Potential adverse outcome pathways with hazard identification of organophosphate esters

Data-driven analysis and pathway-based approaches contribute to reasonable arrangements of limited resources and laboratory tests for continuously emerging commercial chemicals, which provides opportunities to save time and effort for toxicity research. With the widespread usage of organophosphate esters (OPEs) on a global scale, the concentra-tions generally reached up to micromolar range in environmental media and even in organisms. However, potential adverse effects and toxicity pathways of OPEs have not been systematically assessed. Therefore, it is necessary to review the current situation, formulate the future research priorities, and characterize toxicity mechanisms via data -driven analysis. Results showed that the early toxicity studies focused on neurotoxicity, cytotoxicity, and metabolic disorders. Then the main focus shifted to the mechanisms of cardiotoxicity, endocrine disruption, hepatocytes, repro-ductive and developmental toxicity to vulnerable sub-populations, such as infants and embryos, affected by OPEs. In addition, several novel OPEs have been emerging, such as bis(2-ethylhexyl)-phenyl phosphate (HDEHP) and oxidation derivatives (OPAs=O) generated from organophosphite antioxidants (OPAs), leading to multiple potential ecological and human health risks (neurotoxicity, hepatotoxicity, developmental toxicity, etc.). Notably, in-depth statistical anal-ysis was promising in encapsulating toxicological information to develop adverse outcome pathways (AOPs) frame-works. Subsequently, network-centric analysis and quantitative weight-of-evidence (QWOE) approaches were utilized to construct and evaluate the putative AOPs frameworks of OPEs, showing the moderate confidences of the developed AOPs. In addition, frameworks demonstrated that several events, such as nuclear receptor activation, reac-tive oxygen species (ROS) production, oxidative stress, and DNA damage, were involved in multiple different adverse outcome (AO), and these AOs had certain degree of connectivity. This study brought new insights into facilitating the complement of AOP efficiently, as well as establishing toxicity pathways framework to inform risk assessment of emerging OPEs.

Automated summary

Data-driven analysis and pathway-based approaches are important for efficient toxicity research of organophosphate esters (OPEs). The widespread usage of OPEs poses potential risks to the environment and human health, but their adverse effects and toxicity mechanisms have not been fully assessed. By analyzing and evaluating the toxicity pathways and effects of different OPEs, better risk assessment and management can be achieved.