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    FAO Nutrition Meetings 
    Report Series No. 48A 
    WHO/FOOD ADD/70.39




    TOXICOLOGICAL EVALUATION OF SOME
    EXTRACTION SOLVENTS AND CERTAIN 
    OTHER SUBSTANCES




    The content of this document is the 
    result of the deliberations of the Joint 
    FAO/WHO Expert Committee on Food Additives 
    which met in Geneva, 24 June  -2 July 19701




    Food and Agriculture Organization of the United Nations
    World Health Organization


                   

    1 Fourteenth report of the Joint FAO/WHO Expert Committee on Food
    Additives, FAO Nutrition Meetings Report Series in press; Wld Hlth
    Org. techn. Rep. Ser., in press.


    MONOSODIUM GLUTAMATE

    Biological data

    Biochemical aspects

         L-glutamic acid occurs as a common constituent of proteins and
    protein hydrolysates and can be synthesized by the rat and rabbit from
    acetate fragments. Human plasma contains 4.4 - 4.5 mg/l of free
    glutamic acid and 0.9 mg/100 ml, of bound glutamic acid. Human urine
    contains 2.1 - 3.9 g/mg creatinins of free glutamic acid and 200
    g-/mg creatinins of bound glutamic acid (Peters et al., 1969). Human
    spinal fluid contains 0.34-1.64 (mean 1.03 mg/l) free glutamic acid
    (Dickinson & Hamilton, 1966). Human milk contains 1.2% protein of
    which 20% is bound glutamic acid which is equivalent to 3g/1
    calculated as sodium glutamate. The free glutamic acid concentration
    is 300 mg/l. In contrast cows milk contains 3.5% protein equivalent to
    8.8 g/1 calculated as MSG, but only 30 mg/l free glutamic acid (Maeda
    et al., 1958; 1961). Strained infant foods provide 80 Cal/100g with
    wide variations depending on the recipe, while human milk provides 70
    Cal/g (Dept. Health & Soc. Sec., 1970).

         Infant food may contain up to 0.4% added MSG, the natural content
    depending on the basic constituents. Carrots contribute 0.32%. free
    glutamic acid calculated as MSG, tomatoes, 0.45% and cheese 0.7%.
    Substitution of some unprepared foods in equal weights for prepared
    baby foods containing 0.3% added monosodium glutamate would also
    result in an ingestion of greater amounts of glutamate than is
    provided by mothers' milk an a calorie for calorie basis. The level of
    0.3% in prepared foods appears to be an upper level since higher
    concentrations impart an unpleasant flavour.

         Infants aged 3 days and weighing 3kg consume 480 g mothers'
    milk/day. This is equivalent to a daily intake of 1.104 g bound
    glutamic acid, and 0.115 g free glutamic acid corresponding to 0.408
    g/kg body-weight of glutamic acid/day. One-month old infants, weighing
    3.8 kg consume 600 g mothers' milk/day. This is equivalent to a daily
    intake of 1.37 g of bound glutamic acid and 0.144 g free glutamic acid
    corresponding to 0.405 g/kg body-weight of glutamic acid/day.

         Infants aged 5-6 months, weighing 7.5 kg, consume 500 g cows milk
    and 2 jars of baby food/day. The respective daily intake of bound
    glutamic acid amounts to 3.5 g and 0.5 g. The corresponding free
    glutamic acid intake is 0.015 g and 0.060 g/day, which is equivalent
    to 0.62 g/kg body-weight of glutamic acid/day. If the 2 jars
    (200g/jar) contain 0.3% MSG, this increases the total intake of free
    glutamic acid from 0.06 to 0.60 g. In a seven day survey of children
    aged 9 to 12 months the intake of baby foods has been observed to
    range from zero (in 20% of the surveyed cases) to a maximum of 250 g
    daily in which up to 12 different preparations may be represented and
    not all of which have monosodium glutamate added (Berry 1970).

         There is evidence of rapid absorption of dietary glutamate since
    in rats the glutamic acid level in portal blood rose within 1/2/3/4
    hour to 250 per cent. in adults and 150 per cent. in young animals
    over the testing level (Wheeler & Morgan, 1958). L-glutamic acid
    absorption by the dog failed to increase noticeably the amino-N2 of
    the peripheral blood but increased that of portal blood, possibly
    because of increased uptake by tissue (Christenson et al., 1948).

         Groups of 8 rats were given by gavage 200 mg/kg body-weight of
    MSG alone or with 2000 mg/kg raw veal. Blood samples were taken at 10
    minute intervals and after 30 minutes the animals were killed and free
    glutamic acid determined in blood and brain. Plasma glutamic acid rose
    rapidly to a peak in 20 minutes if monosodium glutamate was given
    alone and more slowly to a peak in 30 minutes if given with veal.
    Using 100, 500 and 2500 mg/kg orally produced a dose-related increase
    in plasma level only at the two higher test levels and more if
    monosodium glutamate was given alone. There was no effect on the brain
    glutamate acid levels. Using s.c. 500 mg/kg body-weight produced the
    same plasma levels as oral feeding. There was no adaptation. Brain
    levels were not affected. 100 mg/kg monosodium glutamate was the
    threshold dose before plasma levels rose. There was great variability
    in the response (McLaughlan et al., 1970). Continuous infusion of dogs
    with glutamic acid (05-4 mg/kg/hr) did not result in entry of glutamic
    acid into liver and muscle cells, cerebrospinal fluid or brain. Kidney
    cells appeared to be freely permeable. Metabolism of the infused
    glutamic acid was limited (Kamin & Handler, 1950).

