The First Steps on AOPs' Concepts, Development, and Applications in Teratology.

Abstract

An Adverse Outcome Pathway (AOP) is an analytical model that describes, through a graphical representation, a linear sequence of biologically connected events at different levels of biological organization, causally leading to an adverse effect on human health or the environment. In general, AOPs are constructed based on five central principles: systematic development and review, chemical-agnostic, modular, networks, and living documents. Furthermore, AOPs have the potential to be used, for example, to investigate certain molecular targets; relate the regulation of specific genes or proteins among AOPs; extrapolate biological processes, pathways, or diseases from one species to another; and even predict adverse effects in particular populations. AOPs also emerge as an alternative to animal experimentation in studies of developmental malformations. It's even possible now to develop a quantitative AOP to predict teratogenic effects for some substances. However, the construction of high-quality AOPs requires standardization in the way these models are developed and reviewed, ensuring an adequate degree of flexibility and guaranteeing efficiency. The development of AOPs should strictly be based on the guidance documents developed by the OECD. Nevertheless, an important step for those developing AOPs is the choice of an apical endpoint or an initiating molecular event in order to initiate the construction of the pathway. Another crucial step is a systematic literature review based on the random combination of the blocks of information. With these two fundamental steps completed, it only remains to follow the guidance documents on Developing and Assessing Adverse Outcome Pathways and AOP Developers' Handbook supplement provided by the OECD to organize and construct an AOP. This modern approach will bring radical changes in the field of toxicity testing, regarding the prediction of apical toxic effects using molecular-level effects.