In Response: Quantitative adverse outcome pathways for prediction of adverse effects—An academic perspective

The formulation of the adverse outcome pathway (AOP) concept by Ankley et al. of the US Environmental Protection Agency in 2010 [1] had an astonishing impact on the academic (eco)toxicology community. This high interest is certainly related to the link of the AOP concept to a mechanistic understanding of chemical hazards. Elements of this mechanistic understanding had been included in previous concepts, such as biomarkers [2], effect propagation [3], and toxicity pathways [4], and had been discussed for potential use in qualitative and quantitative structure–activity relationship models [5]. All these previous approaches included at least partial elements of the AOP concept. However, none of them had attempted to characterize the link from molecular initiating events to a final adverse effect in such a detailed, causality-driven, and formal approach, allowing one to address concerns and limitations of existing hazard assessment from an academic viewpoint. Regulatory testing at present, especially in environmental hazard assessment but to a large extent in the human health sector as well, is mainly based on the analysis of apical endpoints, which rarely provide an understanding of the underlying toxicity mechanism. Lacking mechanistic information, it is difficult to properly judge the hazard of chemicals across different species and exposure situations, derive a sufficient risk assessment, or support a reliable read-across. The assembly and evaluation of AOPs provide a powerful tool to focus research with the purpose of 1) characterizing and assembling the existing knowledge; 2) identifying data gaps (for mechanisms, pathways, biomarkers, assay development, nonanimal models, species susceptibility, etc.); and 3) focusing and directing international research efforts to areas where these may be required. This is supported through data sharing and the recently established AOP-wiki and other knowledge repositories. Furthermore, the AOP concept may foster a stronger link between what is needed from a regulatory perspective, with approaches and technology used in academic research (e.g., toxicogenomics). It will revive earlier concepts such as the use of biomarkers or toxicity pathways by establishing a stronger In This Issue:

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