Mn Toxicity and Liver Function Since the original report by Klaassen in 1976 describing the hepatobiliary excretion of Mn from the liver [72], not much work has been done to describe Mn-induced hepatotoxicity. The liver is a known storage organ for Mn; the highest Mn uptake occurs in the liver, only second to brain uptake [36]. Hepatic Mn accumulation in mice intravenously injected with Mn nanoparticles persisted significantly longer than other highly perfused tissues such as kidney and spleen; however, no histopathological damage was observed [75]. Hepatobiliary excretion of Mn represents a primary route of Mn clearance from the body, accounting for 80 % of Mn elimination. Thus, severe liver damage, owing to various chronic liver diseases, can result in an excessive accumulation of Mn in brain with ensuing signs and symptoms clinically called Mn hepatic encephalopathy [106]. With weakened liver function, there is also an increased risk of neurodegeneration with continued Mn exposure [107]. In those patients with chronic hepatic encephalopathy, liver transplant has proven to be effective in reducing brain Mn concentrations. When patients were re-examined 5 months after transplant, the T1- weighted MRI signals in the basal ganglia were absent [106]. These data suggest that the normal liver function is essential to maintain homeostasis of Mn in the body, including the CNS.