From Qualitative to Quantitative AOP: A Case Study of Neurodegeneration

Sinitsyn, Dennis; Garcia-Reyero, Natàlia; Watanabe, Karen H.

doi:10.3389/ftox.2022.838729

Title: From Qualitative to Quantitative AOP: A Case Study of Neurodegeneration

Abstract

Adverse outcome pathways (AOPs) include a sequence of events that connect a molecular-level initiating event with an adverse outcome at the cellular level for human health endpoints, or at the population level for ecological endpoints. When there is enough quantitative understanding of the relationships between key events in an AOP, a mathematical model may be developed to connect key events in a quantitative AOP (qAOP). Ideally, a qAOP will reduce the time and resources spent for chemical toxicity testing and risk assessment and enable the extrapolation of data collected at the molecular-level by in vitro assays, for example, to predict whether an adverse outcome may occur. Here, we review AOPs in the AOPWiki, an AOP repository, to determine best practices that would facilitate conversion from AOP to qAOP. Then, focusing on a particular case study, acetylcholinesterase inhibition leading to neurodegeneration, we describe specific methods and challenges. Examples of challenges include the availability and collection of quantitative data amenable to model development, the lack of studies that measure multiple key events, and model accessibility or transferability across platforms. We conclude with recommendations for improving key event and key event relationship descriptions in the AOPWiki that facilitate the transition of qualitative AOPsmore » to qAOPs.« less

Authors:: Sinitsyn, Dennis; Garcia-Reyero, Natàlia; Watanabe, Karen H.

Publication Date:: Wed Mar 30 00:00:00 EDT 2022

Sponsoring Org.:: USDOE

OSTI Identifier:: 1860282

Resource Type:: Published Article

Journal Name:: Frontiers in Toxicology

Additional Journal Information:: Journal Name: Frontiers in Toxicology Journal Volume: 4; Journal ID: ISSN 2673-3080

Publisher:: Frontiers Media SA

Country of Publication:: Switzerland

Language:: English

Citation Formats


                    Sinitsyn, Dennis, Garcia-Reyero, Natàlia, and Watanabe, Karen H. From Qualitative to Quantitative AOP: A Case Study of Neurodegeneration.  Switzerland: N. p., 2022. 
Web.  doi:10.3389/ftox.2022.838729.

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                    Sinitsyn, Dennis, Garcia-Reyero, Natàlia, & Watanabe, Karen H. From Qualitative to Quantitative AOP: A Case Study of Neurodegeneration.  Switzerland.  https://doi.org/10.3389/ftox.2022.838729

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                    Sinitsyn, Dennis, Garcia-Reyero, Natàlia, and Watanabe, Karen H. Wed .  
"From Qualitative to Quantitative AOP: A Case Study of Neurodegeneration".  Switzerland.  https://doi.org/10.3389/ftox.2022.838729.

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@article{osti_1860282,

  title        = {From Qualitative to Quantitative AOP: A Case Study of Neurodegeneration},

  author       = {Sinitsyn, Dennis and Garcia-Reyero, Natàlia and Watanabe, Karen H.},

  abstractNote = {Adverse outcome pathways (AOPs) include a sequence of events that connect a molecular-level initiating event with an adverse outcome at the cellular level for human health endpoints, or at the population level for ecological endpoints. When there is enough quantitative understanding of the relationships between key events in an AOP, a mathematical model may be developed to connect key events in a quantitative AOP (qAOP). Ideally, a qAOP will reduce the time and resources spent for chemical toxicity testing and risk assessment and enable the extrapolation of data collected at the molecular-level by in vitro assays, for example, to predict whether an adverse outcome may occur. Here, we review AOPs in the AOPWiki, an AOP repository, to determine best practices that would facilitate conversion from AOP to qAOP. Then, focusing on a particular case study, acetylcholinesterase inhibition leading to neurodegeneration, we describe specific methods and challenges. Examples of challenges include the availability and collection of quantitative data amenable to model development, the lack of studies that measure multiple key events, and model accessibility or transferability across platforms. We conclude with recommendations for improving key event and key event relationship descriptions in the AOPWiki that facilitate the transition of qualitative AOPs to qAOPs.},

  doi          = {10.3389/ftox.2022.838729},

  journal      = {Frontiers in Toxicology},

  number       = ,

  volume       = 4,

  place        = {Switzerland},

  year         = {Wed Mar 30 00:00:00 EDT 2022},

  month        = {Wed Mar 30 00:00:00 EDT 2022}

}

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Title: From Qualitative to Quantitative AOP: A Case Study of Neurodegeneration

Abstract

Citation Formats

Mouse model of Parkinsonism: a comparison between subacute MPTP and chronic MPTP/probenecid treatment journal, September 2001

