Building Predictive Adverse Outcome Pathway Models: Role of Molecular Initiating Events and Structure–Activity Relationships

Abstract

Abstract

The original contribution of the adverse outcome pathway (AOP) concept to predictive toxicology is that the use of a range of assays covering the main events of the whole toxicity pathway would improve the prediction of the apical endpoints with alternative tests. This would permit more solid, mechanistically based predictions. However, explicit and systematic quantitative analysis of the AOPs and their integration into larger schemes is at times lacking. This leaves room to subjective implementations. We have investigated the quantitative modeling aspects of AOPs related to important apical endpoints, that is, skin sensitization, endocrine disruptors, and carcinogenicity. A common trend is that the major contribution to the final predictivity is given by in vitro or in silico models of molecular initiating events (MIEs), which appear to be the rate-limiting steps of the toxicity pathways, whereas models for intermediate events have poor correlations with apical endpoints. Since MIEs are in general amenable to quantitative structure–activity relationships (QSAR) analysis, it can be anticipated that the integration of a few in vitro assays with QSAR models is going to provide rapid and inexpensive approaches for the detection of toxins for many endpoints. This evidence agrees with the general experience of modeling: in different fields such as ecology, systems biology, and macroeconomics, grossly simplified models capture important features of the behavior of incredibly complex interacting systems and permit successful predictions. This work also stresses the need of applying quantitative analysis to the toxicity pathways.