Song G, Van Landingham CB, Gentry PR, Taylor MD, Keene AM, Andersen ME, Clewell HJ, Yoon M. Evaluation of Mn bioavailability from drinking water exposure in adult rats using physiologically-based pharmacokinetic modeling [abstract 3233]. Presented at the Society of Toxicology Annual Meeting, Baltimore, MD, March 2017.
Bioavailability of manganese (Mn) following drinking water ingestion remains a major data gap in understanding Mn kinetics in animals and humans. The uncertainty, related to whether there is enhanced absorption of Mn from drinking water intake, raises concerns for dosimetry based risk assessments using current PBPK models. This study (1) modeled the bioavailability of Mn from drinking water as compared to that from diet and (2) evaluated the homeostatic control of Mn uptake and tissue kinetics after drinking water exposure. A published adult rat model (Nong et al., Toxicol. Sci., 2009) was adapted to include drinking water-mediated Mn intake. Two important parameters regulating homeostatic control of Mn kinetics, fractional uptake (Fdietup) and biliary excretion (Kbilec), had to be adjusted so that the model simulations would be consistent with published data from a controlled drinking water study (Foster et al., Toxicol. Sci. 2015). In the drinking water study, rats received 10 ppm-Mn diet with additional Mn provided in drinking water to give a total ingested Mn dose equivalent to that from 200 ppm diet. Following 7 and 61 exposure days, liver, femur, striatum, olfactory bulb, and cerebellum samples were collected to assess tissue Mn concentrations. With the same parameters for uptake and elimination in the published model – dietary uptake (Fdietup= 0.0035) and biliary elimination (Kbilec= 0.0054 L/h/kg), good fits were obtained for time-course Mn tissue concentrations at both 200 ppm dietary exposure or the combined 200 ppm diet and drinking water exposure. Modeling of the drinking water study data indicates that (1) the oral Mn bioavailability is similar for diet and drinking water exposure in the gut and (2) there is homeostatic control of Mn-gut uptake effective for either drinking water or dietary ingestion. Our modeling of the drinking water uptake studies supports the use of total ingested Mn (diet plus drinking water) in the PBPK model instead of separating diet and drinking water exposure. This updated description for absorption of Mn from the intestines has been included in the human Mn-PBPK model to simulate and assess Mn exposure from multiple routes of exposure (i.e., dietary intake, drinking water, inhalation). (Supported by Afton Chemical Co.).