         The intact rat as well as rat liver and rat tissues metabolize
    glutamate by oxidative deamination (von Euler et al., 1938) or
    transamination to oxaloacetic or pyruvic acid (Cohen, 1949) via
    alpha-ketoglutarate to succinate (Meister, 1965). This was shown by
    the use of 2-C14-labelled DL-glutamic acid given i.p. and resulting
    in the production of aspartin acid labelled in the -COOH radical and
    glutaric acid labelled in position 1-C and 2-C. Intracaecally
    administered 2-C14-1abelled DL-glutamic acid is rapidly converted to
    acetate, labelled in the methyl group, by the messaconate and
    citramalate cycle. After gastric intubation of 2C14-labelled
    DL-glutamic acid part is absorbed and metabolized to succinate, the
    rest to methyl labelled acetate (Wilson & Koeppe, 1959). Rat tissue
    has only a poor ability to oxidise D-glutamate. After i.p. or s.c.
    administration conversion to D-pyrrolidone carboxylic acid occurs. Rat
    liver and rat kidney also convert enzymatically D-glutamic acid to
    D-pyrrolidone carboxylic acid (Wilson & Koeppe, 1961). The specific
    enzyme was isolated from the liver and kidney of mice, rats and man
    (Meister et al., 1963). Oral administration of C-monosodium
    L-glutamate (2g/kg) to weanling rats caused a marked increase in the
    specific activity of liver carbamyl phosphate synthesase. Prolonged
    administration resulted in a return to control values, indicating an
    adaptation to the administered substrate (Hutchinson & Labby, 1965).
    Biochemical aspects are summarized in recent reports (Ajinomoto Co.,
    1970).

         I.v. injection of C 14-labelled glutamic acid into intact rats
    and mice showed it to enter rapidly the brain, liver, kidney and
    muscle as such (Lajtha et al., 1959). Glutamic acid was shown to be
    distributed among more than one metabolic pool as animals mature
    (Berl, 1965). Compartmentation of glutamate metabolism in the mouse
    brain has been demonstrated by examining the time course of C14
    incorporation into glutamine and glutamate (Van den Berg, et al.
    1968).

         I.v. injection of sodium P-glutamate produced a prolonged
    increase in the amino-nitrogen content of blood and prolonged urinary
    excretion in rabbits (Yamamura, 1960). Other effects observed were a
    decrease in tryptophan and tyrosine metabolism of the liver following
    daily injection of 1-4 g/kg glutamic acid into rats (Funiwake, 1957) 
    reduction in the activity of liver catalase in mice after single
    injections of D-glutamic acid at 1.5 mg/g reverting to normal after 4
    days and not observed with L-glutamic acid (Ando, 1958), enhanced
    oxygen consumption by rats after injection of 1 mg/kg sodium glutamate
    at low pO2, not observed at normal pO2 (Genkin & Udintsev, 1957)
    and hyperglycaemia after i.p. glutamate in rats due to conversion to
    glucose and additional stimulation of gluconeogensis (Marcus & Reaven,
    1967). The effect on cerebral metabolism was studied by
    intraventricular injection of L-glutamic acid into mice, when 150 mg
    produced convulsions or only incoordinated grooming or circling of the
    cage (Crawford, 1963). Two per cent. intra-arterial sodium glutamate
    increased epileptic fits add intracisternal L-glutamic acid caused
    tonic-clonic convulsions in animals and man. High parenteral dosage of
    L-glutamic acid caused EEG changes only in dogs with previous cerebral
    damage, and no rise was detected in the CSF level of glutamate (Herbst
    et al., 1966). L-glutamic acid is oxidized by the brain to
    alphaketoglutaric acid, NH3 and later CO2 and H2O and is the only
    amino acid that on its own can maintain brain slice respiration
    (Weil-Malherbe, 1936). Decarboxylation to gamma aminobutyric acid is
    significant in the mammalian brain (Roberts, 1951; Perrault & Dry,
    1961).

         I.v. injection of large doses of glutamic acid in rabbits, caused
    ECG changes that could be interpreted as symptoms of myocardial
    lesions. Arterial hypertension induced by glutamic acid preparations
    was demonstrated to be of central origin. Studies with isolated cat
    heart showed that large doses of glutamic acid slowed heart action,
    increased systolic amplitude and constricted coronary vessels. Very
    large doses stopped cardiac action (Mazurowa, et al., 1962).

         Nutritional studies in the rat have shown glutamic acid to be a
    nonessential amino acid replaceable by others and to be required in
    substantial amounts to ensure high growth rates in rats (Hepburn et
    al., 1960). Some interconversion between glutamic acid and arginine
    can occur to cover minor dietary deficiencies (Hepburn & Bradley,
    1964). Gouty patients have raised levels of plasma glutamate compared
    with normals and following a protein meal glutamate reaches excessive
    levels (Pagliari & Goodman, 1969). Premature and full term infants
    hydrolyse any given protein in the stomach to very similar extents

    (Berfenstam et al., 1955). Hepatic glutamate dehydrogenase appears at
    12 weeks of human foetal life, is present in rat foetal liver on day
    17 and reaches its maximum within 2 weeks after birth (Francesconi &
    Villee, 1968),

