Regulatory frameworks to control chemical exposure in general living and occupational environments have changed exposure scenarios towards a widely spread contamination at relatively low doses in developed countries. In such evolving context, some critical aspects should be considered to update risk assessment and management strategies. Risk assessment in low-dose chemical exposure scenarios should take advantage of: toxicological investigations on emerging substances of interest, like those recognised as endocrine disruptors or increasingly employed nanoscale materials; human biological monitoring studies aimed to identify innovative biomarkers for known chemical exposure; "omic" technologies useful to identify hazards of chemicals and their modes of action. For updated risk assessment models, suitable toxicological studies, analyses of dose-responses at low-concentrations, environmental and biological monitoring of exposure, together with exposome studies, and the proper definition of susceptible populations may all provide helpful contributions. These may guide defining preventive measures to control the exposure and develop safe and sustainable chemicals by design. Occupational medicine can offer know-how and instruments to understand and manage such evolution towards a toxic-free environment to protect the safety and health of the workforce and, in turn, that of the general population.