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Toxicological information

Neurotoxicity

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Administrative data

Endpoint:
neurotoxicity
Remarks:
subchronic
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Conducted to a reasonable scientific standard. Dose route is not applicable to human exposure.

Data source

Reference
Reference Type:
publication
Title:
Effects of manganese oxide on monkeys as revealed by a combined neurochemical, histological and neurophysiological evaluation
Author:
Eriksson H, Magiste K, Platin L-O, Fonnum F, Hedstrom K-G, Theodorsson-Norheim E, Kristensson K, Stalberg E & Heilbronn E.
Year:
1987
Bibliographic source:
Arch. Toxicol., 61: 46-52.

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The neurochemical, histological and neuropsychological effects of manganese oxide were assessed in monkeys that were repetitively injected intraperitoneally with a manganese (IV) oxide suspension in olive oil. The monkeys were left for 1 week to 6 months before they were sacrificed.
GLP compliance:
not specified
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): manganese(IV) oxide
- Purity: 99.999%

Test animals

Species:
monkey
Strain:
Macaca fascicularis
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 3.5 - 4.5 kg
- Diet: pellets (ad libitum) and fruit (every day)
- Water: ad libitum

Administration / exposure

Route of administration:
intraperitoneal
Vehicle:
olive oil
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
5 months
Frequency of treatment:
18 separate occasions
Doses / concentrations
Remarks:
Doses / Concentrations:
8 g manganese in total
Basis:
other: amount injected
No. of animals per sex per dose:
4 males
Control animals:
yes, concurrent vehicle

Results and discussion

Effect levels

Dose descriptor:
other: Neurochemical, histological and neurophysiological evaluation
Effect level:
8 other: g in total on 18 occasions over 5 months
Sex:
male
Basis for effect level:
other: overall effects neurobehaviour; neuropathology; neurochemistry;
Remarks on result:
other:

Any other information on results incl. tables

Monkey No 1: Initially developed hyperactive behaviour, which then turned to hypoactivity. Monkey no 2 had similar symptoms, but more pronounced. monkeys No. 3 and 4 were affected as per monkey No. 2 but were sacrificed earlier.

Manganese exposed monkeys showed a severe loss of nerve cells and astrogliosis in the palladium.

The manganese content in different brain regions increased up to 50 times in the globus pallidus and putamen. The increase in the caudate nucleus, substantia nigra, cerebral cortex and cerebellum was not more than 10 -20 fold.

Dopaminergic and serotinergic systems appeared to be affected.

Neurotensin content in both the caudate nucleus and putamen was considerably lower than in the control animals.

The activity of DOPA-decarboxylase in the putamen was found to be 42% compared to that of controls. ChAT activity was reduced in the globus pallidus.

One Mn exposed monkey had a considerably lower glutathione content in all brain regions analysed, as compared to controls.Two others though had a normal glutathione content.

Applicant's summary and conclusion

Conclusions:
The toxic actions of manganese show a selectivity towards the dopaminergic system and the neurotensin-containing neurons. The lack of effect on the glutathione content, simultaneously with significant neurochemical alterations of another kind, does not support the view that an oxidative mechanism is primarily involved during in vivo exposition. As in the case of Parkinson's disease, the dopamine content in the MnO2- exposed monkeys was affected more in the putamen than in the cordate nucleus.

In conclusion, all the observed effects of the manganese intoxication follow the manganese content in the different regions. It is, however, not possible to definitely rule out the chance that this is circumstantial. The effects were not entirely homogenous in the sense that the measured parameters were equally affected in all the analysed brain regions. Thus, the toxic actions of manganese show a selectivity towards the dopaminergic system and the neurotensin containing neurons. Minor effects on the cholinergic and serotonin systems were observed while the GABA-ergic system appears unaffected, which was supported both by a lack of effect on GAD activity had on GABA content.
Executive summary:

The neurochemical, histological and neuropsychological effects of manganese oxide were assessed in monkeys that were repetitively injected intraperitoneally with a manganese (IV) oxide suspension in olive oil. The monkeys were left for 1 week to 6 months before they were sacrificed for analysis.

Under the conditions of the study all animals developed hyperactive behaviour after about 2 months. About 5 months after the start of the exposure the animals became hypoactive with an unsteady gait, and subsequently an action tremor appeared in some of the animals. The animals lost power in both upper and lower limbs and the movements of the hands and feet were very clumsy. The serum content of manganese rose 10- 40 times during the exposure time and the content in brain was generally increased more than 10 times, with the highest content found in globus pallidus and putamen. The observed neurochemical effects were also largest in globus pallidus and putamen. In these regions there was a considerable depletion of dopamine and 3,4-dihydroxyphenylacetic acid, while the homovanillic acid content remained almost unchanged. A severe neuronal cell loss was observed in globus pallidus but not in other regions. This is in accordance with results from a neuropathological study of a human suffering from chronic manganese poisoning where globus pallidus was devoid of neuronal cells while the content of pigmented cells in substantia nigra was normal. These data suggest a reduction in number of dopaminergic nerve terminals, as the activity of the dopamine synthesizing enzyme DOPA-decarboxylase was also lowered.

In conclusion, all the observed effects of the manganese intoxication follow the manganese content in the different regions. It is, however, not possible to definitely rule out the chance that this is circumstantial. The effects were not entirely homogenous in the sense that the measured parameters were equally affected in all the analysed brain regions. Thus, the toxic actions of manganese show a selectivity towards the dopaminergic system and the neurotensin containing neurons. Minor effects on the cholinergic and serotonin systems were observed while the GABA-ergic system appears unaffected, which was supported both by a lack of effect on GAD activity had on GABA content.