Pharmacokinetic Evaluation of the Equivalency of Gavage, Dietary, and Drinking Water Exposure to Manganese in F344 Rats

Manganese is an essential mineral that is found at low levels in virtually all diets (ATSDR, 2012). Ingestion is the principal route by which most people are exposed to manganese, although toxicologically significant inhalation exposures also occur. The gastrointestinal and hepatobiliary systems play an important regulatory role in maintaining tissue manganese concentrations within a relatively narrow physiologic range (Aschner and Aschner, 2005). For example, a moderate increase in dietary manganese intake is accompanied by a compensatory decrease in gut absorption, an increased liver manganese concentration, and an elevated biliary excretion level in order to maintain normal manganese concentrations in the brain and other extrahepatic tissues (Aschner and Aschner, 2005; Dorman et al., 2001). Excessive exposure to manganese and/or hepatic injury can overwhelm these normal homeostatic controls, resulting in elevated tissue manganese and toxicity (Guilarte, 2010). In humans, manganese-induced neurotoxicity is of primary concern and is thought to be the most sensitive endpoint. An extreme case of manganese neurotoxicity is known as manganism, which is usually caused by chronic inhalation of high levels of manganese. Hallmarks of manganism include behavioral changes, extrapyramidal motor dysfunction, and neurochemical and neuropathological changes in the basal ganglia and globus pallidus (Roels et al., 2012). Manganese-induced cognitive deficits have also been reported in workers with exposure to manganese-based welding fumes (Bowler et al., 2006; Chang et al., 2010; Ellingsen et al., 2008; Park et al., 2009). Affected brain regions following high-dose manganese exposure include the striatum, globus pallidus, and other dopaminergic and γ-aminobutyric acid-containing mid-brain structures that control motor functions (Guilarte, 2013). In contrast to the numerous reports describing manganese toxicity following occupational inhalation exposure in humans, there are relatively few reports of manganism arising from water or dietary sources. In part, this trend is due to the relatively low levels of manganese found in these media. For example, most diets in North America result in a manganese intake below the current reference dose of 10 mg/day (Finley and Davis, 1999). Water concentrations of manganese typically range from 1 to 100 µg/l, with most values below 10 µg/l (Keen and Zidenberg-Cherr, 1994). On rare occasions, clinically apparent manganese toxicity can result from ingestion. For example, Kawamura et al. (1941) and Kondakis et al. (1989) documented outbreaks of manganism in Japan and Greece due to the ingestion of water from wells that were contaminated with extremely high levels of manganese (1.8–14 mg Mn/l). There has also been increasing concern regarding the role of environmental manganese exposure and children’s health (Zoni and Lucchini, 2013). For example, several community studies have suggested a link between manganese content in drinking water and a decrease in the IQ of children (Bouchard et al., 2011; Khan et al., 2012; Wasserman et al., 2006), although the toxicological significance of these studies remains to be established (Lucchini et al., 2009). Many questions remain as to the conditions under which ingestion of manganese can result in an increased incidence of human neurological disease (Boyes, 2010). Experimental animal studies remain an important tool for the study of manganese pharmacokinetics and neurotoxicity (Dorman et al., 2012). Animal studies examining the pharmacokinetics and toxicity of ingested manganese often rely on 3 exposure methods: diet, drinking water, and gavage. Most dietary studies rely on the use of a defined rodent diet to which specified amounts of manganese have been added. Drinking water studies often use water combined with manganese chloride (MnCl2), other soluble manganese salts, or insoluble manganese oxides (eg, MnO2). Gavage studies rely on the oral ‘injection’ of a bolus dose of manganese that is typically dissolved in an aqueous media. Both drinking water and dietary exposure studies more closely mimic adult human exposures, as they involve small, repetitive exposures to manganese throughout the day. Although these different methods are used, little data is available to assess the impact of either oral dose rate (eg, gavage versus drinking water) or manganese vehicle (eg, drinking water versus diet) on the pharmacokinetics of manganese exposure. The overall objective of this study was to determine whether dose rate influences the pharmacokinetics of manganese, and evaluate the equivalency of dietary and drinking water manganese intake with regards to tissue manganese concentrations.