         Fifty patients with circulatory hypoxia received orally 1 g three
    times/day of glutamic acid for 1 week. All patients showed less blood
    lactic acid, a better alkali reserve and clinical improvement
    (Gorbunova et al., 1960). 15 g equivalents of unneutralized L-glutamic
    acid, L-glutamic acid-HC1 and monosodium glutamate were given orally
    to man. There was little absorption of the poorly soluble L-glutamic
    acid with very slight elevation of blood levels within one hour from
    20 to 80 mg/l.  Little absorption occurred with L-glutamic and
    acid-HC1, but monosodium glutamate was well absorbed, the blood level
    rising in one hour from 20 to 350 mg/l. (Himwich, 1954). 6-10 male
    healthy children were given 1, 2 a 4 g sodium glutamate. Total
    creatinine excretion was not affected but the amino acid/creatinine
    ratio increased much more than the glucuronic acid/creatinine ratio.
    Values returned to normal within 36 hours after 1-2 g and within 69
    hours after 4 g (Inoue, 1960). Sodium glutamate has been used
    therapeutically in uraemia to reduce blood levels of ammonia. 8 g of
    i.v. glutamic acid caused nausea and vomiting in 11 from 17
    individuals (Smyth et al., 1947).

         Introduction of 0.15 per cent. glutamate solution into the small
    intestine of the dog did not cause a rise in glutamate concentration
    in the blood draining the intestinal loop. Only at 0.5 per cent. did
    the venous blood contain extra glutamate. However, alanine appears in
    high concentration in the portal blood. When this mechanism is
    overwhelmed then glutamate appears also over and above the arterial
    blood level (Neame & Wiseman, 1957). In the cat and rabbit in vivo
    the same phenomenon occurs (Neame & Wiseman, 1958) and in the rat 
    in vitro (Matthews & Wiseman, 1953) and in vivo (Peraino & Harper,
    1962). Further removal of excess portal glutamate and alinine occurs
    in the liver. In man only 2 out of 4 subjects given 0.1 g/kg glutamic
    acid as a 7 per cent. solution orally showed an appreciable rise of
    free glutamic acid in plasma. Hence a similar mechanism may operate.

         Additional glutamic acid, e.g, 10-20 g, if given to man, may
    raise the amount of glutamic acid absorbed from ingested protein.
    (Bessmann et al., 1948). Bound glutamate from proteins and
    polypeptides is released gradually during digestion and would be
    absorbed as alanine into the portal blood (Wiseman, 1970). L-glutamic
    acid and DL-glutamic acid are absorbed orally by the rat to nearly the
    same extent, L - being a little better absorbed (Aroskar & Berg,
    1962). The foetal circulation has a higher amino acid concentration
    than the maternal in the rhesus monkey (Kerr & Waisman, 1967).

         Monosodium glutamate (8g/kg body-weight) was administered orally
    to pregnant Wistar-Imamichi rats on day 19 of gestation. Plasma
    glutamic acid was determined in mothers and foetuses, at 30, 60 and
    120 min. after dosing. In the mothers' plasma, glutamic acid increased
    from approx. 100 g/ml to 1650 g/ml, in the first 30 minutes. At the
    end of the test period the level was 1000 g/ml. No significant
    changes occurred in the plasma glutamic acid of foetuses during this
    period (approx. 50 g/ml) (O'hara et al., 1970a).

         Rats (Wistar-Imamichi), male adults (11-14 weeks of age) and male
    neonates (2-3 days of age), were dosed orally with monosodium
    glutamate (0.5-8 g/kg body-weight for adults, and 0.5-4 g/kg
    body-weight for neonates). Plasma glutamic acid was measured over a 4
    hour period. For adult rats, the highest level tested showed maximum
    plasma glutamic acid, 1650 g/ml, after 30 minutes. At the other dose
    levels there were no appreciable changes in plasma glutamic acid. In
    the case of neonates, levels rose to a maximum of 350 g/ml after 90
    minutes at the 2 g/kg dose level, and 1850 g/ml after 90 minutes at
    the 4.0 g/kg dose level. In a similar study with mice (4CS strain)
    plasma glutamic acid of adults rose to a maximum of 530 g/ml after 30
    minutes, at the 2 g/kg dose level, and 1050 g/ml at the 4 mg/kg dose
    level. Neonate mice showed maximum level of plasma glutamic, 700 g/ml
    30 minutes after treatment at the 2 mg/kg dose level, and 2300 g/ml,
    2 hours after treatment at the 4 mg/kg dose level, (Ichimura et al.,
    1970c). Another study showed that there was a marked correlation
    between liver SOT, SPT and plasma glutamic acid of rats and mice dosed
    orally with 1 g/kg body weight monosodium glutamate. Measurements were
    made during the period 1-100 days of age. (Hashimoto et al., 1970).

         When monosodium glutamate (1 g/kg body-weight) or monosodium
    glutamate (1 g/kg body-weight) plus powdered milk (1.5 g/kg
    body-weight) or powdered milk (1.5 g/kg body-weight) was administered
    orally to 10 day old rats, the maximum levels of plasma glutamic acid
    were 425 g/ml, 160 g/ml and 105 g/ml respectively. These levels
    occurred 30 minutes after dosing (O'hara et al., 1970b).

