The future trajectory of adverse outcome pathways: a commentary

Sewell, Fiona; Gellatly, Nichola; M, Beaumont; Burden, Natalie; Currie, Richard A.; Haan, Lolke de; Hutchinson, Thomas H.; Jacobs, Miriam N.; Mahony, Catherine; Malcomber, Ian; Mehta, Jyotigna; Whale, Graham; Kimber, Ian

doi:10.1007/s00204-018-2183-2

Cited by 26 publications

(25 citation statements)

References 23 publications

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“…The perturbation of the NR signaling pathway due to the action of agonists or antagonists of chemical compounds is associated with various adverse health outcomes [19,21]. Although chemical hazard assessments have traditionally relied upon toxicity data from animal bioassays and epidemiological studies, there are some drawbacks to this testing method, such as high cost, lengthy test durations, and ethical concerns [5,[22][23][24][25][26][27]. To resolve these issues, the in vitro high-throughput screening (HTS) assay has been developed as an alternative approach and improved by the Toxicity Forecaster (ToxCast TM ) program run by the U.S. Environmental Protection Agency (EPA) [5,[28][29][30] and The Toxicology in the 21st Century program (Tox21), an interagency federal collaboration launched by the consortium of the EPA, the U.S. Food and Drug Administration (FDA), the National Institutes of Health (NIH), and the National Toxicology Program (NTP) [5,31].…”

Section: Introductionmentioning

confidence: 99%

Molecular Image-Based Prediction Models of Nuclear Receptor Agonists and Antagonists Using the DeepSnap-Deep Learning Approach with the Tox21 10K Library

Matsuzaka

Uesawa

2020

Molecules

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The interaction of nuclear receptors (NRs) with chemical compounds can cause dysregulation of endocrine signaling pathways, leading to adverse health outcomes due to the disruption of natural hormones. Thus, identifying possible ligands of NRs is a crucial task for understanding the adverse outcome pathway (AOP) for human toxicity as well as the development of novel drugs. However, the experimental assessment of novel ligands remains expensive and time-consuming. Therefore, an in silico approach with a wide range of applications instead of experimental examination is highly desirable. The recently developed novel molecular image-based deep learning (DL) method, DeepSnap-DL, can produce multiple snapshots from three-dimensional (3D) chemical structures and has achieved high performance in the prediction of chemicals for toxicological evaluation. In this study, we used DeepSnap-DL to construct prediction models of 35 agonist and antagonist allosteric modulators of NRs for chemicals derived from the Tox21 10K library. We demonstrate the high performance of DeepSnap-DL in constructing prediction models. These findings may aid in interpreting the key molecular events of toxicity and support the development of new fields of machine learning to identify environmental chemicals with the potential to interact with NR signaling pathways.

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Section: Introductionmentioning

confidence: 99%

Molecular Image-Based Prediction Models of Nuclear Receptor Agonists and Antagonists Using the DeepSnap-Deep Learning Approach with the Tox21 10K Library

Matsuzaka

Uesawa

2020

Molecules

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“…It is important to refine and strengthen AOPs under development for retinoid signalling disturbance [13,303]. Besides only linking the sequential "event-train", recent efforts to define tipping points for transition between key events could make AOPs become quantitative, thus more useful for computational predictive approaches [21,303,304]. An analogous approach to AOPs has also been taken in exposure science with aggregate exposure pathways (AEPs).…”

