Biological systems are disturbed by several factors that are defined by the exposome. Environmental substances, including endocrine disruptors (EDs), represent the chemical exposome. These stressors may alter biological systems, that could lead to toxic health effects. Even if scientific evidence provide links between diverse environmental substances and disorders, innovative approaches, including alternative methods to animal testing, are still needed to address the complexity of the chemical mechanisms of action. Network science appears to be a valuable approach for helping to decipher a comprehensive assessment of the chemical exposome. A computational protein system-system association network (pS-SAN), based on various data sources such as chemical-protein interactions, chemical-system links, and protein-tissue associations was developed. The integrative systems toxicological model was applied to three EDs, to predict potential biological systems they may perturb. The results revealed that several systems may be disturbed by theses EDs, such as the kidney, liver and endocrine systems. The presented network-based approach highlights an opportunity to shift the paradigm of chemical risk assessment towards a better understanding of chemical toxicology mechanisms.