The Human Toxicity Potential (HTP) is a quantitative toxic equivalency potential (TEP) that has been introduced previously to express the potential harm of a unit of chemical released into the environment. HTP includes both inherent toxicity and generic source-to-dose relationships for pollutant emissions. Three issues associated with the use of HTP in life-cycle impact assessment (LCIA) are evaluated here. First is the use of regional multimedia models to define source-to-dose relationships for the HTP. Second is uncertainty and variability in source-to-dose calculations. And third is model performance evaluation for TEP models. Using the HTP as a case study, we consider important sources of uncertainty/variability in the development of source-to-dose models—including parameter variability/uncertainty, model uncertainty, and decision rule uncertainty. Once sources of uncertainty are made explicit, a model performance evaluation is appropriate and useful and thus introduced. Model performance evaluation can illustrate the relative value of increasing model complexity, assembling more data, and/or providing a more explicit representation of uncertainty. This work reveals that an understanding of the uncertainty in TEPs as well as a model performance evaluation are needed to a) refine and target the assessment process and b) improve decision making.