et al. 2017

Enviro Toxic and Chemistry

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Abstract-Our ability to conduct whole-organism toxicity tests to understand chemical safety has been outpaced by the synthesis of new chemicals for a wide variety of commercial applications. As a result, scientists and risk assessors are turning to mechanistically based studies to increase efficiencies in chemical risk assessment and making greater use of in vitro and in silico methods to evaluate potential environmental and human health hazards. In this context, the adverse outcome pathway (AOP) framework has gained traction in regulatory science because it offers an efficient and effective means for capturing available knowledge describing the linkage between mechanistic data and the apical toxicity end points required for regulatory assessments. A number of international activities have focused on AOP development and various applications to regulatory decision-making. These initiatives have prompted dialogue between research scientists and regulatory communities to consider how best to use the AOP framework. Although expert-facilitated discussions and AOP development have been critical in moving the science of AOPs forward, it was recognized that a survey of the broader scientific and regulatory communities would aid in identifying current limitations while guiding future initiatives for the AOP framework. To that end, a global horizon scanning exercise was conducted to solicit questions concerning the challenges or limitations that must be addressed to realize the full potential of the AOP framework in research and regulatory decision-making. The questions received fell into several broad topical areas: AOP networks, quantitative AOPs, collaboration on and communication of AOP knowledge, AOP discovery and development, chemical and crossspecies extrapolation, exposure/toxicokinetics considerations, and AOP applications. Expert ranking was then used to prioritize questions for each category, where 4 broad themes emerged that could help inform and guide future AOP research and regulatory initiatives. In addition, frequently asked questions were identified and addressed by experts in the field. Answers to frequently asked questions will aid in addressing common misperceptions and will allow for clarification of AOP topics. The need for this type of clarification was highlighted with surprising frequency by our question submitters, indicating that improvements are needed in communicating the AOP framework among the scientific and regulatory communities. Overall, horizon scanning engaged the global scientific community to help identify key questions surrounding the AOP framework and guide the direction of future initiatives.

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