Statistical Issues in Toxicokinetic Modeling: A Bayesian Perspective journal, October 2000

Towards a qAOP framework for predictive toxicology - Linking data to decisions journal, February 2022

A Computational Model of the Rainbow Trout Hypothalamus-Pituitary-Ovary-Liver Axis journal, April 2016

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Glutamate neurotoxicity in vitro: antagonist pharmacology and intracellular calcium concentrations journal, January 1990

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Biological basis for extrapolation across mammalian species journal, September 1986

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Developing adverse outcome pathways on silver nanoparticle-induced reproductive toxicity via oxidative stress in the nematode Caenorhabditis elegans using a Bayesian network model journal, November 2018

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A rat model of nerve agent exposure applicable to the pediatric population: The anticonvulsant efficacies of atropine and GluK1 antagonists journal, April 2015

Animal Models That Best Reproduce the Clinical Manifestations of Human Intoxication with Organophosphorus Compounds journal, June 2014

Mouse model of Parkinsonism: a comparison between subacute MPTP and chronic MPTP/probenecid treatment
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Statistical Issues in Toxicokinetic Modeling: A Bayesian Perspective
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Towards a qAOP framework for predictive toxicology - Linking data to decisions
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A Computational Model of the Rainbow Trout Hypothalamus-Pituitary-Ovary-Liver Axis
journal, April 2016

Physiological Pharmacokinetic Analysis Using Population Modeling and Informative Prior Distributions
journal, December 1996

Quantitative MRI predicts status epilepticus-induced hippocampal injury in the lithium–pilocarpine rat model
journal, February 2010

A Computational Model of the Cholinergic Modulation of CA1 Pyramidal Cell Activity
journal, September 2020

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Glutamate neurotoxicity in vitro: antagonist pharmacology and intracellular calcium concentrations
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Chemical hazard prediction and hypothesis testing using quantitative adverse outcome pathways
journal, January 2019

A modular approach for assembly of quantitative adverse outcome pathways
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Quantification of an Adverse Outcome Pathway Network by Bayesian Regression and Bayesian Network Modeling
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Comparative effect of Prunus persica L. BATSCH-water extract and tacrine (9-amino-1,2,3,4-tetrahydroacridine hydrochloride) on concentration of extracellular acetylcholine in the rat hippocampus
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journal, May 2016

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journal, November 2019

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journal, April 2017

Quantitative Response-Response Relationships Linking Aromatase Inhibition to Decreased Fecundity are Conserved Across Three Fishes with Asynchronous Oocyte Development
journal, August 2019

The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models
journal, March 2003

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journal, October 2017

De Novo Development of a Quantitative Adverse Outcome Pathway (qAOP) Network for Ultraviolet B (UVB) Radiation Using Targeted Laboratory Tests and Automated Data Mining
journal, September 2020

Changes in hippocampal acetylcholine and glutamate extracellular levels during soman-induced seizures: Influence of septal cholinoceptive cells
journal, May 1992

Effect of donepezil hydrochloride (E2020) on basal concentration of extracellular acetylcholine in the hippocampus of rats
journal, September 1999

Kinetics of M1 muscarinic receptor and G protein signaling to phospholipase C in living cells
journal, January 2010

Comparative profile of refractory status epilepticus models following exposure of cholinergic agents pilocarpine, DFP, and soman
journal, June 2021

Increasing Scientific Confidence in Adverse Outcome Pathways: Application of Tailored Bradford-Hill Considerations for Evaluating Weight of Evidence
journal, August 2015

Vulnerability of CA1 neurons to glutamate is developmentally regulated
journal, December 1996

Quantitative Adverse Outcome Pathway Analysis of Hatching in Zebrafish with CuO Nanoparticles
journal, September 2015

Biological basis for extrapolation across mammalian species
journal, September 1986

Application of three approaches for quantitative AOP development to renal toxicity
journal, August 2019

Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment
journal, March 2010

Developing adverse outcome pathways on silver nanoparticle-induced reproductive toxicity via oxidative stress in the nematode Caenorhabditis elegans using a Bayesian network model
journal, November 2018

Toward good in vitro reporting standards
journal, January 2019

Building and Applying Quantitative Adverse Outcome Pathway Models for Chemical Hazard and Risk Assessment
journal, August 2019

Robust Likelihood‐Based Approach for Automated Optimization and Uncertainty Analysis of Toxicokinetic‐Toxicodynamic Models
journal, October 2020

A rat model of nerve agent exposure applicable to the pediatric population: The anticonvulsant efficacies of atropine and GluK1 antagonists
journal, April 2015

Animal Models That Best Reproduce the Clinical Manifestations of Human Intoxication with Organophosphorus Compounds
journal, June 2014