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Due to concerns for enhanced absorption of manganese (Mn) from drinking water compared to diet, bioavailability of Mn from drinking water remains a major data gap in understanding Mn kinetics. In this study, PBPK models for adult rats and humans were updated with a drinking water exposure route and were used to assess the homeostatic control of Mn uptake, excretion and tissue kinetics between the two different ingestion modes. Drinking water model parameters were estimated from tissue kinetic data from a drinking water study in rats. The published study included a 10ppm-Mn diet with additional Mn added to drinking water to give a total ingested Mn dose equivalent to that from a 200ppm diet. The 200ppm diet and equivalent mixed drinking water/diet exposures provided Mn concentrations for brain (striatum, olfactory bulb, and cerebellum), liver and bone after 7 and 61days of Mn exposure. Modeling of these data sets indicated that (1) the oral Mn bioavailability is similar for diet or drinking water and (2) homeostatic control of gut uptake of Mn occurs with either drinking water or dietary ingestion. This updated description for absorption and distribution of Mn from gut was added to a human Mn-PBPK model to simulate Mn exposure from multiple routes of exposure (i.e. dietary intake, drinking water, and inhalation). This increases the utility of the Mn PBPK model by allowing for the simulation of multiple Mn exposure scenarios, including variable daily food and drinking water exposures in a human population.Rat PBPK modeling was used to assess Mn bioavailability from diet vs. drinking water.Homeostatic control of Mn gut uptake is dependent on total ingested amount of Mn.Human Mn-PBPK model is updated to simulate Mn exposure through drinking water.The updated multi-route/source model can simulate realistic human exposure to Mn.