Animal models of manganese's neurotoxicity.

Manganese's neurotoxicity continues to present a puzzling array of differences across individuals and across published reports in the profile of effects seen in humans and nonhuman species, but some of the sources of individual variability are becoming clear from studies of animals. The kinetics of manganese is a critical component of any assessment of risk associated with exposure. After inhalation, the uptake of manganese into and elimination from the central nervous system are slow and some manganese remains in the nervous system a year after inhalation. Comparison with other parenteral routes suggests that manganese depots in lung prolongs exposure even after environmental exposure has ended. Manganese's neurotoxicity is associated with its appearance in basal ganglia structures, especially the globus pallidus. Manganese also appears in the pituitary gland but the functional consequences of this are not well understood. Other critical components in characterizing manganese's neurotoxicity appear to be the behavioral endpoints used, the species studied, and the exposure rate. Over neurological signs and excitability are associated with high exposure rates and the appearance of manganese throughout basal ganglia and basal forebrain regions. More focused behavioral endpoints are required to detect the subtle signs associated with slow exposure rates low exposure levels, but when such designs are used the effect is unequivocal. At lower exposure levels, doses of 5 mg/kg and greater, deficits in a task in which a monkey executed a rowing type motion against a spring approximating its body weight were clearly related to manganese exposure while other traditional measures of response patterns under schedules of reinforcement remained intact. Excitability and other signs of emotionality have not been reported at low exposure rates. In rodents, manganese accumulation and alterations in the function or concentration of neurotransmitters have been reported. Investigations of behavioral effects in these species, which usually involved locomotor activity, have resulted in less consistent results. Manganese produces a constellation of neurotoxic signs whose appearance and detection are influenced by dose and exposure rate. Despite investigations of manganese's neurotoxicity in animals over a wide range of exposure levels, a NOAEL has not been identified.