Footprint indicators are used to evaluate chemical substance management. However, determining the impact of chemical restrictions on manufacturing processes and supply chains without a footprint analysis of the entire lifecycle is difficult. Here, we propose a new framework for estimating chemical toxicity footprints utilizing the risk-screening environmental indicators (RSEIs) published by the U.S. Environmental Protection Agency. We conducted an empirical analysis using multi-states input–output data from the U.S. in 2017 to demonstrate the usefulness of the framework, and made policy recommendations based on the obtained results. According to the production-based RSEI scores, Texas, Pennsylvania, Illinois, and Louisiana accounted for 43% of the total human health risk in the U.S. By contrast, California and New York ranked first and second in consumption-based RSEI score (i.e., health risk footprint), respectively; however, the District of Columbia and Alabama ranked first and second in per capita footprint. Three significant risk transfers, accounting for 6% of the total in the U.S. economy, were found: from California to Texas, from New York to Texas, and from Florida to Texas. In conclusion, specific states such as Texas and Louisiana were at considerable risk from major chemical substance emissions triggered by final demands in mega cities such as New York and California. Thus, the federal and state governments should select high priority sectors and states according to the production-based RSEI scores. Relevant taxes can be collected from states based on the consumer’s responsibility. Footprint-based inter-state financial cooperation is crucial in mitigating chemical pollutions in the U.S.