Adverse outcome pathway driven development of human cell-based assays sufficient for safety assessment of estrogenic chemicals

2016 ◽  
Vol 258 ◽  
pp. S142-S143
Author(s):  
R.A. Clewell ◽  
M.M. Miller ◽  
M.E. Andersen
Keyword(s):  
Human Cell ◽  
Safety Assessment ◽  
Adverse Outcome ◽  
Adverse Outcome Pathway ◽  
Estrogenic Chemicals

Adverse Outcome Pathway-based Screening Strategies for an Animal-free Safety Assessment of Chemicals

2013 ◽  
Vol 41 (6) ◽  
pp. 461-471 ◽  
Author(s):  
Brigitte Landesmann ◽  
Milena Mennecozzi ◽  
Elisabet Berggren ◽  
Maurice Whelan
Keyword(s):  
Safety Assessment ◽  
Adverse Outcome ◽  
Adverse Outcome Pathway ◽  
Screening Strategies

scholarly journals A Pragmatic Approach to Adverse Outcome Pathway Development and Evaluation

2021 ◽  
Author(s):  
Terje Svingen ◽  
Daniel L Villeneuve ◽  
Dries Knapen ◽  
Eleftheria Maria Panagiotou ◽  
Monica Kam Draskau ◽  
...  
Keyword(s):  
Systematic Review ◽  
Safety Assessment ◽  
Adverse Outcome ◽  
Adverse Outcome Pathway ◽  
Pragmatic Approach ◽  
Chemical Safety ◽  
Regulatory Toxicology ◽  
Adverse Health Outcomes ◽  
Wide Acceptance ◽  
Modular Units

Abstract The adverse outcome pathway (AOP) framework provides a practical means for organizing scientific knowledge that can be used to infer cause-effect relationships between stressor events and toxicity outcomes in intact organisms. It has reached wide acceptance as a tool to aid chemical safety assessment and regulatory toxicology by supporting a systematic way of predicting adverse health outcomes based on accumulated mechanistic knowledge. A major challenge for broader application of the AOP concept in regulatory toxicology, however, has been developing robust AOPs to a level where they are peer reviewed and accepted. This is because the amount of work required to substantiate the modular units of a complete AOP is considerable, to the point where it can take years from start to finish. To help alleviate this bottleneck, we propose a more pragmatic approach to AOP development whereby the focus becomes on smaller blocks. First, we argue that the key event relationship (KER) should be formally recognized as the core building block of knowledge assembly within the AOP knowledge base (AOP-KB), albeit framing them within full AOPs to ensure regulatory utility. Second, we argue that KERs should be developed using systematic review approaches, but only in cases where the underlying concept does not build on what is considered canonical knowledge. In cases where knowledge is considered canonical, rigorous systematic review approaches should not be required. It is our hope that these approaches will contribute to increasing the pace at which the AOP-KB is populated with AOPs with utility for chemical safety assessors and regulators.

scholarly journals Challenge for Adverse Outcome Pathway (AOP)-based Chemical Safety Assessment

2020 ◽  
Vol 140 (4) ◽  
pp. 481-484
Author(s):  
Takashi Yamada ◽  
Takao Ashikaga ◽  
Hajime Kojima ◽  
Akihiko Hirose
Keyword(s):  
Safety Assessment ◽  
Adverse Outcome ◽  
Adverse Outcome Pathway ◽  
Chemical Safety

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.

Safety assessment of selected cyclodextrins — effect on ciliary activity using a human cell suspension culture model exhibiting in vitro ciliogenesis

2000 ◽  
Vol 193 (2) ◽  
pp. 219-226 ◽  
Author(s):  
Remigius Uchenna Agu ◽  
Mark Jorissen ◽  
Tom Willems ◽  
Guy Van den Mooter ◽  
Renaat Kinget ◽  
...  
Keyword(s):  
Suspension Culture ◽  
Cell Suspension ◽  
Human Cell ◽  
Cell Suspension Culture ◽  
Safety Assessment ◽  
Ciliary Activity ◽  
Culture Model

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
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