Humans are typically exposed to toxic metals in the form of mixtures, as metals are often found together in multiple exposure media (food, water, soil, and air). Furthermore, interaction effects among these metals exist at both the toxicokinetic and toxicodynamic level in the human body. While several different physiologically based toxicokinetic (PBTK) models exist for different environmental chemicals, using them in assessing risks to mixtures of metals is often impractical. Several differences in the formulation of these models exist with respect to (a) physiological structure (e.g., body tissue volumes and blood flow ratios), (b) general modeling assumptions (e.g., for transport and transformation of the chemicals within the body), and (c) exposure-relevant parameters. Since certain assumptions made for one metal (or metal compound) can be incompatible with assumptions made for another metal, current model formulations are generally inadequate for use in assessing health risks from their mixtures. This work presents the development and application of a “generalized” Modeling ENvironment for TOtal Risk (MENTOR) with Physiologically-based Pharmacokinetic modules for Populations (3P). MENTOR-3P utilizes a mechanistically consistent framework for modeling multiple chemicals including multiple metals and metal compounds. Case studies using the multi-metals implementation of MENTOR-3P are presented, along with an analysis of potential interaction parameters and their effects on body burden and biomarker predictions. Relationships between essential element nutrition and toxic metal absorption are addressed, focusing on (a) the biological basis for toxic/essential metal interactions, (b) the potential impacts of nutrition on multi-metal dose modeling for populations, and (c) the stochastic/time-varying nature of toxic metal absorption and impacts on long-term exposures. Disclaimer: This work is funded in part by the USEPA through STAR Grant GAD R 832721-010 and Cooperative Agreement CR-83162501. Viewpoints expressed here are the responsibility of the authors and do not necessarily reflect views of the USEPA or its contractors.