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Neurotoxicity

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Description of key information

Neurotoxic effects of overconsumption of L-Aspartic acid have not been proven in human studies. The diet normally contains a high content of glutamate and aspartate (as protein) and the intestinal epithelium and the liver have the capacity to metabolise large quantities of these amino acids. The blood-brain barrier and the very powerful glial and neuronal uptake systems for glutamate and aspartate help to keep the extracellular concentration of glutamate low in the brain.

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Link to relevant study records
Reference
Endpoint:
neurotoxicity
Remarks:
other: Various.
Type of information:
other: review
Adequacy of study:
supporting study
Study period:
<1993
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: A published review.
Qualifier:
no guideline required
Principles of method if other than guideline:
Review publication and suggestion of mechanisms of neurotoxicity.
Description (incidence and severity):
Migrated information from 'Further observations for developmental neurotoxicity study'

Details on results (for developmental neurotoxicity):The possibility that some acidic amino acids occurring naturally or as additives in the diet can act as excitotoxins producing central nervous system pathology has been the subject of extensive debate in the last 20 years and is here reviewed. High doses of glutamate, aspartate or related excitatory amino acids given in isolation to neonatal rodents produce acute degeneration in periventricular organs. Neuropathology resulting from consumption of glutamate or aspartate has not been described in man.
The diet normally contains a high content of glutamate and aspartate (as protein) and the intestinal epithelium and the liver have the capacity to metabolise large quantities of these amino acids. The blood-brain barrier and the very powerful glial and neuronal uptake systems for glutamate and aspartate help to keep the extracellular concentration of glutamate low in the brain.
(migrated information)
Conclusions:
Neuropathology resulting from consumption of glutamate or aspartate has not been described in man. The diet normally contains a high content of glutamate and aspartate (as protein) and the intestinal epithelium and the liver have the capacity to metabolise large quantities of these amino acids. The blood-brain barrier and the very powerful glial and neuronal uptake systems for glutamate and aspartate help to keep the extracellular concentration of glutamate low in the brain.
Executive summary:

The possibility that some acidic amino acids occurring naturally or as additives in the diet can act as excitotoxins producing central nervous system pathology has been the subject of extensive debate in the last 20 years and is here reviewed. High doses of glutamate, aspartate or related excitatory amino acids given in isolation to neonatal rodents produce acute degeneration in periventricular organs. Neuropathology resulting from consumption of glutamate or aspartate has not been described in man.

The diet normally contains a high content of glutamate and aspartate (as protein) and the intestinal epithelium and the liver have the capacity to metabolise large quantities of these amino acids. The blood-brain barrier and the very powerful glial and neuronal uptake systems for glutamate and aspartate help to keep the extracellular concentration of glutamate low in the brain.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Effect on neurotoxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
neurotoxicity
Remarks:
other: various
Type of information:
other: experimental results plus review
Adequacy of study:
supporting study
Study period:
1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Publication in a recognised journal.
Principles of method if other than guideline:
Review publication.

It is generally accepted that the administration of large quantities of glutamate or aspartate to the newborn mouse and rat produces a variety of neurotoxic effects. These effects include the retinal lesions first described by Lucas and Newhouse in 1957 and confirmed later by other investigators (Lucas and Newhouse, 1957; Cohen, 1957; Freedman and Potts, 1963a, 1963b; Olney, 1969b; Potts et al., 1960); obesity (Knittle and Ginsberg-Fellner, 1970; Maysuyan, 1970; Olney, 1969a; Redding et al., 1971); neuro-endocrine disturbances (Olney, 1969a; Redding et al., 1971); possible learning defects (Pradhan and Lynch, 1972); convulsions (Knaape and Wiechert, 1970; Bhagavan et al., 1971; Johnston, 1973; Mushahwar and Koeppe, 1971); and a massive lesion in the arcuate nucleus of the hypothalamus {Olney, 1969a, 1969b). The hypothalamic neuronal necrosis has been demonstrated in the infant mouse following large oral (Abraham et al., 1971; Burde et al., 1971; Lemkey-Johnston and Reynolds, 1974; Olney and Ho, 1970), or subcutaneous doses (Abraham et al., 1971; Burde et al., 1971; Inouye and Murakami, 1973; Lemkey-Johnston and Reynolds, 1974; Murakami and Inouye, 1971; Olney, 1969a) of glutamate and aspartate. The effect of the two amino acids together is additive (Olney and Ho, 1970).

