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Environ Toxicol Chem. 2018 Apr;37(4):955-969. doi: 10.1002/etc.4090. Epub 2018 Mar 22.

Meta-analysis of fish early life stage tests-Association of toxic ratios and acute-to-chronic ratios with modes of action.

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Department of Bioanalytical Ecotoxicology, UFZ-Helmholtz Centre for Environmental Research, Leipzig, Germany.
Department of Physical and Environmental Sciences, University of Toronto Scarborough, Toronto, Ontario, Canada.
Department of Environmental Engineering, Technical University of Denmark, Lyngby, Denmark.
Department of Cell Toxicology, UFZ-Helmholtz Centre for Environmental Research, Leipzig, Germany.
Environmental Toxicology, Center for Applied Geosciences, Eberhard Karls University Tübingen, Tübingen, Germany.
Environmental Research Department, L'Oréal Advanced Research, Aulnay sous Bois, France.
Institute for Environmental Research (Biology V), RWTH Aachen University, Aachen, Germany.


Fish early life stage (ELS) tests (Organisation for Economic Co-operation and Development test guideline 210) are widely conducted to estimate chronic fish toxicity. In these tests, fish are exposed from the embryonic to the juvenile life stages. To analyze whether certain modes of action are related to high toxic ratios (i.e., ratios between baseline toxicity and experimental effect) and/or acute-to-chronic ratios (ACRs) in the fish ELS test, effect concentrations (ECs) for 183 compounds were extracted from the US Environmental Protection Agency's ecotoxicity database. Analysis of ECs of narcotic compounds indicated that baseline toxicity could be observed in the fish ELS test at similar concentrations as in the acute fish toxicity test. All nonnarcotic modes of action were associated with higher toxic ratios, with median values ranging from 4 to 9.3 × 104 (uncoupling < reactivity < neuromuscular toxicity < methemoglobin formation < endocrine disruption < extracellular matrix formation inhibition). Four modes of action were also found to be associated with high ACRs: 1) lysyl oxidase inhibition leading to notochord distortion, 2) putative methemoglobin formation or hemolytic anemia, 3) endocrine disruption, and 4) compounds with neuromuscular toxicity. For the prediction of ECs in the fish ELS test with alternative test systems, endpoints targeted to the modes of action of compounds with enhanced toxic ratios or ACRs could be used to trigger fish ELS tests or even replace these tests. Environ Toxicol Chem 2018;37:955-969.


Adverse outcome pathways; Alternatives to animal testing; Baseline toxicity; Fish early life stage test; Fish embryo test; Mode of action

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