Hazard Identification

Most of the body's free glutamate pool is concentrated in the tissues, especially brain (homogenate, 10 mmol/L; synaptic vesicles, 100 mmol/L) (Meldrum, 2000). By contrast, the concentration of glutamate in the blood is low, typically about 50 pmol/L in the fasting state (Stegink et al., 1982a, 1983a, 1983b). During absorption of a high-protein meal (1g protein/kg/d), there is about a twofold rise in the concentration of glutamic acid in the systemic plasma (Stegink et al., 1982a), returning to baseline 8 hours after the meal. Addition of monosodium glutamate (34 mg/kg) to the meal,

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which increased the total glutamate intake by 16 percent, did not result in any further increase in glutamate concentration. However, a larger dose of glutamate, 150 mg/kg/d, which increased the total intake by 69 percent, resulted in a larger increase in glutamate level than the meal alone (by about 50 percent) (Stegink et al., 1983b). Both the peak level achieved and the time course of rise in glutamate level have been shown to be highly dependent on the way in which the glutamate is ingested. A single drink of glutamate (150 mg/kg) in water resulted in a large and rapid rise in the plasma level, peaking at about 12 times the basal level at 45 minutes, and falling quickly thereafter (Stegink et al., 1983a). By contrast, a meal consisting of a liquid formula substantially inhibited the rise in glutamate level (Stegink et al., 1983a).

Adverse Effects in Animals. The adverse effects of glutamic acid and its salts have been reviewed in great detail by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) (JECFA, 1988) and the American Institute of Nutrition of the Federation of American Societies for Experimental Biology (FASEB) (Raiten et al., 1995). The acute toxicity has been evaluated in several animal species, with LD50 values for the oral route of administration ranging from 16,200 to 19,200 mg/kg of body weight in mice, 10,000 to 19,900 mg/kg of body weight in rats, and greater than 2,300 mg/kg of body weight in rabbits (JECFA, 1988), indicating a low level of acute toxicity. Subchronic studies in mice showed an increase in body fat and female sterility in animals that had been subcutaneously injected with glutamate (2.2 to 4.2 g/kg/d) from day 1 to day 10 of life (Olney, 1969). Mice given subcutaneous injections of glutamate (3 g/kg) at 2 days of age were also found to have higher body weights (Olney, 1969). In similar studies on rats given up to 2.0 g/kg/d of glutamate, no effects on body weight, growth, and the volume and weights of several organs were detected (Hara et al., 1962). Other studies showed no effects of glutamate on learning or recovery from electroconvulsive shock (Porter and Griffin, 1950; Stellar and McElroy, 1948).

Longer-term investigations of the effects of glutamate in animals have revealed few adverse effects. In two studies on mice given glutamate (1 or 4 percent of the diet) for 2 years, no increase in the incidence of malignant tumors was shown, and in other respects the animals were normal (Ebert, 1979b; JECFA, 1988). Similar negative results were reported from chronic studies (2 year) in rats given diets containing 0, 0.1, and 0.4 percent glutamate (JECFA, 1988) and in rats given diets containing 0, 1, 2, and 4 percent glutamate (Owen et al., 1978a). In addition, rats given diets with 0.1 or 0.4 percent glutamate showed no adverse effects on fertility and survival of the young (Ebert, 1979a). Moreover, no adverse effects on body weight gain, food consumption, behavior, electrocardiogram, ophthal-

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mology, hematology, blood chemistry, organ weights, kidney function, or mortality were observed in dogs given diets with 0, 2.5, 5, or 10 percent glutamate (Owen et al., 1978b).

Adverse Effects in Humans. In humans there is a direct relationship between serum glutamate level and nausea and vomiting with concentrations above 1 mmol/L resulting in vomiting in 50 percent of the individuals (Levey et al., 1949). Glutamate has been used for treatment of a variety of medical conditions. For example, arginine glutamate has been given to treat ammonia intoxication, at a dose of 50 g every 8 hours, but no more than 25 g over 1 to 2 hours in order to avoid vomiting (Martindale, 1967). Chronic glutamate treatment of children with approximately 0.3 g/d of glutamic acid for 6 months (Zimmerman and Burgemeister, 1959) and adults with 45 g/d for 10 weeks (Himwich et al., 1954) showed no adverse effects.

