PNNL

Abstract

Manganese (Mn) is an essential nutrient. Mn deficiency is associated with altered lipid (Kawano et al. 1987) and carbohydrate metabolism (Baly et al. 1984; Baly et al. 1985), abnormal skeletal cartilage development (Keen et al. 2000), decreased reproductive capacity, and brain dysfunction. Occupational and accidental inhalation exposures to aerosols containing high concentrations of Mn produce neurological symptoms with Parkinson-like characteristics in workers. At present, there is also concern about use of the manganese-containing compound, methylcyclopentadienyl manganese tricarbonyl (MMT), in unleaded gasoline as an octane enhancer. Combustion of MMT produces aerosols containing a mixture of manganese salts (Lynam et al. 1999). These Mn particulates may be inhaled at low concentrations by the general public in areas using MMT. Risk assessments for essential elements need to acknowledge that risks occur with either excesses or deficiencies and the presence of significant amounts of these nutrients in the body even in the absence of any exogenous exposures. With Mn there is an added complication, i.e., the primary risk is associated with inhalation while Mn is an essential dietary nutrient. Exposure standards for inhaled Mn will need to consider the substantial background uptake from normal ingestion. Andersen et al. (1999) suggested a generic approach for essential nutrient risk assessment. An acceptable exposure limit could be based on some ‘tolerable’ change in tissue concentration in normal and exposed individuals, i.e., a change somewhere from 10 to 25 % of the individual variation in tissue concentration seen in a large human population. A reliable multi-route, multi-species pharmacokinetic model would be necessary for the implementation of this type of dosimetry-based risk assessment approach for Mn. Physiologically-based pharmacokinetic (PBPK) models for various xenobiotics have proven valuable in contributing to a variety of chemical specific risk assessments (Dixit et al., 2003). With most exogenous compounds, there is often no background exposure and body concentrations are not under active control from homeostatic processes as occurs with essential nutrients. Any complete Mn PBPK model would include the homeostatic regulation as an essential nutritional element and the additional exposure routes by inhalation. Two companion papers discuss the kinetic complexities of the quantitative dose-dependent alterations in hepatic and intestinal processes that control uptake and elimination of Mn (Teeguarden et al., 2006a, b). Radioactive 54Mn has been to investigate the behavior of the more common 55Mn isotope in the body because the distribution and elimination of tracer doses reflects the overall distributional characteristics of Mn. In this paper, we take the first steps in developing a multi-route PBPK model for Mn. Here we develop a PBPK model to account for tissue concentrations and tracer kinetics of Mn under normal dietary intake. This model for normal levels of Mn will serve as the starting point for more complete model descriptions that include dose-dependencies in both oral uptake and and biliary excretion. Material and Methods Experimental Data Two studies using 54Mn tracer were employed in model development. (Furchner et al. 1966; Wieczorek and Oberdorster 1989). In Furchner et al. (1966) male Sprague-Dawley rats received an ip injection of carrier-free 54MnCl2 while maintained on standard rodent feed containing ~ 45 ppm Mn. Tissue radioactivity of 54Mn was measured by liquid scintillation counting between post injection days 1 to 89 and reported as percent of administered dose per kg tissue. 54Mn time courses were reported for liver, kidney, bone, brain, muscle, blood, lung and whole body. Because ip uptake is via the portal circulation to the liver, this data set had information on distribution and clearance behaviors of Mn entering the systemic circulation from liver.