The human health risk assessment of electronic nicotine delivery system (ENDS) ingredients is complex, even for an experienced toxicologist. First, the risk assessor must consider the individual implications of each ingredient, whether mono- or multi-constituent based, along with the mixture of these ingredients in the formulation. Then consideration must be given to the behavior of the ingredients within the device, including reactions before and during product use, such as thermal degradation. It is not unusual for these considerations to result in a single risk assessment covering dozens of discrete substances. The information is coupled with the exposure considerations to allow the risk assessment to progress, taking into account both systemic and local endpoints. Throughout this process, the assessor must also determine the quality of the available data, the impact of the absence of data, how to manage uncertainty and whether additional data is required to conclude the assessment. A tiered approach is useful when evaluating the information gathered and data generated in the course of conducting these types of assessments. During this talk, we will cover several tiers including: 1) Use of literature reviews and screening criteria for hazard identification, including options for managing the potentially very large datasets; 2) Read across using in silico tools and other methods of data gap filling to balance unknowns and uncertainty during risk characterization; and 3) Considerations of the whole formulation and exposure under intended conditions of use.