    Acute toxicity
                                                                                     

    Animal         Route      LD50                    References
                              mg/body-weight
                                                                                 

    Mouse          i.p.       6900                    Yanagisawa et al., 1961
                   p.o.       12961                   Izeki, 1964
                   p.o.       16200 (14200-18400)     Ichimura & Kirimura, 1968
                   i.v.       30000                   Ajinomoto Co., 1970
    Rat            p.o.       19900 (L MSG)           International Minerals 
                                                      & Chem. Corp., 1969
                   p.o.       10000 (DI, MSG)         international Minerals &
                                                      Chem. Corp., 1969
                   p.o.       > 30000 (L-GA)          International Minerals 
                                                      & Chem. Corp., 1969
    Guinea-pig     i.p.       15000                   Ajinomoto Co., 1970
    Rabbit         p.o.       > 2300 (L-GA)           International Minerals 
                                                      & Chem. Corp., 1969
    Cat            s.c.       8000                    Ajinomoto Co., 1970
                                                                                 
    
    Mouse. Mice aged 2 to 9 days were killed 1 to 48 hours after single
    subcutaneous injection of monosodium glutamate at doses from 0.5-4
    g/kg, lesions seen in the preoptic and arcuate nuclei of the
    hypothalamic region on the roof and floor of the third ventricle and
    in scattered neurons in the nuclei tuberales. No pituitary lesions
    were seen but sub-commissural and subfornical organs exhibited
    intracellular oedema and neuronal necrosis. Adult mice given
    subcutaneously 5-7 g/kg monosodium L-glutamate showed similar
    lesions. Similar lesions were seen in another strain of mouse and in
    neonatal rats (Olney, 1969b).

         After a single subcutaneous injection of monosodium glutamate at
    4 g/kg into neonatal mice aged 9-10 days. the animals were killed from
    30 minutes to 48 hours. The retinas showed an acute lesion on electron
    microscopy with swelling dendrites and early neuronal changes leading
    to necrosis followed by phagocytosis (Olney, 1969a).

         Sixty-five neonatal mice aged 10-12 days received single oral
    very high loads of monosodium glutamate at 0.5, 0.75, 1.0 and 2.0 g/kg
    body-weight by gavage. 10 were controls and 54 mice received other
    amounts. After 3-6 hours all treated animals were killed by perfusion.
    Brain damage as evidenced by necrotic neurons was evident in arcuate
    nuclei of 51 animals. 62 per cent. at 0.5 g/kg, 81 per cent. at 0.75
    g/kg, 100 per cent. at 1 g/kg and 100 per cent. at 2 g/kg. The lesions
    were identical both by light and electron microscopy to s.c. produced
    lesions. The number of necrotic neurons rose approximately with dose.

    Four animals tested with glutamic acid also developed the same lesions
    at 1 g/kg body-weight. The effect was additive with aspartate (Olney,
    1970b).

         Groups of five 3-day and 12-day old mice receiving subcutaneously
    or orally a single acute dose (1g/kg) monosodium glutamate,
    monopotassium glutamate, sodium chloride, sodium gluconate or
    distilled water, were sacrificed 3 hours and 24 hours after treatment.
    Preliminary light microscopic studies of the large mid brain area,
    showed similar non-specific scattered tissue changes in all treatment
    groups. (Oser et al., 1970). In another study, mice, 5-9 days old,
    received a single dose of monosodium glutamate (4 g/kg in phosphate
    buffer), either subcutaneously or orally. Animals were sacrificed at
    24 hours. Light microscopy of the hypothalmic area of the brain
    indicated abnormal neuronal cells in 12/30 of the mice receiving a
    subcutaneous injection of the test substance  only 5/35 mice receiving
    the oral dose showed some change (Coulston et al., 1970). Six, nine to
    ten day old mice. dosed orally with 10% monosodium glutamate (2
    gm/kg), showed characteristic brain lesions (Geil, 1970).

         Monosodium glutamate caused reversible blockage of beta wave in
    the electroretinogram in immature mice and rats indicating
    retinotoxicity (Potts et al., 1960). The timing of treatment of mice
    was quite critical. After 10 to 11 days postnatal age, it was
    difficult to produce significant lesions of the retina (Olney, 1969a).
    A study of the glutamate metabolizing enzymes of the retina of the
    glutamate treated rat indicated a decrease in glutaminase activity, an
    increase in glutamic aspartate transaminase, and no change in glutamyl
    synthetase and glutamotransference. The effects appear to be due to
    repression and induction of enzyme synthesis (Freedman & Potts, 1962;
    Freedman & Potts, 1963). Glutamate uptake by retina, brain and plasma
    decreases with age and is slower at 12 days when compared with 50 day
    old animals (Freedman & Potts, 1963).

         Obesity and acute irreversible degeneration in liver and retina
    of neonatal mice has been seen following parenteral administration of
    monosodium glutamate (Cohen, 1967). S.c. injection of L-monosodium
    glutamate at 4-8 g/kg into mice caused retinal damage with ganglion
    cell necrosis within a few hours. In very young animals there was
    extensive damage to the inner layers (Lucas & Newhouse, 1957).

         Rat. Groups each of 20, ten day old rats, Charles River Strain,
    (10 male, 10 female) were dosed orally with 0.2 ml of either strained
    baby food containing no monosodium glutamate, strained baby food
    containing monosodium glutamate up to 0.4%, or strained baby food
    containing monosodium glutamate equal to a dosage level of 0.5 mg/kg,
    additional to that found in normal commercially distributed baby food
    (390 mg per jar), The rats were mated and half of the offspring were
    removed from parental females, and sacrificed after 5 hours.
    Histological studies were made of brain in the area of the hypothalmus
    at the roof and the floor of the third ventricle. The remaining rats
    were returned to parental females and allowed to grow to maturity (90
    days post weaning), then sacrificed, and histological studies made of

    the brain. No lesions were observed in the brain of animals sacrificed
    at either 5 hour post treatment, or after reaching maturity. Animals
    which were reared to maturity showed normal growth and food
    consumption (Geil, 1970).

