Health risk assessment (HRA) has been recognized as a useful tool for identifying health risks of human activities. In particular, this method has been well applied to spatially defined units, such as a production plant, a treatment facility, and a contaminated site. However, the management strategies based on the risk information will be more efficient if the comprehensive picture of total risks from all kinds of sources is depicted. In principle, the total risks can be obtained when all risk sources are assessed individually. Apparently, this approach demands huge amount of efforts. This study develops a methodology that combines substance flow and risk estimation to facilitate examination of risk in a systemic way and provide comprehensive understanding of risk generation and distribution corresponding to flows of substances in the anthroposphere and the environment. Substance flow analysis (SFA) and HRA method is integrated to produce a systemic risk assessment method, from which substance management schemes can be derived. In this study, the chromium cycle in Taiwan is used as an example to demonstrate the method, by which the associated substance flow in the economy and the risk caused by the substance in the environmental system is determined. The concentrations of pollutants in the environmental media, the resultant risks and hazard quotients are calculated with the widely-used CalTOX multimedia model.