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Investigating Alternatives to the Fish Early Life-Stage Test: A Strategy for Discovering and Annotating Adverse Outcome Pathways for Early Fish Development
Villeneuve, Dan, D. Volz, M. Embry, G. Ankley, S. Belanger, M. Leonard, K. Schirmer, R. Tanguay, L. Truong, AND L. Wehmas. Investigating Alternatives to the Fish Early Life-Stage Test: A Strategy for Discovering and Annotating Adverse Outcome Pathways for Early Fish Development. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY. Society of Environmental Toxicology and Chemistry, Pensacola, FL, 33(1):158-169, (2014).
Traditional whole animal toxicity testing paradigms, while effective for characterizing chemical hazards, are neither cost effective nor efficient enough to address societal needs to evaluate hazards associated with large inventories of chemicals in the environment. In response to this, the proposed paradigm for toxicity testing in the 21st century advocates increased focus on measurements of the initiation of toxicity, rather than direct measurement of toxicity testing outcomes as a means to decrease costs and increase efficiency while still providing information that supports regulatory decision-making. Adverse outcome pathways (AOPs) represent an important framework organize information in order to support extrapolation of mechanistic toxicology data, collected at low levels of biological organization (e.g., molecular, biochemical, cellular) to increased probability or severity of adverse outcomes at the levels that are relevant to risk assessment (e.g., impacts on survival, growth, and reproduction in the case of ecotoxicology). As a result, development of scientifically-credible AOPs can be viewed as a critical foundation for the design, development, and acceptance of alternative test methods. The current paper describes application of a generalized approach to adverse outcome pathway discovery aimed at supporting the development of alternatives to the OECD 210 (OCSPP 850.1400) fish early-life stage toxicity test, the most widely used chronic ecotoxicity test, world-wide. The paper supports both efforts within the international scientific community to develop viable alternatives to this guideline test and provides an example of a strategy that can be applied to other AOP development activities. As such, this work directly supports the aims of the AOP Development and Discovery Project under ORD’s Chemical Safety for Sustainability Research Program.
The fish early life-stage (FELS) test (OECD Test Guideline 210) is the primary test used internationally to estimate chronic fish toxicity in support of ecological risk assessments and chemical management programs. As part of an on-going effort to develop efficient and cost-effective alternatives to the FELS test, there is a need to identify and describe potential adverse outcome pathways (AOPs) relevant to FELS toxicity. To support this endeavor, we outline and illustrate an overall strategy for discovery and annotation of FELS AOPs. Key events represented by major developmental landmarks were organized into a preliminary conceptual model of fish development. Using swimbladder inflation as an example, a weight-of-evidence-based approach was used to support linkage of key molecular initiating events to adverse phenotypic outcomes and reduced young-of-year survival. Based on an iterative approach, we explored the feasibility of using key events as the foundation for expanding a network of plausible linkages and AOP knowledge and, in the process, identify important knowledge gaps. Given the scope and scale of the task, prioritization of AOP development was recommended and key research objectives were defined relative to factors such as current animal use restrictions in the European Union and increased demands for fish toxicity data in chemical management programs globally. The example and strategy described are intended to guide collective efforts to define FELS-related AOPs and develop resource-efficient predictive assays that address the toxicological domain of the OECD 210 test.