         Groups of 5 3-and 12-day old rats receiving subcutaneously or
    orally a single acute dose (1g/kg) monosodium glutamate, mono
    potassium glutamate, sodium chloride, sodium gluconate or distilled
    water, were sacrificed 24 hours after treatment. Preliminary light
    microscopic studies of the large midbrain area showed similar
    non-specific scattered tissue changes in all treated groups (Oser et
    al., 1970).

         Dog. Intravenous casein hydrolysate or synthetic amino acid
    mixture caused nausea and vomiting in dogs (Madden et al., 1944).
    Groups of 3 dogs at 3 days or 35 days of age received subcutaneously
    or orally a single acute dose (1 g/kg) monosodium glutamate,
    monopotassium glutamate, sodium chloride, sodium gluconate or
    distilled water; and were sacrificed 3 hours and 24 hours after
    treatment. Preliminary light microscopic studies of the large midbrain
    area showed similar non-specific scattered tissue changes in all
    treated groups (Oser et al., 1970).

         Monkey. A newborn (8 hours old) rhesus infant, probably
    somewhat premature was given subcutaneously 2.2 g/kg body-weight
    monosodium glutamate. After 3 hours (no abnormal behaviour noted) the
    monkey was killed and the brain perfused in situ for 20 minutes. A
    lesion was seen in the periventricular arcuate region of the
    hypothalamus identical to those seen in mice given similar treatment.
    Electron microscopic pathological changes were seen in dendrites and
    neuron cells but not in glia or vascular components (Olney & Sharpe,
    1969). Monkeys, 4 day old, received a single dose of monosodium
    glutamate (4 g/kg in phosphate buffer), either subcutaneously or
    orally. Animals receiving subcutaneous injections were sacrificed at
    3, 24 and 72 hours, the one receiving an oral dose at 24 hours. No
    brain lesions were observed. (Coulston at al., 1970).

         Man

          Pharmacological effects were studied in 56 men given 1-12 g
    monosodium L-glutamate orally on an empty stomach. Burning of the face
    and trunk, facial pressure and chest pain were noted as well as
    headache, the last sometimes as the only symptom. Amounts of 3 g or
    less were effective in all. Similar effects were obtained by 3-5 g of
    monopotassium glutamate L-glutamic acid and DL-glutamic acid but no
    effects were seen with monosodium D-glutamate or other L-aminoacids.
    Thirteen subjects received i.v. 25-125 mg sodium glutamate with
    symptoms occurring within 20 seconds. The burning sensation is due to
    a peripheral mechanism and no genetic predisposition was noted
    (Schaumburg et al., 1969). A survey was made of 912 Japanese
    individuals to determine if any of these symptoms were noted after
    eating a Prepared Oriental Type Noodle, containing 0.61-1.36 g
    monosodium glutamate/serving. In no case were any of the

    characteristic symptoms reported (Ichimura et al., 1970a). In another
    study, the effect of monosodium glutamate on 61 healthy men was
    determined by the double blind method. The doses of monosodium
    glutamate administered were 2.2 g, 4.4 g or 8.7 g.Intake was either on
    a non-empty stomach (30 minutes after meal) or an empty stomach
    (overnight fast). In experiments on the non-empty stomach conditions
    the number of persons showing some symptoms were the same for the
    Placebo and the others. In the case of the empty stomach conditions a
    number of the test subjects on the highest level of monosodium
    glutamate experienced two of the typical symptoms at the same time. No
    individual experienced three of the symptoms. The effect of monosodium
    glutamate intake (2.2 g, 4.4 g or 8.7 g) on changes in blood pressure,
    pulse rate, ECG and sodium and glutamate levels in blood, was measured
    in 5 persons who had not experienced any symptoms, and 9 who had
    experienced some symptoms. There were no differences in increase in
    glutamic acid in the blood in either group. Sodium content of the
    blood and all other parameters measured showed no changes in either
    group (Ichimura et al., 1970b).

    The occurrence of nausea and vomiting following the i.v.
    administration of various preparations in a series of 57 human
    subjects was found to parallel the free glutamic acid content of the
    mixture. There was a direct relationship between free serum glutamic
    acid and the occurrence of toxic effects, following i.v.
    administration. When the serum glutamic acid reached 12 to 15 mg/100
    ml, nausea and vomiting occurred in half the subjects. Other amino
    acids appear to potentiate the effect (Levey et al., 1949).

         Intravenous glutamic acid (100 mg/kg) produces vomiting (Madden
    et al., 1945).

         Intravenous solutions of 2.9 per cent. monosodium glutamate in 5
    per cent. dextrose are given in hepatic coma but too rapid injection
    causes salivation, flushing and vomiting; afterwards oral doses of
    5-20 g are given daily. High doses (3 g) are said to produce Kwok's
    disease, pain in the chest, tingling sensations or temporary numbness
    of back and arms, weakness and palpitation in susceptible people
    (Kwok, 1968). 25 g have no effect in non-sensitives (Schaumburg &
    Byck, 1968).

         Arginine glutamate may be used in the treatment of ammonia
    intoxication. It is given by intravenous infusion in doses of 25 to 50
    g every 8 hours for 3-5 days in dextrose and infused at a rate of not
    more than 25 g of arginine glutamate over 1-2 hours. More rapid
    infusions may cause vomiting (Martindale, 1967).

