Mapping physiology: A systems biology approach for the development of alternative methods in toxicology.

Chemical safety assessment still heavily relies on animal testing, which is associated with ethical dilemmas and has limited human predictive value. New approach methodologies (NAMs), including in vitro and in silico techniques, offer alternative solutions. In silico toxicology has made progress in predicting chemical effects but frequently lacks biological mechanistic founda­tions. Recent developments focus on the mechanistic understanding of adverse effects caused by chemicals, as embedded in (quantitative) adverse outcome pathways (AOPs). However, there is a demand for more detailed mechanistic insights at the gene and cell levels, encompassing both pathology and physiology. Drawing inspiration from the Disease Maps Project, this paper introduces physiological maps (PMs) as comprehensive graphical representations of biochemical processes related to specific organ functions. PMs are standardized using Systems Biology Graphical Notation (SBGN) and controlled vocabularies and annotations. Curation guidelines have been developed to ensure reproducibility and usability. We present the methodology used to build PMs, emphasizing the essential collaboration between domain experts and curators. PMs offer user-friendly, stand­ardized visualization for data analysis and educational purposes. Enabling a better understanding of (patho)physiology, they also complement and support the development of AOPs by providing detailed mechanistic information at the gene and cell level. Furthermore, PMs contribute to devel­oping in vitro test batteries and to building (dynamic) in silico models aiming to predict the toxicity of chemicals. Collaborative efforts between the toxicology and systems biology communities are crucial for creating standardized and comprehensive PMs, supporting and accelerating the devel­opment of human-relevant NAMs for next-generation risk assessment.