A History of the Molecular Initiating Event

Abstract

The adverse outcome pathway (AOP) framework provides an alternative to traditional in vivo experiments for the risk assessment of chemicals. AOPs consist of a number of key events (KEs) linked by key event relationships across a range of biological organization backed by scientific evidence. The first KE in the pathway is the molecular initiating event (MIE)-the initial chemical trigger that starts an AOP. Over the past 3 years the AOP conceptual framework has gained a large amount of momentum in toxicology as an alternative to animal methods, and so the MIE has come into the spotlight. What is an MIE? How can MIEs be measured or predicted? What research is currently contributing to our understanding of MIEs? In this Perspective we outline answers to these key questions.

Relationship Between Adverse Outcome Pathways and Chemistry-BasedIn SilicoModels to Predict Toxicity

“…Information from the Molecular Initiating Event (MIE) is one of the key drivers for in silico models derived from an AOP. [25][26][27][28] Before computational modelling approaches are considered, it should be recognised that there are different types of MIEs and each may require a different modelling approach. These have been summarised in general terms in Table 1, along with examples and the types of models that can be derived from the different types of MIE.…”

“…At the outset it is well acknowledged that AOPs can support computational modelling. 21 In addition, the use of AOPs to support computational modelling deriving structural alerts [25][26][27][28] for toxicity prediction or as part of a grouping strategy leading to read-across, and for QSAR development, is well established. 29 Other computational approaches, beyond the ab initio risk assessment consideration, that utilise and extend the AOP framework are the development of Integrated Assessment and Testing Approaches (IATAs).…”

Molecular fingerprint-derived similarity measures for toxicological read-across: Recommendations for optimal use

“…In particular, the focus of the study was to examine scenarios in which these similarity values might be useful for read-across based upon pairwise comparison to one or a few chemicals, with measured endpoint data, for the purpose of toxicological data gap filling. Specific objectives were to assess the performance and reliability of different molecular fingerprints used in similarity analysis, with a view to determine when similarity computed in this fashion works well and does not work well, as well as to consider how molecular similarity can be placed into a mechanistic framework to predict toxicity taking in account molecular initiating events (MIEs) (Allen et al, 2016. It should also be made clear that the purpose of this study was not to conclusively establish an optimum method for predicting toxicity.…”

The adverse outcome pathway: A multifaceted framework supporting 21st century toxicology

“…An AOP consists of a series of measurable key events (KEs) linked to one another by key event relationships ( Figure 1). The first KE generally is a molecular initiating event (MIE), which captures the interaction of a chemical with a biological macromolecule, that triggers subsequent KEs which could result in an adverse outcome (AO) at the individual or population level [8,9]. Explicit in an AOP is that the KEs are causally linked to one-another, an attribute that can be formally assessed using weight-of-evidence analyses [10,11].…”