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[Display omitted] • Estimating API emissions to wastewater on city-scale is feasible. • Choice of excretion fraction impacts model performance substantially. • Model-based emission estimation can offer an informative alternative for monitoring. • Availability + accessibility of use data limit application to other contaminants. With increasing numbers of chemicals used in modern society, assessing human and environmental exposure to them is becoming increasingly difficult. Recent advances in wastewater-based epidemiology enable valuable insights into public exposure to data-poor compounds. However, measuring all >26,000 chemicals registered under REACH is not just technically unfeasible but would also be incredibly expensive. In this paper, we argue that estimating emissions of chemicals based on usage data could offer a more comprehensive, systematic and efficient approach than repeated monitoring. Emissions of 29 active pharmaceutical ingredients (APIs) to wastewater were estimated for a medium-sized city in the Netherlands. Usage data was collected both on national and local scale and included prescription data, usage in health-care institutions and over-the-counter sales. Different routes of administration were considered as well as the excretion and subsequent in-sewer back-transformation of conjugates into respective parent compounds. Results suggest model-based emission estimation on a city-level is feasible and in good agreement with wastewater measurements obtained via passive sampling. Results highlight the need to include excretion fractions in the conceptual framework of emission estimation but suggest that the choice of an appropriate excretion fraction has a substantial impact on the resulting model performance. [ABSTRACT FROM AUTHOR]