Adverse outcome pathways – development and potential regulatory application

Introduction: Over the last two decades, chemical safety assessment and regulatory toxicology have progressed from empirical science based on direct observation of apical adverse outcomes in whole organisms to a predictive practice that infers outcomes and risks on the basis of accumulated understanding of toxicological mechanisms and modes of action. Objective: To provide general concepts on how Adverse Outcome Pathways (AOPs) are developed and examples related to skin sensitization, endocrine, disruption, and mitochondrial dysfunction. Method: Narrative review based on data of the scientific literature relevant to the theme addressed and on the experience of the authors. Results: An AOP framework provides a systematic approach to organize knowledge about mechanisms of toxicity that may inform analytical domains in regulatory decision-making. AOPs are open structures that may indicate not only data gaps in the understanding of a toxicity process, but also testing procedures that will generate the necessary knowledge to fill those gaps. Every AOP should be continuously refined through the collaborative efforts of the scientific community. Depending on the amount and detail of information that is successively inserted, AOP may progress from the stage of a putative AOP to the stages of qualitative and quantitative AOPs, which are more fit-for-purpose to support regulatory decision-making. Conclusions: Continuous collaboration between AOP developers within the scientific community and the regulatory corps toward the development of this mechanistic structure will support the advancement of toxicological sciences, regardless of its immediate application for regulatory purposes.

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When Are Adverse Outcome Pathways and Associated Assays “Fit for Purpose” for Regulatory Decision‐Making and Management of Chemicals?

Integrated Environmental Assessment and Management ◽

10.1002/ieam.4153 ◽

2019 ◽

Vol 15 (4) ◽

pp. 633-647 ◽

Cited By ~ 5

Author(s):

Katie Coady ◽

Patience Browne ◽

Michelle Embry ◽

Thomas Hill ◽

Eeva Leinala ◽

...

Keyword(s):

Decision Making ◽

Adverse Outcome ◽

Regulatory Decision ◽

Fit For Purpose ◽

Adverse Outcome Pathways ◽

Management Of Chemicals

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sAOP: linking chemical stressors to adverse outcomes pathway networks

Bioinformatics ◽

10.1093/bioinformatics/btz570 ◽

2019 ◽

Cited By ~ 3

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.

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AOP4EUpest: mapping of pesticides in adverse outcome pathways using a text mining tool

Bioinformatics ◽

10.1093/bioinformatics/btaa545 ◽

2020 ◽

Vol 36 (15) ◽

pp. 4379-4381 ◽

Cited By ~ 1

Author(s):

Florence Jornod ◽

Marylène Rugard ◽

Luc Tamisier ◽

Xavier Coumoul ◽

Helle R Andersen ◽

...

Keyword(s):

Adverse Outcome ◽

Experimental Studies ◽

Adverse Outcomes ◽

Vulnerable Groups ◽

Supplementary Information ◽

Human Populations ◽

Biological Organization ◽

Linear Representations ◽

Pubmed Database ◽

Adverse Outcome Pathways

Abstract Motivation Exposure to pesticides may lead to adverse health effects in human populations, in particular vulnerable groups. The main long-term health concerns are neurodevelopmental disorders, carcinogenicity as well as endocrine disruption possibly leading to reproductive and metabolic disorders. Adverse outcome pathways (AOP) consist in linear representations of mechanistic perturbations at different levels of the biological organization. Although AOPs are chemical-agnostic, they can provide a better understanding of the Mode of Action of pesticides and can support a rational identification of effect markers. Results With the increasing amount of scientific literature and the development of biological databases, investigation of putative links between pesticides, from various chemical groups and AOPs using the biological events present in the AOP-Wiki database is now feasible. To identify co-occurrence between a specific pesticide and a biological event in scientific abstracts from the PubMed database, we used an updated version of the artificial intelligence-based AOP-helpFinder tool. This allowed us to decipher multiple links between the studied substances and molecular initiating events, key events and adverse outcomes. These results were collected, structured and presented in a web application named AOP4EUpest that can support regulatory assessment of the prioritized pesticides and trigger new epidemiological and experimental studies. Availability and implementation http://www.biomedicale.parisdescartes.fr/aop4EUpest/home.php. Supplementary information Supplementary data are available at Bioinformatics online.

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Adverse Outcome Pathways--Organizing Toxicological Information to Improve Decision Making

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.115.228239 ◽

2015 ◽

Vol 356 (1) ◽

pp. 170-181 ◽

Cited By ~ 109

Author(s):

S. W. Edwards ◽

Y.-M. Tan ◽

D. L. Villeneuve ◽

M. E. Meek ◽

C. A. McQueen

Keyword(s):

Decision Making ◽

Adverse Outcome ◽

Adverse Outcome Pathways

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Highlight Report: Adverse outcome pathways: the need of research on mechanisms of toxicity

Archives of Toxicology ◽

10.1007/s00204-019-02596-2 ◽

2019 ◽

Vol 93 (11) ◽

pp. 3385-3386

Author(s):

Hermann M. Bolt

Keyword(s):

Adverse Outcome ◽

Mechanisms Of Toxicity ◽

Adverse Outcome Pathways

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Novel Methods and Approaches for Safety Evaluation of Nanoparticle Formulations: A Focus Towards In Vitro Models and Adverse Outcome Pathways

Frontiers in Pharmacology ◽

10.3389/fphar.2021.612659 ◽

2021 ◽

Vol 12 ◽

Author(s):

Mounika Gayathri Tirumala ◽

Pratibha Anchi ◽

Susmitha Raja ◽

Mahesh Rachamalla ◽

Chandraiah Godugu

Keyword(s):

Risk Assessment ◽

Adverse Outcome ◽

Safety Concern ◽

Single Cells ◽

High Surface ◽

Adverse Outcomes ◽

Novel Methods ◽

Adverse Outcome Pathways

Nanotoxicology is an emerging field employed in the assessment of unintentional hazardous effects produced by nanoparticles (NPs) impacting human health and the environment. The nanotoxicity affects the range between induction of cellular stress and cytotoxicity. The reasons so far reported for these toxicological effects are due to their variable sizes with high surface areas, shape, charge, and physicochemical properties, which upon interaction with the biological components may influence their functioning and result in adverse outcomes (AO). Thus, understanding the risk produced by these materials now is an important safety concern for the development of nanotechnology and nanomedicine. Since the time nanotoxicology has evolved, the methods employed have been majorly relied on in vitro cell-based evaluations, while these simple methods may not predict the complexity involved in preclinical and clinical conditions concerning pharmacokinetics, organ toxicity, and toxicities evidenced through multiple cellular levels. The safety profiles of nanoscale nanomaterials and nanoformulations in the delivery of drugs and therapeutic applications are of considerable concern. In addition, the safety assessment for new nanomedicine formulas lacks regulatory standards. Though the in vivo studies are greatly needed, the end parameters used for risk assessment are not predicting the possible toxic effects produced by various nanoformulations. On the other side, due to increased restrictions on animal usage and demand for the need for high-throughput assays, there is a need for developing and exploring novel methods to evaluate NPs safety concerns. The progress made in molecular biology and the availability of several modern techniques may offer novel and innovative methods to evaluate the toxicological behavior of different NPs by using single cells, cell population, and whole organisms. This review highlights the recent novel methods developed for the evaluation of the safety impacts of NPs and attempts to solve the problems that come with risk assessment. The relevance of investigating adverse outcome pathways (AOPs) in nanotoxicology has been stressed in particular.

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