We describe a framework for developing response recommendations to unexpected toxic pollutant releases in commercial buildings. It may be applied in conditions where limited building- and event-specific information is available. The framework is based on a screening-level methodology to develop insights, or rules-of-thumb, into the behavior of airflow and pollutant transport. A three-stage framework is presented: (1) develop a building taxonomy to identify generic, orprototypical, building configurations, (2) characterize uncertainty and conduct simulation modeling to predict typical airflow and pollutant transport behavior, and (3) rank uncertainty contributions to determine how information obtained at a site might reduce uncertainties in the model predictions. The approach is applied to study a hypothetical pollutant release on the first floor of a five-story office building. Key features that affect pollutant transport are identified and described by value-ranges in the building stock. Simulation modeling provides predictions and uncertainty estimates of time-dependent pollutant concentrations, following a release, for a range of indoor and outdoor conditions. In this exercise, we predict concentrations on the fifth floor to be an order of magnitude less than on the first, coefficients of variation greater than 2, and information about the HVAC operation and window position most reducing uncertainty in predicted peak concentrations.