         Single and double blind studies were done with single oral doses
    of monosodium glutamate in human male volunteers on a fasting stomach
    (18 hours after last meal). 98 received 5 grams of monosodium
    glutamate in single blind studies, 6 received 8 grams and 5 received
    12 grams in double blind studies. Physical examinations were done on
    all subjects. Complaints were registered In all groups ranging from
    23-80%6. There was a low incidence of most complaints except for

    lightheadedness and tightness in the face. No subject reported or was
    observed to have experienced the complete triad of symptoms as
    described in the original Chinese-Restaurant syndrome (Kwok's
    disease). In the double blind studies where clinical chemistry, blood
    pressure and pulse were measured in addition to clinical examination,
    no significant differences between monosodium glutamate and sodium
    chloride were detected (Rosemblum et al., 1969).

    Short-term studies

         Mouse. 38 neonate mice were observed for 9 months. 20 received
    subcutaneous monosodium glutamate daily for 1 to 10 days in doses of
    0.5 g/kg to 4 g/kg. 18 were controls. Although treated animals
    remained skeletally stunted and both males and females gained more
    weight than controls from 30 to 150 days yet treated animals consumed
    less food than controls. Test animals were lethargic, females failed
    to conceive but male fertility was not affected. At autopsy of test
    animals massive fat accumulation was seen in test mice, fatty livers,
    thin uteri and adenohypophysis had overall fewer cells in the
    adenohypophysis.

         10 test neonates received a single subcutaneous injection of 3
    gm/kg monosodium glutamate 2 days after birth, 13 neonates were
    controls. Again test animals were heavier than controls after 9 months
    but less so than mice given repeated injection treatment. It was
    postulated that an endocrine disturbance would lead to skeletal
    stunting, adiposity and female sterility. Lesions differed from those
    due to gold thioglucose or bipiperidyl mustard which affect the
    ventro-medial nucleus and cause hyperphagia (Olney, 1969b).

         Rat. Natural monosodium L-glutamate, synthetic monosodium
    L-glutamate, and synthetic monosodium D-glutamate in amounts of 20,
    200 and 2000 mg/kg body-weight were given orally to groups of 5 male
    rats each once a day for a period of 90 days. No effects on
    body-weight, growth, volume and weight of cerebrum, cerebellum, heart,
    stomach, liver, spleen and kidneys in comparison with the control
    group were observed. No histological changes in internal organs were
    found by macroscopic and microscopic examination (Hara et al., 1962).

         Nine groups of 20 rats were given 0.5 per cent. and 6 per cent.
    of calcium glutamate in their diet. No effect was noted on maze
    learning or recovery from ECT shock (Porter & Griffin, 1950). Two
    groups of 14 rats received 200 mg L-monosodium glutamate per animal
    for 35 days. No difference in their learning ability for maze trails
    was noted (Stella & McElroy, 1948). 8 male rats fed 5% dietary
    DL-glutamic acid in a low protein diet (6% protein) showed little or
    no depression of growth, when compared to low protein controls. There
    was a 50% increase in the free glutamic acid in the plasma
    (Sauberlich, 1961).

         Man. Monosodium glutamate has been used in the treatment of
    mentally retarded children in doses up to 48 g daily but on average
    10-15 g was given.

         150 children aged 4-15 years were treated with glutamic acid for
    six months and compared with 50 controls. There was a rise in verbal
    intelligence quotient but was not statistically significant. 64 per
    cent. showed improvement of behavioural traits (Zimmerman &
    Burgemeister, 1950).

         17 patients received up to 15 g monosodium glutamate three times
    a day but showed a raised blood level for 12 hours only. No effect on
    BMR, EEG, ECG, BP, heart rate, respiration rate, temperature and
    weight was noted over 11 months (Himwich et al., 1954a). 15 g then 30
    g monosodium glutamate were given per dose for one week each, followed
    by 45 g for 12 weeks to 53 patients without any effect on basal plasma
    levels of glutamic acid (Himwich et al., 1954b).

         DL-glutamic acid HC1 was given in doses of 12, 16 and 20 g to 8
    patients with petit mal and psychomotor epilepsy without adverse
    effects (Price et al., 1943). Five episodes of hepatic coma in 3
    patients treated with i.v. 23 g of monosodium glutamate with
    improvement (Walshe, 1953). 10-12 g of L-glutamic acid given to
    epileptics and mental defectives appeared to improve 9 out of 20 cases
    (Waelsch, 1949).

    Long-term studies

         Mouse. 1 control group of 200 male mice and 6 test groups of
    100 male mice received 0 per cent., 1 per cent. or 4 per cent. in
    their diet of either L-glutamic acid, monosodium L-glutamate or
    DL-monosodium glutamate. No malignant tumours appeared after 2 years
    that could be related to the administration of test material. Growth
    and haematology were normal, histopathology showed no abnormalities in
    the test animals (Little, 1953a).

         Rat. Groups of 75 male and 75 female rats received for 2 years
    dietary levels of 0, 0.1 per cent. or 0.4 per cent. either monosodium
    L glutamate, monosodium DL-glutamate or L-glutamic acid respectively.
    No adverse effects were noted on body-weight, growth, food intake,
    haematology, general behaviour, survival rate, gross and
    histopathology or tumour incidence (Little, 1953b).

