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School of Biological Sciences, University of Surrey, Guildford GU2 5XH, Surrey, UK and * Food and Nutrition Division, FAO, 00100 Roma, Italy
2To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONThe safety evaluation of...Idiosyncratic intolerance...JECFA safety evaluationThe Scientific Committee for...FASEB and the FDAREFERENCES |
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KEY WORDS: • humans • safety • food safety • food additives • monosodium glutamate • toxicity
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONThe safety evaluation of...Idiosyncratic intolerance...JECFA safety evaluationThe Scientific Committee for...FASEB and the FDAREFERENCES |
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Members of JECFA are independent scientists, drawn mainly from government or academic research institutes, who serve in their individual expert capacity and not as representatives of their governments or institutions. Members are assisted by Temporary Advisers (WHO) or Consultants (FAO), also appointed in their personal capacity. In relation to food additives, the goals are to establish safe levels of intake and to develop specifications for identity and purity.
Through mid-1998, 51 meetings of JECFA have been held. The reports are published in the WHO Technical Report Series and the toxicological evaluations, which form the basis of the safety assessment, are published in the WHO Food Additives Series; specifications are published in the FAO Food and Nutrition Paper Series.
The safety evaluation of monosodium glutamate (MSG) by JECFA was
conducted along with the group of related compounds, i.e.,
L-glutamic acid and its ammonium, calcium, monosodium and
monopotassium salts. These substances were first evaluated at the
fourteenth and seventeenth meetings in 1971 and 1974, respectively
(FAO/WHO 1971
and 1974
). At that time, an Acceptable
Daily Intake (ADI) of 0–120 mg/kg body weight was allocated,
encompassing the L-glutamic acid equivalents of the salts;
this was considered additional to the intake from all nonadditive
dietary sources. In the absence of human infant data at that time, and
in view of the observation that neonatal rodents appeared to be more
sensitive than adults to the neurologic effects of high blood levels of
glutamate, it was stated that the ADI did not apply to infants <12 wk
of age. A more recent and comprehensive safety evaluation was conducted
in 1987 (Joint FAO/WHO Expert Committee on Food Additives 1988
); the basis of that evaluation will be discussed below.
The Scientific Committee for Food of the Commission of the European
Communities (SCF) also reviewed the data in 1991 and reached
conclusions similar to those of the JECFA (SCF 1991
).
Subsequently, the Federation of American Societies for Experimental
Biology (FASEB) conducted a review of reported adverse reactions to MSG
and reported in 1995 (FASEB 1995
). This report and the
response of U.S. Food and Drug Administration (FDA) will also be
mentioned briefly.
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The safety evaluation of the JECFA |
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-ketoglutarate;
glutamine, 
-aminobutyrate and glutathione are other quantitatively
minor but physiologically important metabolites. Excess
glutamate, after deamination, may be utilized in gluconeogenesis. The
available data indicated that, under normal conditions, mammals have
the metabolic capacity to handle large oral doses although the more
readily available nature of free MSG compared with the slow release
during protein digestion must be borne in mind. As a consequence of the
ready metabolism, concentrations of glutamate in portal blood show only
a small rise after administration of MSG unless very large bolus doses
are administered by gavage. Further metabolism occurs in the liver, and
systemic blood levels rise only when such large bolus doses are given
as to overwhelm this hepatic metabolism or if MSG is given by
irrelevant parenteral routes. Gavage doses in excess of ~30 mg/kg
body weight are required to produce detectable elevations of blood
levels, and the same dose of MSG administered in food produces lower
peak plasma levels than if administered in aqueous solution. Foods rich
in available carbohydrate were most effective in blunting the peak
plasma levels. In fact, only slight rises in plasma glutamate were
observed after a dose of 150 mg MSG/kg body weight in human adults.
Infants, including premature babies, could also metabolize similar
doses given in infant formulae (Tung and Tung 1980
). The conventional toxicologic database available for review by the JECFA was very extensive, including acute, subchronic and chronic toxicity studies in rats, mice and dogs, together with studies on reproductive toxicity and teratology.