Despite the generally low level of toxicity of glutamic acid demonstrated in the studies on animals and humans, there has remained concern over its continued use as a flavor-enhancing agent. This has been fueled by the discovery that high doses of glutamate can under certain circumstances be neurotoxic (Olney, 1969), and by the reported occurrence of distressing symptoms after the consumption of Asian foods, generally known as Chinese restaurant syndrome. As glutamate is an excitatory neurotransmitter, its potential for neurotoxicity has been studied extensively. In 1957 it was shown that injection of glutamate into suckling mice resulted in degeneration of the inner neural layers of the retina (Lucas and Newhouse, 1957). Later work showed that neuronal destruction also occurred in several regions of the brain in mice after glutamate was parenterally administered (Olney, 1969). Neurons are destroyed by excessive activation by glutamate of excitatory receptors located on the dendrosomal surfaces of neurons (Olney, 1989). The most sensitive areas of the brain are those that are relatively unprotected by the blood-brain barrier, notably the arcuate nucleus of the hypothalamus.

In a detailed analysis of the literature on the neurotoxic effects of glutamate in several species, JECFA (1988) concluded that parenteral administration of glutamate results in reproducible lesions in the central nervous system. However, lesions have never been observed in animals taking glutamate with food, although lesions were noted when the glutamate was given as a large dose by gavage. The neonatal mouse is the most sensitive, the sensitivity declining in weanlings through adults. Moreover, the sensitivity is lower in rats, hamsters, guinea pigs, and rabbits, and effects have rarely been detected in nonhuman primates. In addition, there have been a number of reports of behavioral abnormalities in mice and rats given large doses of glutamate in the early neonatal period (Berry et

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al., 1974; Iwata et al., 1979; Nikoletseas, 1977; Olivo et al., 1986; Pinto-Scognamiglio et al., 1972; Poon and Cameron, 1978; Pradhan and Lynch, 1972). There are also reports of reproductive abnormalities in animals given glutamate as neonates (Lamperti and Blaha, 1976, 1980; Matsuzawa et al., 1979; Pizzi et al., 1977). However, a number of other studies have shown no effect on reproduction (Anantharaman, 1979; Prosky and O'Dell, 1972; Yonetani et al., 1979), and one study reported an enhancement of fertility (Semprini et al., 1971).

No signs of neurological damage have been reported in humans. For example, in adult males given a chemically defined diet in which glutamate was the only source of dispensable nitrogen for periods of 14 to 42 days, no changes in neurologic or hepatic function were detected (Bazzano et al., 1970). However, concern was raised by a report that a large dose of glutamate taken orally stimulated the secretion of prolactin and cortisol (Carlson et al., 1989). Earlier findings that rats injected with 1 g/kg of glutamate showed stimulation in the secretion of luteinizing hormone and testosterone (Olney et al., 1976) were interpreted as indicating that the high concentration of glutamate had penetrated the neuroendocrine parts of the hypothalamus. Similarly, it was shown that the same dose of glutamate stimulated release of prolactin and inhibited the release of growth hormone (Terry et al., 1981). The data of Carlson and coworkers (1989) might therefore be interpreted to imply that the elevated concentration of glutamate was penetrating the hypothalamus in humans, and that neuroendocrine disturbances might be a potential consequence. However, a more recent and more strictly controlled study, employing 12.7 g of monosodium glutamate (160 mg/kg of body weight), failed to show significant changes in prolactin and cortisol or of luteinizing hormone, follicle stimulating hormone, growth hormone, or thyroid stimulating hormone (Fernstrom et al., 1996).