    Special studies

         Mouse. The 4CS strain and Swiss white strains were studied.
    Groups of 6 mice (3 male, 3 female), were maintained on diets
    containing 0 per cent., 2% (=4 g/kg/day) or 4 per cent. (= 8 g/kg/day)
    monosodium glutamate. Mice were mated after 2 to 4 weeks on the test
    diet. Offspring (F1) were weaned at age 25 days, and fed the same
    diet as parents. At age 90 days, selected (F1) male and female mice
    from each group were allowed to produce a single litter (F2). Parent

    mice were maintained on test diets, for 100 days after delivery and
    F1, mice for 130 days of age. F2 mice were reared until 20 days of
    age. No effects were observed on growth, feed intake, estrous cycle,
    date of sexual maturation (F1 generation), organ weight, litter size
    and body-weight of offspring, and histopathology of major organs
    (including brain and eyes) of parent and F1 generation. Day of eye
    opening, general appearance and roentgenographic skeletal examination
    of F2 generation showed no abnormalities (Yonetani et al., 1970).

         Rat. 6 groups of 5-6 male and 5-10 female rats received by oral
    incubation daily 25 mg/kg or 125 mg/kg body-weight of glutamic acid
    mono-hydrochloride. Males and females received the compound during
    days 5-19 of one month, days 20-31 of the following month and days
    1-10 during the third month. No adverse effects were noted on weight
    gain, feed intake or sexual cycles of females. No organ weight changes
    were seen in females but males on the higher dose level had enlarged
    spleens. Animals were mated at the end of the experiment and pups were
    normal (Furuya, 1967).

         Rats were given thalidomide combined with 2 per cent. L-glutamic
    acid and showed essentially the same defects in the pups as groups
    treated with thalidomide alone. A group receiving L-glutamic acid
    alone was no different from controls (McColl et al., 1965).

         Four females and 1 male fed for 7 months on either 0 per cent.,
    0.1%, 0.4% of monosodium L-glutamate, monosodium DL-glutamate or
    L-glutamic acid were mated and number of pups per litter was similar
    in all groups. Only 15-20 per cent. survived because of cannibalism.
    No abnormalities regarding fertility were seen on mating other groups
    of 4 females and 1 male at nine and eleven months. The F1 generation
    was mated at 10 months and an F2 generation produced in most groups
    but only the groups as 0.1 and the 0.4% L-glutamic acid produced an
    F3 and F4 generation. No impairment of fertility was noted (Little,
    1953).

         Monosodium glutamate. was administered orally in doses up to 7
    g/kg/day to pregnant rats on 6-15 or 15-17 days following conception,
    it produced no adverse effect in the progeny up to the period of
    weaning. Further physical development to maturity was also normal
    except that the progeny obtained from gravida treated on the 15-17
    days during gestation showed impaired ability to reproduce (Kbera et
    al., 1970).

         Two female rats received 4 g/kg body weight of monosodium
    glutamate commencing at day one of pregnancy. There was no effect on
    pregnancy or lactation. Pups were divided into 3 groups. Two groups
    were nursed by parents receiving monosodium glutamate, and one group
    by untreated parent. At weaning (day 20), one group of pups that had
    been nursed by a parent receiving monosodium glutamate received
    approx. 5 g/kg monosodium glutamate daily for 220 days. Parents
    received 4 g/kg monosodium glutamate for 336 days. No effects were
    observed on growth or oestrus cycle. All pups developed normally, and

    no abnormalities were noted in growth rate, time of sexual maturity,
    oestrus cycle and fertility. (Suzuki & Tagahashi, 1970). For
    histological studies, brain, hypophysis and eye were fixed in 10%
    neutral buffered formalin. Sections were stained with
    Hematoxylin-Eosin and Luxol fast blue-cresyl echt violet. No
    differences were observed between arcuate nuclei, medium eminence of
    hypothalmus and retina of control and monosodium glutamate treated
    groups. (Shimizu & Aibara, 1970).

         Rabbit. In one group of 10 female and 4 male rabbits only the
    females received orally 25 mg/kg body-weight of glutamic acid for 27
    days. Two of the females were pregnant and the others were not
    pregnant, A second group of 4 female and 2 males received orally 25
    mg/kg glutamic acid with 25 mg/kg vitamin B6. A third group of 6
    females and 2 males received orally 25 mg/kg glutamic acid alone. A
    fourth group of 20 females and 8 males served as controls. The test
    substance was given by gavage. The first group showed two animals with
    delayed pregnancy, the uterus containing degenerate foetuses. Two
    others had abortions of malformed foetuses. Two animals delivered at
    the normal time but the pups had various limb malformations. Four
    animals did not conceive. The pups did not become pregnant during
    seven months and showed limb deformities, decreased growth and
    development compared with controls. The histopathology showed
    scattered atrophy or hypertrophy of different organs. The second group
    produced 2 pregnant females which delivered malformed pups. These died
    soon after birth and showed bony deformities as well as atrophic
    changes in various organs. The third group produced 3 pregnant females
    which delivered pups with limb deformities. All 3 groups showed
    testicular atrophy in parents and multiple changes in the pups
    (Turgrul, 1965).

         4 groups of rabbits (24 females and 16 males) received either 0,
    0.1 per cent., 0.825 per cent. or 8.25 per cent. of monosodium
    glutamate in their diet for 2-3 weeks before mating. A positive
    control group of 22 pregnant females received 100 mg/kg thalidomide
    from day 8 to 16 of pregnancy. All does were sacrificed on day 29 or
    30 of gestation and the uteri and uterine contents were examined. All
    males were sacrificed and the gonads and any abnormal organs examined.
    No significant effect on body-weight gain or food consumption was
    seen, nor on general appearance and behaviour. Gross and
    histopathology revealed no toxic effects an embryos, resorption and
    pups and all litter data were comparable among test animals and
    negative controls (Hazleton Laboratories, 1966). The brains of 5
    female and 5 male pups at the 8.25 per cent. level were subsequently
    checked for neuronal necrosis compared with controls, but none was
    found (Hazleton, 1969a). Similar investigations on 5 male and 5 female
    pups at the 0.1 and 0.825 per cent. levels were also negative
    (Hazleton, 1969b).

