Leveraging integrative toxicogenomic approach towards development of stressor-centric adverse outcome pathway networks for plastic additives

Abstract

Plastics are widespread pollutants found in atmospheric, terrestrial and aquatic ecosystems due to their extensive usage and environmental persistence. Plastic additives, that are utilized to achieve specific functionality in plastics, leach into the environment upon plastic degradation and pose considerable risk to ecological and human health. Limited knowledge concerning the presence of plastic additives throughout the plastic life cycle has hindered their effective regulation, thereby posing risks to product safety. In this study, we leveraged the adverse outcome pathway (AOP) framework to understand the mechanisms underlying plastic additives-induced toxicities. We first identified an exhaustive list of 6470 plastic additives from chemicals documented to be found in plastics. Next, we leveraged heterogenous toxicogenomics and biological endpoints data from five exposome-relevant resources, and identified associations between 1287 plastic additives and 322 complete and high quality AOPs within AOP-Wiki. Based on these plastic additive-AOP associations, we constructed a stressor-centric AOP network, wherein the stressors are categorized into 10 priority use sectors and AOPs are linked to 27 disease categories. We visualized the plastic additives-AOP network for each of the 1287 plastic additives and made them available in a dedicated website: https://cb.imsc.res.in/saopadditives/. Finally, we showed the utility of the constructed plastic additives-AOP network by identifying 28 highly relevant AOPs associated with benzo[a]pyrene, and thereafter, explored the associated toxicity pathways leading to respiratory and gastrointestinal system diseases in humans and developmental disorders in aquatic species. Overall, the constructed plastic additives-AOP network will enable regulatory risk assessment of plastic additives, thereby contributing towards a toxic-free circular economy for plastics.