This report develops a framework to guide decisions whether to incorporate physiologically based pharmacokinetic (PBPK) modeling into the cumulative risk assessment process. It is not restricted to Food Quality Protection Act (FQPA) applications and intends to guide the risk assessor through choosing to conduct and conducting a dosimetry based cumulative risk assessment, addressing the level of toxicant in the target tissue, rather than relying on exposure concentrations and the hazard index approach. This report includes data and values for several compounds to demonstrate the proposed approach by means of example. It is not intended to present an analysis of the internal exposures or risks from these mixtures. Some of the example chemicals (trichloroethylene, tetrachloroethylene) are the subject of ongoing U.S. Environmental Protection Agency (U.S. EPA) risk assessments, and risk values for other chemicals are those developed by Agency for Toxic Substances and Disease Registry (ATSDR), rather than by the U.S. EPA. The main objectives are (1) to improve the science and risk assessment by moving the measure of dose from concentration in the environmental contact medium to inside the body (i.e., tissue dose rather than exposure dose); (2) to achieve this objective is via PBPK modeling; (3) to incorporate PBPK modeling into the cumulative risk assessment process and (4) to make the optimal use of in vitro techniques, including the use and application of human tissues.