Given tremendous progress in biology, toxicology, and chemistry knowledge in recent decades, the time is right for serious consideration of options to move away from animal experimentation in chemical hazard and risk assessment. Individual alternative and animal-free assays as a replacement of individual animal studies have met with understandable reluctance in the scientific and regulatory arenas. An integrated conceptual approach based on mechanistic information built from all available information on biology, chemistry, and mechanisms of toxicity, might allow sufficient coverage of the biological system to provide the basis for reliable animal-free chemical hazard and risk assessment for man. We describe construction of an ontology, which can be considered a network of adverse outcome pathways, including feedback loops representing homeostasis. Basic elements in the ontology are subjects (such as enzymes, receptors, and cell types) and their quantitative relationships (response-response relationships), together forming a multidimensional network of biological interactions. This network can be modeled in silico, providing an integrated system toxicology computational model with which toxicity predictions can be made at the level of adverse outcomes in the intact individual. The model will indicate critical rate-determining steps in the network that can be monitored in a battery of dedicated in vitro assays, providing a testing strategy to collect data feeding into the systems model. Connecting this integrated dynamic model with exposure models allows quantitative hazard and risk assessment for man, avoiding animal experiments.