New Insights into\nthe Visual Toxicity of Organophosphate\nEsters: An Integrated Quantitative Adverse Outcome Pathway and Cross-chemical\nExtrapolation

Organophosphate esters (OPEs) have been documented to\nadversely\naffect visual function, potentially impacting wildlife survival and\nhuman health, thereby necessitating a comprehensive risk assessment.\nDespite the quantitative adverse outcome pathway (qAOP) holding promise\nfor addressing this concern mechanistically, unclear mode of action\nand inadequate quantitative understanding across biological levels\ncurrently impede its development. Herein, we employed an integrated\nstrategy, combining multiomics analyses, targeted bioassays, and modular\nmodel-fitting, to develop and validate a qAOP framework for visual\ntoxicity of OPEs, exemplified by tris(2-butoxyethyl) phosphate, triphenyl\nphosphate, and tris(1,3-dichloro-2-propyl) phosphate. Our results\nrevealed that these OPEs induce visual dysfunction in zebrafish larvae\nprimarily via oxidative stress, then cascade to damaging photoreceptors\nand retinal structures, ultimately resulting in the disruption of\nvisual behaviors (i.e., decreased optokinetic response, phototaxis,\nand visual motor response). The qAOP, validated through cross-chemical\nextrapolation, enabled the prediction for vision-related effects of\nOPEs within a certain domain. Integrating toxicokinetic modeling could\ncompensate for the uncertainty in qAOP predictions, since adjusting\nfor internal concentrations as inputs significantly enhanced the accuracy\nand applicability of the predictions. This work contributes to a better\nunderstanding of visual toxicity by OPEs and presents a promising\nparadigm for quantitative risk assessment based on the qAOP framework.