Chinese Restaurant Syndrome. Despite the failure to show any neurological damage in humans resulting from glutamate ingestion, there are many reports of symptoms associated with Chinese Restaurant Syndrome, also called MSG (monosodium glutamate) Symptom Complex (Raiten et al., 1995) and Idiosyncratic Intolerance. These symptoms, which have frequently been reported anecdotally after eating Asian food, have been described as a burning sensation at the back of the neck, forearms, and chest; facial pressure or tightness; chest pain; headache; nausea; upper body tingling and weakness; palpitation; numbness in the back of the neck, arms, and back; and drowsiness. After initial reports of this complaint, the symptoms were attributed to the high concentration of MSG in Asian food (Ambos et al., 1968; Schaumburg and Byck, 1968).

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Studies indicated that some of those who reported being susceptible were sensitive to less than 3 g, and that all but one of those studied suffered some symptom at sufficiently high doses (Schaumburg et al., 1969). Later work suggested that as many as 25 to 30 percent of the population might be susceptible (Kenney and Tidball, 1972; Reif-Lehrer, 1976). However, a more recent assessment, using a randomized double-blind crossover design in which the characteristic taste of MSG had been carefully disguised, failed to detect any greater incidence of adverse symptoms after consuming glutamate at a meal (1.5 or 3 g) compared with the placebo (Tarasoff and Kelly, 1993). In fact, a significant negative correlation was found between MSG dose and adverse symptoms. In another study, six adults who believed themselves to be sensitive to MSG were challenged with MSG (6 g) or placebo in a strongly flavored drink to mask the MSG in a double-blind study (Kenney, 1986). Four of the six did not react to either MSG or the placebo, whereas the other two reacted to both. Similarly, 24 individuals, 18 of whom believed themselves to be subject to flushing symptoms after eating Chinese food, were challenged with MSG (3 to 18.5 g), but no cases of flushing occurred (Wilkin, 1986).

Thus in 1988, JECFA concluded that properly conducted and controlled clinical trials had failed to establish a relationship between Chinese Restaurant Syndrome and the ingestion of MSG. Subsequently, the FASEB report (Raiten et al., 1995) concluded that there was no scientifically verifiable evidence of adverse effects in most individuals exposed to high levels of MSG.

FASEB (Raiten et al., 1995) also acknowledged that there was sufficient evidence for the existence of a small subgroup of healthy people that were sensitive to MSG, and that they showed symptoms when exposed to an oral dose of 3 g in the absence of food. A recent double-blind, placebo-controlled study on a self-selected group of individuals who believed themselves to be sensitive to MSG has shown that many have the specific symptoms under experimental conditions that they had previously identified as representing their sensitivity to MSG (Yang et al., 1997). They also identified a dose of 2.5 g as the threshold for the induction of symptoms. A more recent study of similar design confirmed these findings, and also reported that responses did not occur when MSG was given with food (Geha et al., 2000). It was also noted that neither persistent nor serious effects from MSG were observed.

Asthma. Triggering of asthma was another, and potentially more serious, symptom of the MSG Symptom Complex listed by FASEB (Raiten et al., 1995). A recent review by Stevenson (2000) analyzed six studies on asthmatic patients, and has pointed out a number of deficiencies. Two studies indicated that single-blind administration of MSG (1.5 to 2.5 g) was

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associated with bronchospasm in 14 of 32 (Allen et al., 1987) and 2 of 30 asthmatics (Moneret-Vautrin, 1987). However, the subsequent four studies, employing double-blind approaches, showed no incidence of broncho-spasm after MSG ingestion in a total of 45 asthmatic patients (Germano et al., 1991; Schwartzstein et al., 1987; Woessner et al., 1999; Woods et al., 1998). Clearly there is a need for further study in this area to clarify the inconsistencies, but overall they show no convincing evidence that MSG precipitates asthma attacks.

It has also been suggested that MSG exacerbates urticaria. In a single systematic study of patients with chronic idiopathic urticaria, involving single- and double-blind, placebo-controlled challenges, two patients had positive single-blind, but neither had positive double-blind challenges, suggesting that only a very small proportion of the patients, if any, were sensitive to MSG (Simon, 2000).

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