TY - JOUR
T1 - From Qualitative to Quantitative AOP
T2 - A Case Study of Neurodegeneration
AU - Sinitsyn, Dennis
AU - Garcia-Reyero, Natàlia
AU - Watanabe, Karen H.
N1 - Funding Information:
DS was supported through an ORISE fellowship with award ERDC-EL-2020-0035. This research was supported in part by the Biological Data Science program in the School of Mathematical and Natural Sciences at ASU, and the Joint Program Committee Military Operational Medicine Research Program.
Publisher Copyright:
Copyright © 2022 Sinitsyn, Garcia-Reyero and Watanabe.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - acetylcholinesterase inhibition
KW - chemical risk assessment
KW - KER description
KW - qAOP
KW - toxicity testing research needs
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U2 - 10.3389/ftox.2022.838729
DO - 10.3389/ftox.2022.838729
M3 - Article
AN - SCOPUS:85159640161
SN - 2673-3080
VL - 4
JO - Frontiers in Toxicology
JF - Frontiers in Toxicology
M1 - 838729
ER -