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Department of Animal Sciences, University of Illinois, Urbana, IL 61801
2 To whom correspondence should be addressed. E-mail: pgarlick{at}uiuc.edu.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • amino acid • adverse effects • toxicity • high intake • dietary • excessive
Introduction
In the last two decades there has been increasing interest in the safety of individual amino acids when taken in addition to the normal dietary intake of protein. This is the result of the rapidly growing use of single amino acids as dietary supplements for enhancing health or performance as well as their use as flavoring agents. In 1970 Harper et al. (1) produced a review of the effects of disproportionate intake levels of amino acids, and the information was updated in 1984 by Benevenga and Steele (2). These reviews dealt mainly with the effects of certain specific amino acids when given in excess to growing animals and documented the pronounced growth depression produced by some, especially methionine. Since that time, at least three reports were published by committees established to investigate the safety of amino acids including the Joint WHO/FAO Expert Committee on Food Additives (JECFA; ref. 3),3 the Life Sciences Research Office (LSRO; ref. 4), and the Food and Nutrition Board of the Institute of Medicine (FNB; ref. 5). Unlike the previous reviews, which concentrated mainly on literature from animals studies, these reports focused more on the safety of human consumption. For some amino acids, considerable literature exists from human and animal studies; in particular, glutamate, aspartate, and phenylalanine are well represented because of their use as food-flavoring agents [glutamate as monosodium gluatamate (MSG) and aspartate and phenylalanine in aspartame]. In addition, information exists on the toxicity of tryptophan because of its apparent involvement in the etiology of eosinophilia-myalgia syndrome, whereas rather less data are available on glutamine and the branched-chain amino acids (BCAAs), which were studied in relation to trauma recovery and athletic performance improvement. For many other amino acids much less information is available, particularly on adverse effects in humans. This article is a brief and by no means comprehensive summary of the available evidence regarding the safety of L-amino acids. Because few common mechanisms seem to relate the adverse effects of the different amino acids, they are discussed in alphabetical order.
Alanine
Alanine intake is not associated with any serious adverse effects. In rats on low-protein diets, little or no depression of growth and food intake is observed (1). Somewhat more information is available for humans. No overt side effects were reported when up to 4 g of alanine was given in oral rehydration solution over 2 d to 48 male infants (6) or when up to 132 g of alanine was given in oral rehydration solution over 4 d to 20 male infants aged <1 y (7). Moreover, in adults, no adverse events were reported after i.v. infusion of up to 35 g of alanine over 5 min (8). In several studies, oral loads of up to 50 g of alanine did not result in adverse effects other than transient nausea and abdominal cramping (9–11).
Arginine
In acute studies, arginine infusion stimulated the secretion of insulin and glucagon in food-deprived dogs (12). Arginine administration has been studied extensively for its apparent ability to enhance immunity and wound healing (13), and no adverse effects have been noted. Arginine was also investigated in animal models of cancer, where a number of studies indicated inhibition of tumor growth (13). However, in other studies on cultured cells or immune-deficient animals (e.g., athymic nude mice), stimulation of tumor protein synthesis and growth was observed (14,15). This suggests that arginine has the ability to either inhibit or enhance tumor growth, possibly depending on whether it also activates the immune system (14,15).
In humans, several studies investigating possible immunity enhancement and wound-healing improvement by up to 30 g/d of arginine hydrochloride reported no adverse effects except nausea and diarrhea (13). Moreover, i.v. infusion of patients with 30 g of arginine to evaluate pituitary hormone secretion was well tolerated except for increased plasma K+ in subjects with diabetes (16). For human patients with cancer, there are no direct measurements of the effect of arginine on tumor growth or progression. However, in patients with breast cancer, the rates of protein synthesis in the tumor and expression of tumor proliferation marker Ki67 were enhanced after 3 d of arginine (30 g/d) supplements (17). By contrast, in a similar study on patients with head and neck tumors, arginine supplements had no apparent effects (18). It is presently unclear to what extent these effects on tumors should be considered to be adverse.
Asparagine
There appears to be no information available relevant to the safety of asparagine in either animals or humans.
Aspartic acid
The toxicity of aspartic acid was examined because in dipeptide form with phenylalanine, it is a component of the artificial sweetener aspartame. In animals, aspartic acid closely resembles its analog, glutamic acid (see below). For example, the hypothalamic lesions that occurred in infant mice after glutamic acid administration (see below) also occurred with aspartic acid (19), and chronic feeding of growing animals on low-protein diets with aspartic acid depressed growth (1). However, no lesions were observed in infant monkeys treated with aspartic acid (20). In humans, the administration of a 10-g bolus dose of aspartic acid did not result in secretion of pituitary hormones (21), and administration of 75–130 mg·kg–1·d–1 aspartic acid as a supplement to an exercise regimen did not induce any reported adverse effects (22–25). In a review of the literature, the FNB noted (5) that supplements of up to 8 g/d in humans in addition to 
3 g/d from food did not result in any documented adverse effects. Similarly, there was little evidence of toxicity in subjects given aspartic acid as aspartame (4,5).
