Adequacy and Consistency of Animal Studies to Evaluate the Neurotoxicity of Chronic Low-Level Manganese Exposure in Humans

Abstract

The adequacy of existing animal studies to understand the effects of chronic low-level manganese exposures in humans is unclear. Here, a collection of subchronic to chronic rodent and nonhuman primate studies was evaluated to determine whether there is a consistent dose-response relationship among studies, whether there is a progression of effects with increasing dose, and whether these studies are adequate for evaluating the neurotoxicity of chronic low-level manganese exposures in humans. Neurochemical and behavioral effects were compared along the axis of estimated internal cumulative manganese dose, independent of the route of exposure. In rodents, motor effects emerged at cumulative doses below those where occupationally exposed humans start to show motor deficits. The main neurochemical effects in rodents were an increase in striatal gamma-aminobutyric acid (GABA) concentration throughout the internal cumulative dose range of 18 to 5300 mg Mn/kg but a variable effect on striatal dopamine concentration emerging at internal cumulative doses above ∼200 mg Mn/kg. Monkey studies showed motor deficits and effects on the globus pallidus at relatively low doses and consistent harmful effects on both the globus pallidus and the caudate and putamen at higher doses (> 260 mg Mn/kg). Internal cumulative manganese doses of animal studies extend more than two orders of magnitude (< 1 to 5300 mg Mn/kg) above the doses at which occupationally exposed humans show neurological dysfunction (10–15 mg Mn/kg). Since the animal data indicate that manganese neurotoxicity may be different at low compared to elevated exposures, most existing animal model studies might be of limited relevance for the risk assessment of chronic low-level manganese exposure to humans.