TY - JOUR
T1 - Adverse outcome pathway development II
T2 - Best practices
AU - Villeneuve, Daniel L.
AU - Crump, Doug
AU - Garcia-Reyero, Natàlia
AU - Hecker, Markus
AU - Hutchinson, Thomas H.
AU - LaLone, Carlie A.
AU - Landesmann, Brigitte
AU - Lettieri, Teresa
AU - Munn, Sharon
AU - Nepelska, Malgorzata
AU - Ottinger, Mary Ann
AU - Vergauwen, Lucia
AU - Whelan, Maurice
N1 - Publisher Copyright:
© The Author 2014.
PY - 2014/12/1
Y1 - 2014/12/1
N2 - Organization of existing and emerging toxicological knowledge into adverse outcome pathway (AOP) descriptions can facilitate greater application of mechanistic data, including those derived through high-throughput in vitro, high content omics and imaging, and biomarker approaches, in risk-based decision making. The previously ad hoc process of AOP development is being formalized through development of internationally harmonized guidance and principles. The goal of this article was to outline the information content desired for formal AOP description and some rules of thumb and best practices intended to facilitate reuse and connectivity of elements of an AOP description in a knowledgebase and network context. For example, key events (KEs) are measurements of change in biological state that are indicative of progression of a perturbation toward a specified adverse outcome. Best practices for KE description suggest that each KE should be defined as an independent measurement made at a particular level of biological organization. The concept of "functional equivalence" can help guide both decisions about how many KEs to include in an AOP and the specificity with which they are defined. Likewise, in describing both KEs and evidence that supports a causal linkage or statistical association between them (ie, a key event relationship; KER), best practice is to build from and contribute to existing KE or KER descriptions in the AOP knowledgebase rather than creating redundant descriptions. The best practices proposed address many of the challenges and uncertainties related to AOP development and help promote a consistent and reliable, yet flexible approach.
AB - Organization of existing and emerging toxicological knowledge into adverse outcome pathway (AOP) descriptions can facilitate greater application of mechanistic data, including those derived through high-throughput in vitro, high content omics and imaging, and biomarker approaches, in risk-based decision making. The previously ad hoc process of AOP development is being formalized through development of internationally harmonized guidance and principles. The goal of this article was to outline the information content desired for formal AOP description and some rules of thumb and best practices intended to facilitate reuse and connectivity of elements of an AOP description in a knowledgebase and network context. For example, key events (KEs) are measurements of change in biological state that are indicative of progression of a perturbation toward a specified adverse outcome. Best practices for KE description suggest that each KE should be defined as an independent measurement made at a particular level of biological organization. The concept of "functional equivalence" can help guide both decisions about how many KEs to include in an AOP and the specificity with which they are defined. Likewise, in describing both KEs and evidence that supports a causal linkage or statistical association between them (ie, a key event relationship; KER), best practice is to build from and contribute to existing KE or KER descriptions in the AOP knowledgebase rather than creating redundant descriptions. The best practices proposed address many of the challenges and uncertainties related to AOP development and help promote a consistent and reliable, yet flexible approach.
KW - Adverse outcome pathway
KW - Extrapolation
KW - Knowledgebase
KW - Predictive toxicology
KW - Regulatory toxicology
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U2 - 10.1093/toxsci/kfu200
DO - 10.1093/toxsci/kfu200
M3 - Article
AN - SCOPUS:84922465985
SN - 1096-6080
VL - 142
SP - 321
EP - 330
JO - Toxicological Sciences
JF - Toxicological Sciences
IS - 2
ER -