Editorial

Predictive toxicology based upon mechanistic information has become a critical aspect of chemical risk assessment in the last two decades. A major step in this direction came with the introduction of the mode-of-action concept in 2001, which encompasses a series of key events along a biological pathway from the initial chemical interaction to the adverse outcome.^1–3 The mode-of-action concept was first used by the U.S. Environmental Protection Agency and adopted by others in the cancer field,^4–7 but seemed equally exploitable for noncancer endpoints. ⁸ Another milestone was the seminal report published by the U.S. National Academy of Science in 2007, presenting a vision on toxicology in the 21st century and placing both in vitro toxicology and toxicity pathways in the foreground. These toxicity pathways denote cellular pathways that, when disturbed, can lead to adverse health effects. ⁹ Toxicity pathways align to a large extent with adverse outcome pathways (AOPs), introduced in 2010 in the field of ecotoxicology. ¹⁰ An AOP refers to a conceptual construct that portrays existing knowledge concerning the linkage between a direct molecular initiating event and an adverse outcome at a biological level of organization relevant to risk assessment. Although conceptually very similar, the scope of an AOP is broader compared with the mode-of-action, as it can go up to the population and even ecological level. Furthermore, while the mode-of-action tends to be chemical-specific and takes into account kinetic aspects, such as metabolism, AOPs are chemical-agnostic in that they describe a toxicological process from a purely dynamic, biological perspective.^11–15

AOPs were intended specifically to support regulatory decision-making based on the desire to make effective use of mechanistic data, particularly novel data streams that can be generated more rapidly and cost-effectively in a high-throughput format, rather than relying only on apical outcome data traditionally measured in whole-organism guideline toxicity tests.^12,13,15,16 The specific application of an AOP is usually dictated by the amount of available experimental and observational data and the AOP's degree of maturity. AOPs can serve as the basis for generating integrated approaches to testing and assessment (IATA).^17,18 While IATAs provide a platform for data integration and a means for targeted testing for a specific purpose, it is not necessarily framed by a mechanistic rationale. AOPs could be used to provide this mechanistic basis and thus to identify data gaps or to contextualize a diverse universe of existing data.^16,17 Another AOP application includes the development of chemical categories based on biological responses. A chemical category is defined as a group of chemicals whose physicochemical and human health properties are likely to be similar or to follow a regular pattern. The similarities are typically based on common functional features. The next step is to substantiate the tentative group with experimental data and nontesting approaches, such as quantitative structure–activity relationship methodologies. Once the chemical category is fully established, it can be used for data gap filling strategies, such as read-across techniques that apply relevant information from analogous substances to predict the toxicological properties of a target substance. ¹⁸ AOPs may also facilitate prioritization of chemicals for assessment. In this process, substances are screened for their potential to trigger a specific and measurable biological response, which in an AOP context could be related to one or several molecular initiating events, key events, and/or adverse outcomes. Substances identified as presenting an unreasonable risk to cause an adverse outcome are subsequently ranked according to potency, whereby the most potent substances receive highest priority to undergo more detailed testing and/or evaluation.^12,18

This special issue of Applied In Vitro Toxicology contains several articles outlining new developments in the AOP field. Focus is hereby put on aspects of generating AOPs as such, as well as their applications, all in the light of in vitro and in silico toxicology.