Development and application of the adverse outcome pathway framework for understanding and predicting chronic toxicity: I. Challenges and research needs in ecotoxicology

Abstract

To elucidate the effects of chemicals on populations of different species in the environment, efficient testing and modeling approaches are needed that consider multiple stressors and allow reliable extrapolation of responses across species. An adverse outcome pathway (AOP) is a concept that provides a framework for organizing knowledge about the progression of toxicity events across scales of biological organization that lead to adverse outcomes relevant for risk assessment. In this paper, we focus on exploring how the AOP concept can be used to guide research aimed at improving both our understanding of chronic toxicity, including delayed toxicity as well as epigenetic and transgenerational effects of chemicals, and our ability to predict adverse outcomes. A better understanding of the influence of subtle toxicity on individual and population fitness would support a broader integration of sublethal endpoints into risk assessment frameworks. Detailed mechanistic knowledge would facilitate the development of alternative testing methods as well as help prioritize higher tier toxicity testing. We argue that targeted development of AOPs supports both of these aspects by promoting the elucidation of molecular mechanisms and their contribution to relevant toxicity outcomes across biological scales. We further discuss information requirements and challenges in application of AOPs for chemical- and site-specific risk assessment and for extrapolation across species. We provide recommendations for potential extension of the AOP framework to incorporate information on exposure, toxicokinetics and situation-specific ecological contexts, and discuss common interfaces that can be employed to couple AOPs with computational modeling approaches and with evolutionary life history theory. The extended AOP framework can serve as a venue for integration of knowledge derived from various sources, including empirical data as well as molecular, quantitative and evolutionary-based models describing species responses to toxicants. This will allow a more efficient application of AOP knowledge for quantitative chemical- and site-specific risk assessment as well as for extrapolation across species in the future.

A framework for predicting impacts on ecosystem services from (sub)organismal responses to chemicals

“…State variables such as mass and energy reflect the most important features at each level (e.g., health status and productivity) and are conserved across levels of biological and ecological complexity. Energy production and use also underlie AOPs [55,56]. At the suborganismal level, exposure to chemicals induces changes in energy acquisition and allocation; for example, less energy is allocated to growth/reproduction, or energy is shifted to maintenance of tissues, which ensures survival.…”

Does cadmium affect the toxicokinetics of permethrin in Chironomus dilutus at sublethal level? Evidence of enzymatic activity and gene expression

“…Gene expression is an upstream key event at gene level in adverse outcome pathway and their response determines the response of subsequent key events, such as enzyme activity and toxicokinetic process (Groh et al, 2015). Gene expression profiles gradually become a powerful endpoint for ecological studies and improve our understanding molecular mechanism of toxic outcome.…”

“…As gene expression is more sensitive than traditional toxic endpoints, it has been increasingly used in ecotoxicology as an early warning (Groh et al, 2015). Meanwhile, gene expression also provides mechanistic explanation on aquatic toxicity due to environmental stress, such as metabolizing xenobiotics and oxidative stress.…”

Regulatory Forum Opinion Piece: Carcinogen Risk Assessment

“…It is equally clear that this is not a simple undertaking and that this modeling process will certainly involve multiple, interconnected, pathway-based assays to make predictions. These methods may not be one-to-one replacements of the animal-based tests, but will instead predict likely safe exposures for specific toxicity pathways, rather than target organ toxicity per se (Lin and Will 2011;Groh et al 2015;Jackson 1995;Li and Chan 2009;Vinken 2013). …”