         In another experiment on rabbits, these animals received 2.5
    mg/kg bodyweight, 25 mg/kg and 250 mg/kg of L-glutamic acid
    hydrochloride at 70 hours post coition and 192 hours post coition.
    Operative removal of foetuses was performed on the 11th, 17th and 30th

    day post coition in 3 different series. The corpora lutea, the
    resorbed, implanted, normal and deformed foetuses were examined. No
    significant effects due to L-glutamic acid were noted with respect to
    teratogenesis (Gottschewski, 1968).

         Glutamic acid hydrochloride in a dose of 25 mg/kg body-weight was
    given orally to 15 pregnant rabbits once a day for a period of 15 days
    after copulation, monosodium glutamate in the same dose and for the
    same period of time to 9 pregnant rabbits and saline solution to 11
    pregnant rabbits which served as control group. No differences were
    noted between the treated groups and the controls as to rate of
    conception. mean litter size. and nursing rate. The average
    body-weight of the young in the treated groups was slightly lower as
    compared with the control group, but the weights of testes. ovaries
    and adrenal glands in the young and ovaries, adrenal glands, liver,
    kidneys and spleen in the mothers were not different from those in the
    controls. In the young, no external and skeletal malformations were
    observed. There were some abnormal changes in gestation such as
    abortion or resorption of foetuses, but these observations were made
    in all groups, with an incidence of 21 per cent. in the glutamic acid
    hydrochloride group, of 25 per cent. after administration of
    monosodium glutamate, and of 27 per cent. in the controls. There were
    no external and skeletal malformations in the aborted foetuses
    (Yonetani, 1967).

         Chick embryo. Fertilised hen eggs were incubated after a single
    injection of 0.01-0.1 mg glutamic acid into the yolk sac. The
    mortality of embryos was raised compared with controls (53 per cent.
    against 24 per cent.) and there was a higher incidence of
    developmental defects (24 per cent. against 3 per cent.) especially
    depression of development of the spine, pelvis and lower limbs
    (Aleksandrov et al., 1965). In another study many variables were
    studied such as route of injection, dose and time of injection. No
    obvious toxicity or teratogenicity was observed (US Food & Drug
    Administration, 1969).

    Tests on tissue cultures

         Cells (kangaroo-rats cell line) were exposed continuously for 72
    hours at 0.1% monosodium glutamate without showing any toxic effect
    (US Food & Drug Administration, 1969).

    Comments

         Glutamic acid is a component of proteins and comprises some 20
    per cent. of ingested protein. Much is known about its metabolism in
    various animal species. During gastrointestinal absorption
    transanimation to alanine occurs. As a consequence there is only a
    slight rise in glutamate levels in the portal blood. A similar
    mechanism probably also occurs in man. However, if the capacity of
    this mechanism and the further conversion of glutamate in the liver is
    overwhelmed, or if monosodium glutamate is administered parenterally
    in large doses, it is possible to obtain significantly high blood

    levels. For primates and man it has been demonstrated that blood
    levels of glutamate are higher in the foetus compared with the mother,
    particularly during the early phases of foetal development. Recent
    data show that after glutamate loading of the mother, the full term
    prenatal rat foetus has less glutamate in its circulation than exists
    in the maternal circulation.

         Numerous reproduction studies in mice, rats and rabbits revealed
    no deleterious effects on the offspring if the parent generation was
    fed glutamate in high doses, suggesting that an earlier claim of
    teratogenic effects in the rabbits was not related to glutamate
    administration. There is evidence that glutamate administered
    parenterally or orally is retinotoxic but only during a brief period
    of neonatal life and not in utero or after weaning.

         Work using subcutaneous injection suggests a vulnerability of the
    developing mouse, rat and primate central nervous system to high
    levels of glutamate in addition to other amino acids. Attempts at
    reproducing these effects after oral administration were successful
    only in mouse by the use of high doses.

         Acute reactions reported after ingestion of glutamate as food
    additive are probably due to the rapid absorption of large mounts of
    the substance. These occur fairly frequently, and particularly
    sensitive persons develop Kwok's disease.

    Evaluation

         On the data provided it is possible to arrive at a formal
    acceptable daily intake making allowance for the fact that glutamate
    is a normal constituent of protein. In arriving at the ADI the acute
    reactions due to rapid absorption have been taken into consideration.
    In view of the uncertainty regarding the possible susceptibility of
    the very early human neonate to high oral intakes of glutamate, it
    would be prudent not to add monosodium glutamate to foods specifically
    intended for infants under one year of age. When the further work on
    this aspect has become available, it may be possible to arrive at an
    acceptable daily intake for these infants as well.

    Level causing no toxicological effect in the mouse

         4 per cent. in the diet equivalent to 6000 mg/kg body-weight

    Estimate of acceptable daily intake in man

                                  mg/kg body-weight

    Unconditional acceptance*            0-120

    *Except for infants under one year. This figure is additional to
    intake from all dietary sources.

    Further work required

    1. Oral no-effect level of monosodium glutamate in neonatal mice.

    2. Determination of the period of susceptibility to monosodium
    glutamate in neonatal mammals.

    3. Age correlation between neonatal experimental animals and the human
    infants.

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    See Also:
       Toxicological Abbreviations