Song G, Van Landingham CB, Gentry PR, Taylor MD, Keene AM, Andersen ME, Lewell HJ, Yoon M. Incorporation of variability in dietary and drinking water Mn uptake in a PBPK model of manganese in the human [abstract 3177]. Presented at the Society of Toxicology Annual Meeting, San Antonio, TX, March 2018.
Dose-dependent gut uptake and biliary excretion of manganese (Mn) play an important role in homeostatic control of Mn following dietary Mn exposures. Concern has been raised regarding Mn exposures from drinking water. To allow this to be addressed in dosimetry-based risk assessments, the potential variability in Mn intake from diet and drinking water was assessed with a human Mn PBPK model. Modeling of a drinking water study data in rats demonstrated that the same parameters used for dietary uptake and elimination in the published adult rat model accurately described the time-course of Mn tissue concentrations for an equivalent drinking water exposure. The results indicated that oral Mn bioavailability is similar for diet and drinking water exposure in the gut, supporting the use of total ingested Mn (diet plus drinking water) in the PBPK model. Fractional Mn absorption (‘Fdietup’) as a function of daily Mn intake has now been estimated for human dietary Mn intakes across the normal ingestion range of 1.2 to 10 mg/day. Nonlinear regression analysis was performed for Fdietup as a function of dietary Mn intake (mg/day) and a function for Fdietup dependence on intake was obtained (R2=0.972). Using this model, comparisons were made to the data in publications, including data on Mn drinking water exposure in children of Bangladesh (Wasserman et al. 2006). Using average food concentrations (a conservative estimate of 2.25 mg/day obtained from NHANES), the model predicted blood concentration of Mn was ~10 µg/L which is only slightly under the observed mean value of 12.8 µg/L reported in Wasserman et al. (2006).