Whether lesions are produced in species other than the rodent is highly controversial at this point. Even the rodent, however, shows strain susceptibility to these amino acids (Lemkey-Johnston and Reynolds, 1974).

The most critical data obviously deal with the infant subhuman primate. In 1969, Olney and Sharpe (1969) reported an extensive glutamate-induced neuronal lesion in a single premature primate following injection of glutamate at 2.7 g/kg body weight. They reported a massive lesion similar to that described in the mouse (Olney, 1969a). Later, Olney et al. (1972) redescribed the site and size of the original lesion in the primate following additional oral studies with glutamate. They reported the lesion size to be dose-related (Olney et al., 1972, 1973b), noting massive lesion at high load levels (4 g/kg) and only a small lesion, involving as few as 50-90 cells, at lower load levels. However, at least four separate research groups have failed to reproduce this lesion in the primate (Abraham et al., 1971; Reynolds et al., 1971; Wen et al., 1973; Newman et al., 1973), with Reynolds et al. (1971, 1972), reporting no neuronal damage in either monkey fetus or neonate, after administration of glutamate from 45 to 125 days of gestation in utero, or birth to 14 days of age. Reynolds et al. (1971) did observe artifactual damage similar to that described by Olney and Sharpe (1969) in inadequately perfused brains from control animals. Further, Reynolds has recently (1974) informed the author of her failure to observe even die 50-90 cell microlesion in a newborn primate administered glutamate at a massive dose of 4 g/kg body weight. In this exacting study, the entire hypothalamus and cortical regions were serially sectioned and carefully examined without finding neuronal necrosis.

There is little doubt that the administration of dicarboxylic amino acids to the neonatal mouse produces neuronal necrosis. However, the mouse is a poor experimental model for extrapolation of such studies to man, or even to higher species. First, the rodent metabolizes glutamate and aspartate in a different manner than the pig or primate. Second, the rodent is particularly susceptible to brain lesions, and other dietary substances such as salt and sucrose also produce brain lesions in the infant mouse at similar levels (Lemkey-Johnston et al., 1974, 1975).

The data of Stegink et al., 1974 indicate no neuronal necrosis at plasma glutamate plus aspartate levels below 50-60 µmol/dl. Thus, even the acutely sensitive neonatal mouse tolerates a 5- to 6-fold elevation in plasma levels without effect.

The adult mouse is known to be more resistant to dicarboxylic amino acid-induced neuronal necrosis than the neonate (Olney, 1969a; Lemkey-Johnston and Reynolds, 1974).

It is clear that (1) marked elevations in plasma glutamate and aspartate must occur for development of neuronal necrosis; and (2) the threshold level required to produce neuronal necrosis under high osmotic load is about 50-60 µmol/dl in the acutely sensitive neonatal mouse but must be over 1000-2000 µmol/dl in the neonatal primate. Loading studies in man and neonatal pig (Stegink et al., 1973b; Stegink et al., 1972) indicate that plasma glutamate levels are increased to about 25 µmol/dl after administration of glutamate at 100 mg/kg body weight orally. This plasma concentration is far below the toxic level for even the acutely sensitive neonatal mouse.

Conclusions:
Neurotoxic effects of glutamate and aspartate in animal species other than the rodent are highly controversial. In the most critical animal species, the infant subhuman primate, at least four research groups have failed to duplicate the original report of glutamate-induced neuronal necrosis.
Executive summary:

The dicarboxylic amino acids, aspartate and glutamate, occupy unique positions in intermediary metabolism, particularly in the mitochondria, where they play important roles in nitrogen and energy metabolism. 

