Leveraging Zebrafish Embryo Phenotypic Observations to Advance Data-Driven Analyses in Toxicology

Abstract

Zebrafish have emerged as a central model organism in toxicological research. Zebrafish embryos are exempt from certain animal testing regulations, which facilitates their use in toxicological testing. Next to the zebrafish embryo acute toxicity test (ZFET) according to the OECD TG 236, fish embryos are used in mechanistic investigations, chemical screenings, ecotoxicology, and drug development. However, inconsistencies in the applied test protocols and the monitored endpoints in addition to a lack of standardized data formats impede comprehensive meta-analyses and cross-study comparisons. To address these challenges, we developed the Integrated Effect Database for Toxicological Observations (INTOB), a comprehensive data management tool that standardizes the collection of metadata and phenotypic observations using a controlled vocabulary. By incorporating data from more than 600 experiments into the database and subsequent comprehensive data analyses, we demonstrate its utility in improving the comparability and interoperability of toxicity data. Our results show that the ZFET can detect toxicity spanning 7 orders of magnitude at the scale of effect concentrations. We also highlight the potential of read-across analyses based on morphological fingerprints and their connection to chemical modes of action, provide information on control variability of the ZFET, and highlight the importance of time for mechanistic understanding in chemical exposure-effect assessments. We provide the full Findable, Accessible, Interoperable, and Reusable (FAIR) data set as well as the analysis workflow and demonstrate how professional data management, as enabled with INTOB, marks a significant advancement by offering a comprehensive framework for the systematic use of zebrafish embryo toxicity data, thus paving the way for more reliable, data-driven chemical risk assessment.