Section: Discussion -Implications For Risk Assessmentmentioning

confidence: 99%

Highlighting the gaps in hazard and risk assessment of unregulated Endocrine Active Substances in surface waters: retinoids as a European case study

et al. 2021

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Regulatory hazard and risk assessment of endocrine-active substances currently specifies four modes of action: interference with sex hormone (oestrogen, androgen) pathways, steroidogenesis, and thyroid hormone signalling. This does not encompass the full complexity of the endocrine system and its extended interfaces with environmental pollutants that can potentially disrupt the carefully maintained balance. Here we take the retinoid signalling pathway as a European case study for both, under- and unregulated endocrine pathways and outline the different levels of interference, discuss their adversity, and indicate crosstalk to other signalling pathways. Retinoid compounds already exist in drinking water sources, occur naturally in cyanobacterial blooms and/or enter surface waters via wastewater discharge, where they pose a potential hazard to the environment and human health - a situation that can be expected to worsen due to water shortages induced by climate-change and population growth. We briefly review relevant aspects of current endocrine disruptor (ED) testing for regulatory purposes and then expand upon the needs for inclusion of disruption of retinoid signalling in (ED) regulatory safety assessment contributing to adverse health outcomes that include cognitive function and neurological disease. An overview of developmental effects of retinoid signalling disruption across species highlights critical processes and potential crosstalk with other signalling pathways. A focused weight of evidence-based evaluation of the biologically plausible associations between neurological disorders and altered retinoid signalling highlights the evidence gaps. We show that monitoring only a limited number of anthropogenic priority chemicals in water is insufficient to address the environmental risks of retinoid signalling disruption. To comprehensively assess impacts on the endpoints, processes, and pathways of the endocrine system that are most vulnerable to chemical interference we need further investigation of the true mixture composition in environmental matrices. On a weight of evidence-basis this information can then be integrated into a reliable, inclusive, quantitative approach that ultimately accommodates all the critical pathways. By focusing on the retinoid signalling pathway, we intend to improve the scope and relevance of an integrated approach for the risk assessment of endocrine disruptors.

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“…• Single linear AOPs should not be considered-rather "networks" need be built that link shared/overlapping key events between different toxicity pathways. [23,24] • Suitable and clear guidance on applying WoE to decision-making will mean in theory firmly fixed or predefined test batteries will no longer be required and there will be greater flexibility in terms of the methods and data that can be utilized. WoE approaches can also include data from the open or "grey" literature and guidance is needed to guide quality assessments and interpretation of such data.…”

Section: Accelerating Validation Processes and Adoption In Practicementioning

confidence: 99%

Opportunities and Challenges for Integrating New In Vitro Methodologies in Hazard Testing and Risk Assessment

Burden

Clift

Jenkins

et al. 2021

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Nanomaterials are defined as materials with at least one dimension of 100 nm or less. Their small size confers unique properties that may alter the toxicity profile when compared to larger forms of the same material, requiring additional considerations for safety assessment. There has been a rise in the development of nanomaterials for many applications, and although traditional approaches for toxicity testing may address some of the new toxicity concerns, many may not be directly applicable to nanomaterials and new tools or approaches may need to be developed. Since nanomaterials can exist in many different forms, each of which may cause different adverse biological effects, reliance on traditional in vivo models for safety assessment will simply not be feasible or sustainable, given the volume of materials that may need to be tested. It is essential to consider and develop new in vitro methods that can be applied for hazard identification and risk assessment. Many challenges are associated with using alternative approaches to ensure they are as robust and reliable as traditional in vivo approaches, but by overcoming these issues and adopting new testing strategies there are opportunities to improve safety assessments and reduce the reliance on animal‐based toxicity testing strategies.

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The future trajectory of adverse outcome pathways: a commentary

Cited by 26 publications

References 23 publications

Molecular Image-Based Prediction Models of Nuclear Receptor Agonists and Antagonists Using the DeepSnap-Deep Learning Approach with the Tox21 10K Library

Molecular Image-Based Prediction Models of Nuclear Receptor Agonists and Antagonists Using the DeepSnap-Deep Learning Approach with the Tox21 10K Library

Highlighting the gaps in hazard and risk assessment of unregulated Endocrine Active Substances in surface waters: retinoids as a European case study

Opportunities and Challenges for Integrating New In Vitro Methodologies in Hazard Testing and Risk Assessment

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