LRI-ECO20 Development of an alternative testing strategy for the fish early life-stage (FELS) test (OECD 210)

Background

The use of conventional whole-organism (vertebrate) bioassays for estimating chronic ecological hazards has been limited due to low efficiency, high cost, extensive animal use, and, for aquatic toxicity studies, generation of large volumes of contaminated water.  Moreover, most animal guideline tests provide little or no informative mechanistic toxicity data due to the principal focus on apical endpoints such as survival, growth, and reproduction. Due to these limitations, resource-efficient alternatives to conventional toxicity testing - including high-throughput in vitro and in silico screening assays - have been proposed as key components of a future testing paradigm for mechanism-based regulatory toxicology and ecotoxicology (Bradbury et al. 2004; NRC 2007; Villeneuve and Garcia-Reyero 2011). However, the predictive power of molecular or cellular perturbations (e.g., modeled or detected in vitro) for apical endpoints relevant to ecological risk assessment (i.e., survival, growth, and reproduction) must be sufficiently high to minimize uncertainties and provide meaningful data for regulatory decision-making.

To begin identifying useful predictive assays and testing strategies for regulatory ecotoxicology, Ankley and colleagues recently proposed the use of Adverse Outcome Pathways (AOPs) as a conceptual framework for summarizing existing knowledge about linkages between a direct, molecular-level initiating event and an adverse outcome at a level of biological organization relevant to ecological risk assessment (Ankley et al. 2010).  Predictive linkages are implicitly defined when developing AOPs, providing a scientific framework for identification of targeted alternative assays and models that represent key events at multiple levels of biological levels of organization. Linked with biologically based, concentration-response models (e.g., toxicokinetic and toxicodynamic models), these alternative assays, once developed, can facilitate extrapolation to organism- and population-level endpoints and significantly decrease reliance on whole-animal regulatory toxicity tests as the primary source of hazard data for ecological risk assessment and environmental decision-making (NRC 2007).

The fish early life-stage (FELS) test (OECD 210) is the primary guideline used to estimate chronic toxicity of regulated chemicals (pesticides, industrial chemicals, pharmaceuticals, food/feed additives, and cosmetics).  In addition, the FELS will be used to screen and prioritize hundreds to thousands of chemicals regulated under Registration, Evaluation, Authorization and Restriction of Chemical (REACH), Toxic Substances Control Act (TSCA), and other national or international chemical management programs.  This effort will require development of a rapid, cost-efficient, and mechanism-based tiered testing strategy.  For example, to begin addressing this challenge, development of a three-tiered testing strategy was recently proposed (Volz et al. 2011) as an outcome of an international meeting on development of approaches to address chronic toxicity and endocrine disruption testing needs in the context of animal alternatives.  Volz et al. (2011) suggested an initial tier representing high-throughput, adverse outcome pathway (AOP)-based in vitro (cell-based) assays (Tier 1); the second tier representing medium-to-high-throughput in vivo (zebrafish embryo) assays (Tier 2); and the highest tier representing the current FELS guideline test (Tier 3).  In the long-term, implementation of a tiered testing strategy as a new paradigm for toxicity testing may help reduce reliance on long-term and costly FELS tests required for assessing the hazard of thousands of chemicals currently in commerce.