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central nervous system pathology and behavioral changes, although these changes are not necessarily identical to those seen in humans. A review by Newland (1999) suggests that manganese toxicity occurs at progressively lower doses when manganese is administered in food, in water, or by injection, respectively. Differences in toxic potency by route of administration may be an order of magnitude or more. The lowest dose study of manganese administered in food identified by Newland (1999) was by Komura and Sakamoto (1992). They fed male mice diets high in manganese (2 g/kg food) for 12 months (either as MnCl2, manganese acetate, MnCO3, or MnO2). Thus, a 30-gram mouse eating 4 g/day of food would have ingested about 266 mg/kg/day of manganese. Changes in brain regional biogenic amines and decreases in locomotor activity were observed, but changes were somewhat different for each salt. In general, manganese dioxide was found to be more toxic than other forms, and manganese chloride was least toxic.

Several studies have examined neurotoxic effects of manganese in drinking water or administered by gavage. The two lowest dose studies are reviewed here. Bonilla (1984) gave male rats 0.1 or 5.0 mg/mL of manganese in drinking water for 8 months and measured locomotor activity throughout this period. A significant increase in activity during the first month was found at both doses. Activity returned to normal for months 2 through 6, but in the seventh and eighth months, activity was less than that of control subjects in both groups. In a related study, Bonilla and Prasad (1984) gave rats 0.1 or 1.0 mg/L of manganese in drinking water for 8 months. They observed decreases of norepinephrine in striatum and pons of rats treated with the lower dose. Increases in the dopamine metabolite dihydroxyphenylacetic acid were found in striatum and hypothalamus at both doses. Homovanillic acid (another dopamine metabolite) decreased in striatum of the lower dose group. Changes in serotonin and its metabolite, 5-hydroxyindole acetic acid, were seen in some brain regions in the high dose group. As with the Komura and Sakamoto (1992) study, the actual doses of manganese in this study can only be approximated. Assuming that a 300 g rat ingests about 30 mL/day of water, then the daily dose of manganese in this study was about 10 mg/kg/day.

Senturk and Oner (1996) exposed rats to 0.357 to 0.714 mg/kg/ day of manganese (as MnCl2) by gavage in distilled water for 39 days. Manganese levels in brain regions were elevated, and learning in a T-maze task was retarded. The learning impairment was associated with hypercholesterolemia, and the impairment was not seen

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