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

Environmental chemicals affectimpact health through diverse pathways, underscoring the need for approaches beyond traditional animal-based testing to capture their transport, transformation, and mechanisms for risk assessment. Network toxicology offers an in silico framework to elucidate such exposure pathways and toxicity mechanisms, thereby supporting new approach methodologies for toxicity assessment. This study utilized network-based approaches to comprehensively characterize the impacts of inorganic arsenic and cadmium contamination in India from a One Health perspective. First, aggregate exposure pathways (AEPs) were constructed by systematically curating India-specific data on the presence of inorganic arsenic and cadmium across environmental and biological states to understand their transport and transformation. Next, inorganic arsenic- and cadmium-induced toxicities were explored by mapping their toxicity endpoints from six exposome-relevant databases to key events across adverse outcome pathways (AOPs) cataloged in AOP-Wiki, revealing 51 and 78 associated AOPs, respectively. Construction of AOP networks further aided in inferring novel taxonomic applicability information. Moreover, the combined AEP-AOP constructs facilitated mechanistic case studies of human and ecological health-relevant pathways and highlighted critical knowledge gaps in terms of human exposures and bioaccumulation within tissues. Further, stressor-species networks constructed using ECOTOX data identified vulnerable species and those with bioaccumulative potential. Additionally, species sensitivity distributions (SSDs) and toxicity-normalized SSDs provided a comparative framework for prioritizing these compounds, and their integration into stressor-species networks highlighted sensitive species, enhancing their relevance for ecological risk assessment. Finally, the risk quotient analysis for Indian rivers revealed that many regions exhibited elevated ecological risks. Overall, this study underscores the value of network toxicology in supporting a One Health-based framework to inform regulatory decision-making and enhance mitigation strategies for inorganic arsenic and cadmium in India.