Administration of large quantities of glutamate and aspartate to the newborn mouse produces a variety of neurotoxic effects, the most marked of which is neuronal necrosis. Neurotoxic effects of glutamate and aspartate in animal species other than the rodent are highly controversial. In the most critical animal species, the infant subhuman primate, at least four research groups have failed to duplicate the original report of glutamate-induced neuronal necrosis.

Marked elevations in plasma glutamate or aspartate must occur for development of neuronal necrosis. In the highly sensitive neonatal mouse, plasma glutamate plus plasma aspartate levels must reach 60-80 µmol/dl to produce even minimal neuronal necrosis. In the healthy neonatal primate, loads producing plasma glutamate levels ranging from 50 to 1600 µmol/dl failed to produce neuronal necrosis in the present studies. Thus, it is clear that (1) marked elevations in plasma glutamate and aspartate must occur for neuronal necrosis, and (2) threshold levels required to produce neuronal necrosis vary greatly with species.

The available data indicate little danger to the healthy primate and humans from ingestion of the dicarboxylic amino acids under anything resembling a reasonable intake. However, there is no doubt that these amino acids are toxic to the neonatal mouse at high dose levels.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Effect on neurotoxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
neurotoxicity
Remarks:
other: Various.
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Review article in a recognised journal.
Qualifier:
no guideline required
Principles of method if other than guideline:
Review publication.
GLP compliance:
no
Conclusions:
Two dicarboxylic amino acids, L-glutamate and L-aspartate, are now thought to act as neurotransmitters in the central nervous system. Considerable evidence supports the view that L-glutamate and L-aspartate function as excitatory transmitters. In contrast to acetyl-choline, these amino acids are not inactivated metabolically to release the excitatory effect. Rather, it appears that a high affinity uptake system into nerve terminals represents the physiological mechanism for terminating action of these transmitters. Both dicarboxylic amino acids excite neurones throughout the central nervous system but appear to act at different synapses.
Executive summary:

Possible roles for glutamate and aspartate in central nervous system function.

At one time, central nervous system deficiencies were postulated to result from brain glutamate deficiency, leading to tests of glutamate therapy. Although early results were encouraging, more detailed studies failed to support the hypothesis that glutamate therapy improved central nervous system function. However, both dicarboxylic amino acids are now thought to act as neurotransmitters in the central nervous system. Considerable evidence supports the view that L-glutamate and L-aspartate function as excitatory transmitters. In contrast to acetyl-choline, these amino acids are not inactivated metabolically to release the excitatory effect. Rather, it appears that a high affinity uptake system into nerve terminals represents the physiological mechanism for terminating action of these transmitters. Both dicarboxylic amino acids excite neurones throughout the central nervous system but appear to act at different synapses.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Justification for selection of effect on neurotoxicity via oral route endpoint:
Two dicarboxylic amino acids, L-glutamate and L-aspartate, are now thought to act as neurotransmitters in the central nervous system. Considerable evidence supports the view that L-glutamate and L-aspartate function as excitatory transmitters. In contrast to acetyl-choline, these amino acids are not inactivated metabolically to release the excitatory effect. Rather, it appears that a high affinity uptake system into nerve terminals represents the physiological mechanism for terminating action of these transmitters. Both dicarboxylic amino acids excite neurones throughout the central nervous system but appear to act at different synapses.

Justification for selection of effect on neurotoxicity via inhalation route endpoint:
Neurotoxic effects of overconsumption of L-Aspartic acid have not been proven in human studies. The diet normally contains a high content of glutamate and aspartate (as protein) and the intestinal epithelium and the liver have the capacity to metabolise large quantities of these amino acids. The blood-brain barrier and the very powerful glial and neuronal uptake systems for glutamate and aspartate help to keep the extracellular concentration of glutamate low in the brain.

Justification for selection of effect on neurotoxicity via dermal route endpoint:
Neurotoxic effects of glutamate and aspartate in animal species other than the rodent are highly controversial. In the most critical animal species, the infant subhuman primate, at least four research groups have failed to duplicate the original report of glutamate-induced neuronal necrosis.

Justification for classification or non-classification

No adverse effects observed.

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