Glutamate has a very low acute toxicity under normal circumstances; the oral dose that is lethal to 50% of subjects (LD50) in rats and mice is ~15,000–18,000 mg/kg body weight, respectively. Subchronic and chronic toxicity studies of up to 2 y duration in mice and rats, including a reproductive phase, did not reveal any specific adverse effects at dietary levels of up to 4%. A 2-y study in dogs at dietary levels of 10% also did not reveal any effects on weight gain, organ weights, clinical indices, mortality or general behavior. Reproduction and teratology studies using the oral route of administration have been uneventful even when the dams were fed glutamate at high doses, indicating that the fetus and suckling neonate was not exposed to toxic levels from the maternal diet through transplacental transfer. This latter observation is in accord with reports that glutamate levels in fetal blood do not rise in parallel with maternal levels. For example, in rats, although single oral doses of 8000 mg/kg given to pregnant females late in gestation caused plasma levels to rise from 100 to 1650 nmol/mL, no significant increases were observed in plasma levels of the fetuses. Similarly, in pregnant rhesus monkeys, the infusion of 1 g MSG/h led to a 10- to 20-fold increase in maternal plasma levels but no changes in fetal plasma levels. In rats and monkeys, oral ingestion of these large doses of MSG did not lead to detectable increases in glutamic acid levels in maternal milk.
The toxicologic picture arising from conventional studies therefore seemed quite reassuring. Nevertheless, two other major issues had to be addressed in relation to high intakes of MSG, namely, 1) potential neurotoxicity, especially to the infant, and 2) the putative role of MSG in "Chinese Restaurant Syndrome" (e.g., flushing, tightness of the chest or difficulty in breathing ) after consumption of Chinese foods.
In relation to the neurotoxicity, the Committee considered reports of
59 studies conducted in mice (40), rats (12), hamsters, guinea pigs,
chicks, ducks, rabbits, dogs and primates (21). Lesions (focal
necrosis) in the arcuate nucleus of the hypothalamus were observed
reproducibly in rodents and rabbits after parenteral administration
of glutamate (intravenously or subcutaneously) or after very high
bolus doses by gavage. These neural lesions were observable within
hours of administration. The mouse appeared to be the most sensitive
species, and there were significant differences with age and maturity;
the neonate was particularly sensitive. Notably, most of the studies in
primates were negative with regard to hypothalamic lesions; these were
reported in only 2 of 21 studies, both conducted in the same laboratory
(Olney and Sharpe 1969
, Olney et al. 1972
)
The oral gavage doses required to produce the lesions were on the order of 1000 mg/kg body weight as a bolus dose, and in only one study were lesions seen after "voluntary" ingestion of MSG. In that case, weanling mice were deprived of food and water overnight, then given solutions containing 5 or 10% MSG as the sole drinking fluid. No such lesions were seen when MSG was given at 10% of the diet even though plasma glutamate levels were doubled, nor after administration at high concentrations in drinking water ad libitum.
In relation to the question of the relevance of this neurotoxicity for humans receiving MSG in the diet, biochemical and human studies have been crucial. The transport rate of glutamate from blood to brain in mature animals is much lower than that for neutral or basic amino acids, and normal plasma levels of glutamate are nearly four times the Michaelis-Menten constant (Km) of the transport system to the brain i.e. the concentration associated with half maximal velocity. This implies that this transport system is virtually saturated under physiologic conditions. However, the blood-brain barrier may be less effective in the neonatal mouse, which raises the possibility that this is the reason for the exquisite sensitivity of this model. However, the question of the comparability of the mouse and the human infant remains an issue, in that the level of brain development in the two species is quite dissimilar at parturition.
The threshold blood levels associated with neuronal damage in the mouse (the most sensitive species) are 100–130 µmol/dL in neonates rising to 380 µmol/dL in weanlings and >630 µmol/dL in adult mice. In humans, plasma levels of this magnitude have not been recorded even after bolus doses of 150 mg/kg body weight (~10 g for an adult). Additionally, the studies in infants previously mentioned have confirmed that the human infant can metabolize glutamate as effectively as adults. It is thus concluded that blood levels of glutamate + aspartate do not rise significantly even after abuse doses of up to 10 g, and infants are no more at risk than adults. Similarly, the comparisons of maternal and fetal blood levels after high doses indicate that the fetus is not at greater risk. Intake levels associated with the use of MSG as a food additive and natural levels of glutamic acid in foods, therefore, do not raise toxicologic concerns even at high peak levels of intake because the mechanism of toxicity appears to be related to the peak plasma level achieved rather than the area under the curve. A putative mechanism for the neuronal damage is that high levels of glutamate at the target site lead to continuous excitation of the glutaminergic neurons, depleting ATP and leading to cell death. Such a situation is difficult to achieve with oral administration in food. Furthermore, the JECFA noted that the oral ED50 for production of hypothalamic lesions in the neonatal mouse is ~500 mg MSG/kg body weight by gavage, whereas the largest palatable dose for humans is ~60 mg/kg body weight with higher doses causing nausea; thus, voluntary ingestion would not exceed this level.
