Network toxicology focused investigation on the impacts of inorganic arsenic and cadmium on human and ecosystem health

Heavy metals like arsenic and cadmium are persistent environmental pollutants that pose serious health risks to humans and ecosystems due to their toxicity, bioaccumulation potential, and frequent presence in consumer products. Network toxicology offers a holistic in silico framework to elucidate the complex biological mechanisms of toxicity, thereby supporting New Approach Methodologies (NAMs) for toxicity assessment. In this study, network toxicological tools were utilized to investigate arsenic- and cadmium-induced toxicities. Toxicity endpoints associated with inorganic arsenic and cadmium compounds were curated from six exposome-relevant databases and mapped to key events (KEs) across adverse outcome pathways (AOPs) cataloged in AOP-Wiki. This led to construction of stressor-AOP networks, revealing 51 AOPs associated with arsenic and 78 with cadmium, and facilitated mechanistic case studies of pathways relevant to human and ecological health. Toxicity concentrations and bioconcentration factors from the ECOTOX database were then used to construct stressor-species networks, that helped identify species that are vulnerable and potentially bioaccumalate these chemicals. Further, the construction of species sensitivity distributions (SSDs) and toxicity-normalized SSDs (SSDn), provided a comparative framework for prioritizing these compounds in risk assessments. Further, integrating SSD data with stressor-species networks identified species groups particularly sensitive to arsenic and cadmium exposure, enhancing these networks utility for ecological risk assessment. The networks and related data generated in this study are freely available for further research at https://cb.imsc.res.in/heavymetaltox/. Overall, this study offers a comprehensive perspective on the toxicological impact of inorganic arsenic and cadmium compounds, supporting a One Health approach to their regulatory and mitigation strategies.