Pharmacokinetic Modeling of Manganese. I. Dose Dependencies of Uptake and Elimination

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Abstract
Homeostatic mechanisms controlling uptake, storage, and elimination of dietary manganese (Mn) afford protection against fluctuations in tissue manganese (Mn) levels. Homeostatic control of inhaled Mn is less well understood, but important in assessing likely risks of Mn inhalation. Two compartmental kinetic models were used to characterize the influence of Mn exposure level and route (oral, inhalation) on uptake, elimination, and transport of Mn. The models were fitted to or used to interpret data from five whole-body Mn elimination studies: one dietary Mn balance study, two biliary elimination studies, and one acute and one chronic. As dietary Mn concentrations increased from low sufficiency (1.5 ppm) to sufficiency (20 ppm), control of Mn uptake shifts from the intestine (principally) to more proportional control by both intestinal tissues and liver. Using a two-compartment distribution model, the increased elimination of 54Mn tracer doses in response to increases in dietary Mn (rats and mice) or inhaled Mn (rats) resulted from elevation in Mn elimination rate constants rather than changes in intercompartmental transfer rate constants between a central compartment and deep compartment. The pharmacokinetic (PK) analysis also indicated differential control of absorption in single gavage oral dose studies versus continuous high oral doses in the feed. The gavage study indicated increased elimination rate constants, and the chronic study showed reduced rate constants for absorption. These dose dependencies in uptake and elimination are necessary inputs for comprehensive PK models guiding human health risk assessments with Mn.