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Idiosyncratic intolerance (Chinese Restaurant Syndrome) |
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TOPABSTRACTINTRODUCTIONThe safety evaluation of...Idiosyncratic intolerance...JECFA safety evaluationThe Scientific Committee for...FASEB and the FDAREFERENCES |
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In its conclusion on this matter, the JECFA stated "controlled double-blind crossover trials have failed to demonstrate an unequivocal relationship between ‘Chinese Restaurant Syndrome’ and consumption of MSG. MSG has not been shown to provoke bronchoconstriction in asthmatics."
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JECFA safety evaluation |
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TOPABSTRACTINTRODUCTIONThe safety evaluation of...Idiosyncratic intolerance...JECFA safety evaluationThe Scientific Committee for...FASEB and the FDAREFERENCES |
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The JECFA also noted the evidence that it was not necessary to treat pregnant women and infants as special cases; however, they did retain the previously expressed position that food additives, in general, should not be used in infant foods to be consumed before 12 wk of age.
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The Scientific Committee for Food of the Commission of the European Communities |
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TOPABSTRACTINTRODUCTIONThe safety evaluation of...Idiosyncratic intolerance...JECFA safety evaluationThe Scientific Committee for...FASEB and the FDAREFERENCES |
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conducted a safety evaluation
similar to that of the JECFA and reached the same conclusion, i.e.,
that MSG could be allocated an "ADI not specified," and this is the
current situation in the European Union. |
FASEB and the FDA |
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TOPABSTRACTINTRODUCTIONThe safety evaluation of...Idiosyncratic intolerance...JECFA safety evaluationThe Scientific Committee for...FASEB and the FDAREFERENCES |
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The FASEB report was submitted to the FDA in July 1995
(FASEB 1995
). In this report, the term "MSG symptom
complex" is used instead of "Chinese Restaurant Syndrome" because
the latter was considered pejorative and characterized the symptoms as
an acute, temporary and self-limiting complex including the
following: 1) a burning sensation of the back of the neck,
forearms and chest; 2) facial pressure or tightness;
3) chest pain; 4) headache; 5) nausea;
6) upper body tingling and weakness; 7)
palpitation; 8) numbness in the back of the neck, arms and
back; 9) bronchospasm (in asthmatics only); and
10) drowsiness.
In passing, it is interesting to note the term "MSG symptom complex" was used when the terms of reference clearly included protein hydrolysates and other natural sources of glutamic acid.
The report concluded that, although there was no scientifically
verifiable evidence of adverse effects in most individuals exposed to
high levels of MSG, there is sufficient documentation to indicate that
there is a subgroup of presumably healthy individuals that responds,
generally within 1 h of exposure, with manifestations of the MSG
symptom complex when exposed to an oral (bolus) dose of MSG of 3 g
in the absence of food. Although the FDA appears to have
accepted this conclusion of the existence of the MSG symptom complex
(Hattan, 1996
), it was pointed out that the key data
relate to single-dose challenges in capsules or simple solutions
and are limited in their ability to predict adverse reactions resulting
from the use of MSG in food. This is an important caveat because
available carbohydrate in foods appears to modulate the
pharmacokinetics. The Hattan memorandum also indicates that the FDA did
not consider the evidence regarding sensitivity of asthmatics to MSG
compelling and questioned the inclusion of bronchoconstriction in the
MSG symptom complex in the absence of confirmatory data in a
well-controlled study. The reasons are outlined and relate to
limitations in the key study (Allen et al. 1987
), and a call was made for further work in this
area.
The FASEB report concludes that there is no evidence to support a role for dietary MSG or other forms of free glutamate in causing or exacerbating serious, long-term medical problems resulting from degenerative nerve cell damage. The FDA accepted the conclusion that serious neurotoxicologic effects from MSG are limited to animals given very large doses by parenteral, pharmacologic or other nondietary conditions of use or administration.
With regard to the potential disruption of the neuroendocrine axis, the
FASEB Expert Panel gave particular consideration to the potential of
dietary MSG to affect adversely the structure and function of areas of
the brain not protected by the blood-brain barrier. The Panel
focused their evaluation on a study conducted by Carlson et al. (1989)
of the stimulation of pituitary hormone secretion by
neurotransmitter amino acids, which showed that a dose of 10 g
glutamic acid in saline caused a twofold increase in peak serum
concentrations of prolactin and cortisol over baseline values. However,
a subsequent study (Fernstrom et al. 1996
) using
equivalent (pharmacologic) doses of MSG rather than the free acid
failed to demonstrate any effect on plasma prolactin, luteinizing
hormone, follicle-stimulating hormone, testosterone, growth
hormone, cortisol, thyroid-stimulating hormone or thyroid hormones
despite an 11-fold increase in plasma glutamate levels (cf.
