Pharmacokinetic data needs to support risk assessments for inhaled and ingested manganese

Manganese (Mn)-deficiency or Mn-excess can lead to adverse biological consequences. Central nervous system tissues, rich in dopaminergic neurons, are the targets whether the Mn gains entrance by inhalation, oral ingestion, or intravenous administration. Risk assessments with Mn need to ensure that brain concentrations in the globus pallidus and striatum stay within the range of normal. This paper first provides a critical review of the biological factors that determine the disposition of Mn in tissues within the body. Secondly, it outlines specific data needs for developing a physiologically based pharmacokinetic (PBPK) model for Mn to assist in conducting risk assessments for inhaled and ingested Mn. Uptake of dietary Mn appears to be controlled by several dose-dependent processes: biliary excretion, intestinal absorption, and intestinal elimination. Mn absorbed in the divalent form from the gut via the portal blood is complexed with plasma proteins that are efficiently removed by the liver. Absorption of Mn via inhalation, intratracheal instillation or intravenous infusions bypasses the control processes in the gastrointestinal tract. After absorption into the blood system by these alternate routes, Mn is apparently oxidized by ceruloplasmin and the trivalent Mn binds to the iron carrying protein, transferrin. Brain uptake of Mn occurs via transferrin receptors located in various brain regions. Transferrin-bound trivalent Mn is not as readily removed by the liver, as are protein complexes with divalent Mn. Thus, Mn delivered by these other dose routes would be available for uptake into tissues for a longer period of time than the orally administered Mn, leading to quantitative differences in tissue uptake for different dose routes. Several important data gaps impede organizing these various physiological factors into a multi-dose route PK model for Mn. They include knowledge of (1) oxidation rates of Mn in blood, (2) uptake rates of protein-bound forms of Mn by the liver, (3) neuronal transfer rates within the CNS, and (4) quantitative analyses of the control processes that regulate uptake of ingested Mn by the intestines and liver. These data gaps are the main obstacles to developing a risk assessment strategy for Mn that considers contributions of both inhalation and ingestion of this essential nutrient in determining brain Mn concentrations.