Determination of the Zebrafish Embryo Developmental Toxicity Assessment (ZEDTA) as an Alternative Non-Mammalian Approach for the Safety Assessment of Agrochemicals.

Abstract

With the US Environment Protection Agency reducing requests for (and funding of) mammalian studies alongside the proposed elimination of requests by 2035, there is an urgent need for fully validated New Approach Methods (NAMs) to fill the resultant gap for safety assessment of agrochemicals. One promising NAM for assessing the potential for human prenatal developmental toxicity potential is the Zebrafish Embryo Developmental Toxicity Assessment, a bioassay that has been used by the pharmaceutical industry for more than a decade in early-stage drug safety assessment. Despite its promise, little data has been generated to assess the validity of ZEDTA for assessing Developmental and Reproductive Toxicity of new agrochemical products. Addressing this knowledge gap, we tested 67 compounds (insecticides, herbicides and fungicides) spanning multiple different chemical groupings and mechanisms of action. ZEDTA assay results were compared with the European Chemicals Agency (ECHA) Classification and Labelling (C&L) for mammalian hazard classification and with publicly available data to determine the ZEDTA's translation power. Overall, the ZEDTA assay had an effective detection capability of 65% for sensitivity and 64% for specificity as compared with the ECHA-C&L classification and publicly available data. Comparing the ZEDTA data there were both strengths and weaknesses in alignments for across the different chemical classes and chemical mechanisms of action. Overall, the data generated, show the performance of the ZEDTA assay was comparable with other bioassays highlighted as alternatives for mammalian assessment and holds good promise as a NAM for screening agrochemical prenatal developmental toxicity during new product human safety assessment.