Carlson et al. 1989
). The FDA concurred with the
conclusion (from animal studies) that large doses of glutamate can
influence hormonal function but concluded further that it did not
believe that there was evidence to indicate that MSG as ordinarily
consumed in foods disrupts the neuroendocrine axis in humans.
It has been contended in some quarters that glutamate in commercial products such as MSG or hydrolyzed protein, is different in some way from naturally occurring glutamate. The FASEB Panel rejected this contention.
Finally, the FDA interpreted the findings of the FASEB Report to be generally consistent with the safety assessments of other authoritative organizations (presumably including the JECFA and SCF) that have affirmed the safety of MSG at levels normally consumed by the general population, and concurred with the conclusion that there is no evidence linking current MSG food use to any serious, long-term medical problems in the general population.
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FOOTNOTES |
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3 Abbreviations used: ADI, acceptable daily
intake; CAC, Codex Alimentarius Commission; CNS, central nervous
system; FASEB, Federation of American Societies for Experimental
Biology; FDA, Food and Drug Administration; JECFA, Joint FAO/WHO Expert
Committee on Food Additives; LD50, dose that is lethal to
50% of subjects; MSG, monosodium glutamate; SCF, Scientific Committee
for Food.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONThe safety evaluation of...Idiosyncratic intolerance...JECFA safety evaluationThe Scientific Committee for...FASEB and the FDAREFERENCES |
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1. Allen D. H., Delohery J., Baker G. Monosodium L-Glutamate-induced asthma. J. Allergy Clin. Immunol. 1987;80:530-537[Medline]
2. Carlson H. E., Miglietta J. T., Roginsky M. S., Stegink L. D. Stimulation of pituitary hormone secretion by neurotransmitter amino acids in humans. Metabolism 1989;38:1179-1182[Medline]
3. FAO/WHO (1971) Evaluation of food additives: specifications for the identity and purity of food additives and their toxicological evaluation; some extraction solvents and certain other substances; and a review of the technological efficiency of some antimicrobial agents. 14th Report of the Joint FAO/WHO Expert Committee on Food Additives. FAO Nutrition Meetings Report Series no. 48, WHO Technical Report Series no. 462.
4. FAO/WHO (1974) Toxicological evaluation of certain food additives with a review of general principles and of specifications. 17th Report of the Joint FAO/WHO Expert Committee on Food Additives. FAO Nutrition Meetings Report Series no. 53, WHO Technical Report Series no. 539.
5. FASEB (1995) Analysis of Adverse Reactions to Monosodium Glutamate (MSG), Report. Life Sciences Research Office, Federation of American Societies for Experimental Biology, Washington, DC.
6. Fernstrom J. D., Cameron J. L., Fernstrom M. H., Maconaha , Weltzin T. E., Kaye W. H. Short term neuroendocrine effects of a large oral dose of monosodium glutamate in fasting male subjects. J. Clin. Endocrinol. Metab. 1996;81:184-191[Abstract]
7. Hattan, G. G. (1996) Evaluation of the Federation of American Societies for Experimental Biology (FASEB) July 1995 report: Analysis of Adverse Reactions to Monosodium Glutamate (MSG). Memorandum from Director of Health Effects Evaluation to Dr. Lawrence Lin, HFS-206, dated August 30.
8. Joint FAO/WHO Expert Committee on Food Additives L-glutamic acid and its ammonium, calcium, monosodium and potassium salts. Toxicological Evaluation of Certain Food Additives and Contaminants 1988:97-161 New York Cambridge University Press
9.
Olney J. W., Sharpe L. G. Brain lesions in an infant rhesus monkey treated with monosodium glutamate. Science (Washington DC) 1969;166:386-388
10. Olney J. W., Sharpe L. G., Fergin R. D. Glutamate-induced brain damage in infant primates. J. Neuropathol. Exp. Neurol. 1972;31:464-488[Medline]
11. SCF Reports of the Scientific Committee for Food on a First Series of Food Additives of Various Technological Functions, Commission of the European Communities, Reports of the Scientific Committee for Food, 25th Series 1991 Brussels Belgium.
12. Tung T. C., Tung T. S. Serum free amino acid levels after oral glutamate intake in infant and adult humans. Nutr. Rep. Int. 1980;22:431-443
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