Tiered Approaches to Incorporate the Adverse Outcome Pathway Framework into Chemical-Specific Risk-Based Decision Making

2018 ◽  
pp. 235-261 ◽  
Author(s):  
Jeremy Leonard ◽  
Shannon Bell ◽  
Noffisat Oki ◽  
Mark Nelms ◽  
Yu-Mei Tan ◽  
...  
Keyword(s):  
Decision Making ◽  
Adverse Outcome ◽  
Adverse Outcome Pathway ◽  
Specific Risk

The Adverse Outcome Pathway Concept: A Basis for Developing Regulatory Decision-making Tools

2016 ◽  
Vol 44 (5) ◽  
pp. 417-429 ◽  
Author(s):  
Nathalie Delrue ◽  
Magdalini Sachana ◽  
Yuki Sakuratani ◽  
Anne Gourmelon ◽  
Eeva Leinala ◽  
...  
Keyword(s):  
Decision Making ◽  
Adverse Outcome ◽  
Adverse Outcome Pathway ◽  
Regulatory Decision

scholarly journals sAOP: linking chemical stressors to adverse outcomes pathway networks

2019 ◽  
Author(s):  
Alejandro Aguayo-Orozco ◽  
Karine Audouze ◽  
Troels Siggaard ◽  
Robert Barouki ◽  
Søren Brunak ◽  
...  
Keyword(s):  
Decision Making ◽  
Human Health ◽  
Adverse Outcome ◽  
Adverse Outcomes ◽  
Supplementary Information ◽  
Adverse Outcome Pathway ◽  
Supplementary Data ◽  
Biological Organization ◽  
Regulatory Decision ◽  
Pathway Networks

Abstract Motivation Adverse outcome pathway (AOP) is a toxicological concept proposed to provide a mechanistic representation of biological perturbation over different layers of biological organization. Although AOPs are by definition chemical-agnostic, many chemical stressors can putatively interfere with one or several AOPs and such information would be relevant for regulatory decision-making. Results With the recent development of AOPs networks aiming to facilitate the identification of interactions among AOPs, we developed a stressor-AOP network (sAOP). Using the ‘cytotoxitiy burst’ (CTB) approach, we mapped bioactive compounds from the ToxCast data to a list of AOPs reported in AOP-Wiki database. With this analysis, a variety of relevant connections between chemicals and AOP components can be identified suggesting multiple effects not observed in the simplified ‘one-biological perturbation to one-adverse outcome’ model. The results may assist in the prioritization of chemicals to assess risk-based evaluations in the context of human health. Availability and implementation sAOP is available at http://saop.cpr.ku.dk Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Combined In Vitro and In Vivo Approaches to Propose a Putative Adverse Outcome Pathway for Acute Lung Inflammation Induced by Nanoparticles: A Study on Carbon Dots

Nanomaterials ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 180
Author(s):  
Maud Weiss ◽  
Jiahui Fan ◽  
Mickaël Claudel ◽  
Luc Lebeau ◽  
Françoise Pons ◽  
...  
Keyword(s):  
Carbon Dots ◽  
Lung Inflammation ◽  
Adverse Outcome ◽  
Cellular Responses ◽  
Target Cells ◽  
Inflammasome Activation ◽  
Adverse Outcome Pathway ◽  
Acute Lung Inflammation

With the growth of nanotechnologies, concerns raised regarding the potential adverse effects of nanoparticles (NPs), especially on the respiratory tract. Adverse outcome pathways (AOP) have become recently the subject of intensive studies in order to get a better understanding of the mechanisms of NP toxicity, and hence hopefully predict the health risks associated with NP exposure. Herein, we propose a putative AOP for the lung toxicity of NPs using emerging nanomaterials called carbon dots (CDs), and in vivo and in vitro experimental approaches. We first investigated the effect of a single administration of CDs on mouse airways. We showed that CDs induce an acute lung inflammation and identified airway macrophages as target cells of CDs. Then, we studied the cellular responses induced by CDs in an in vitro model of macrophages. We observed that CDs are internalized by these cells (molecular initial event) and induce a series of key events, including loss of lysosomal integrity and mitochondrial disruption (organelle responses), as well as oxidative stress, inflammasome activation, inflammatory cytokine upregulation and macrophage death (cellular responses). All these effects triggering lung inflammation as tissular response may lead to acute lung injury.

scholarly journals Internal exposure dynamics drive the Adverse Outcome Pathways of synthetic glucocorticoids in fish

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Luigi Margiotta-Casaluci ◽  
Stewart F. Owen ◽  
Belinda Huerta ◽  
Sara Rodríguez-Mozaz ◽  
Subramanian Kugathas ◽  
...  
Keyword(s):  
Predictive Power ◽  
Adverse Outcome ◽  
Plasma Concentrations ◽  
Internal Exposure ◽  
Adverse Outcome Pathway ◽  
Conceptual Tool ◽  
Fish Model ◽  
Species Specific

Abstract The Adverse Outcome Pathway (AOP) framework represents a valuable conceptual tool to systematically integrate existing toxicological knowledge from a mechanistic perspective to facilitate predictions of chemical-induced effects across species. However, its application for decision-making requires the transition from qualitative to quantitative AOP (qAOP). Here we used a fish model and the synthetic glucocorticoid beclomethasone dipropionate (BDP) to investigate the role of chemical-specific properties, pharmacokinetics, and internal exposure dynamics in the development of qAOPs. We generated a qAOP network based on drug plasma concentrations and focused on immunodepression, skin androgenisation, disruption of gluconeogenesis and reproductive performance. We showed that internal exposure dynamics and chemical-specific properties influence the development of qAOPs and their predictive power. Comparing the effects of two different glucocorticoids, we highlight how relatively similar in vitro hazard-based indicators can lead to different in vivo risk. This discrepancy can be predicted by their different uptake potential, pharmacokinetic (PK) and pharmacodynamic (PD) profiles. We recommend that the development phase of qAOPs should include the application of species-specific uptake and physiologically-based PK/PD models. This integration will significantly enhance the predictive power, enabling a more accurate assessment of the risk and the reliable transferability of qAOPs across chemicals.

scholarly journals Molecular Modelling Study of the PPARγ Receptor in Relation to the Mode of Action/Adverse Outcome Pathway Framework for Liver Steatosis

2014 ◽  
Vol 15 (5) ◽  
pp. 7651-7666 ◽  
Author(s):  
Ivanka Tsakovska ◽  
Merilin Al Sharif ◽  
Petko Alov ◽  
Antonia Diukendjieva ◽  
Elena Fioravanzo ◽  
...  
Keyword(s):  
Molecular Modelling ◽  
Mode Of Action ◽  
Adverse Outcome ◽  
Liver Steatosis ◽  
Adverse Outcome Pathway ◽  
Modelling Study

Anchoring molecular mechanisms to the adverse outcome pathway for skin sensitization: Analysis of existing data

2014 ◽  
Vol 44 (7) ◽  
pp. 590-599 ◽  
Author(s):  
Jochem W. van der Veen ◽  
Lya G. Soeteman-Hernández ◽  
Janine Ezendam ◽  
Rob Stierum ◽  
Frieke C. Kuper ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Adverse Outcome ◽  
Adverse Outcome Pathway ◽  
Skin Sensitization ◽  
Existing Data
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