Branched-chain amino acids
In studies on animals fed low-protein diets, excess leucine was shown to cause depression of food intake and growth (reviewed in ref. 1). However, this was reversed by provision of isoleucine and valine; this effect was attributed to antagonism (1). Interestingly, excess isoleucine or valine had little effect on growth (1). The BCAAs were shown to compete with aromatic amino acids for transport into brain and to lower neurotransmitter synthesis (26,27). However, the significance of this effect is not completely clear (5). In addition, long-term studies provide no evidence of carcinogenesis in the absence of an initiating agent (28).
In humans, there have been no investigations specifically on toxicity, although many studies to date sought clinical or physiological benefits from leucine or BCAA mixtures. Few, if any, adverse effects are reported. For example, several investigators administered leucine (5–6 g, i.v. or orally) and observed no signs of toxicity (4,5) although these doses resulted in elevated concentrations of the amino acids in the blood. Maple syrup urine disease, the genetic disorder in which the oxidation of the branched-chain keto acids is deficient, also leads to increased concentrations of BCAAs and their keto acids in the blood and to mental retardation. However, there is no evidence that administration of BCAA supplements results in such high levels of the amino acids or keto acids in the blood or in neurological damage.
Cysteine
Low-protein diets that contain a range of cysteine levels (0.5–10%) were shown to reduce weight gain and food intake and result in high mortality in animals (1). Plasma cholesterol levels also changed, with an increase in rats on low-cholesterol diets and a decrease in rats on high-cholesterol diets (29–31). In addition, histopathological changes were consistently reported in kidney and liver (1). Neonatal animals showed effects on the brain (hypothalamus) and retina that were similar to those induced by glutamic acid (32). In studies on humans, 5–10-g doses of cysteine induced nausea, lightheadedness, and dissociation (21). Also, in healthy subjects given increasing doses up to 20 g of cysteine (with tranylcypromine), fatigue, dizziness, nausea, and insomnia, which were dose dependent, were reported (33).
Glutamic acid
Adverse effects attributed to glutamic acid are discussed at length in many reports (3–5,34,35). In animal studies, the acute toxicity of glutamic acid was shown to be low (LD50, 10–20 g/kg) (3–5). Little chronic toxicity (no tumors or sterility) was noted, although there was a slight growth depression in animals on low-protein diets (1). However, injecting neonatal mice with large doses of glutamate subsequently resulted in increases in body fat and sterility and damage to the hypothalamus (36). As summarized by the JECFA (3), the sensitivity to these effects declines rapidly with age and is species dependent in the order of mice > rats, hamsters, guinea pigs > nonhuman primates. Moreover, lesions occurred with parenteral administration and gavage of large doses, but no lesions were detected in animals given glutamate with food. As glutamate is an excitatory neurotransmitter, the mechanism of these effects is believed to operate through excessive activation of excitatory receptors located in the dendrosomal surfaces of neurons (37). This may result from an increase in Ca2+ influx through the permeable N-methyl-D-aspartate and 
-amino-3-hydroxy-5-methylisoxazole-4-propionic acid–selective glutamate-receptor channels, leading to generation of free radicals; activation of proteases, phospholipases, and endonucleases; and transcriptional activation of apoptotic programs (38). 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.
Subchronic studies in mice showed increases in body weight, body fat, and female sterility in animals given glutamate (2–4 g·kg–1·d–1, s.c.) during the first few days of life (36,39). However, similar studies on rats given up to 2.0 g·kg–1·d–1 glutamate in the diet showed no effects on the weights of several organs or the whole body (40,41). Other studies showed no effects of glutamate on learning or recovery from electroconvulsive therapy shock (42). Longer-term investigations of the effects of glutamate in animals revealed few adverse effects; for example, no increase in the incidence of malignant tumors (43,44) and no decreases in fertility and survival of the young (45).
In humans, i.v. administration of glutamate causes nausea and vomiting in proportion to the serum glutamate level, and concentrations >1 mmol/L result in vomiting in 50% of subjects (46). Glutamate given as arginine glutamate (50 g/8 h) in divided doses to avoid vomiting was used to treat ammonia intoxication (3). Moreover, chronic treatment of children with up to 48 g/d for 6 mo (47) and adults with 45 g/d for 11 mo (48) revealed no adverse effects.
However, in view of the neurotoxic effects of glutamate in young animals, there has been much concern about its use as the monosodium salt (MSG) as a flavor-enhancing agent. This was fueled by reported occurrences of adverse symptoms after the consumption of Asian foods, which collectively are generally known as "Chinese restaurant syndrome" but are also called "MSG symptom complex" (4) and "idiosyncratic intolerance." The symptoms, which are often reported after an individual consumes food from Asian restaurants, are 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; drowsiness; and bronchospasm (only in asthmatics) (4). Studies indicated that those who complained of being susceptible were sensitive to <3 g of MSG, and nearly all suffered some symptom at sufficiently high doses (49). However, although some studies suggested that as much as 25–30% of the population might be susceptible (50,51), later work employing more rigorously controlled experimental designs to mask the characteristic taste of MSG failed to detect any greater incidence of adverse symptoms after ingestion of glutamate (1.5 or 3 g) compared with the placebo (52–54). The JECFA (3) concluded that properly conducted and controlled clinical trials failed to establish a relationship between Chinese restaurant syndrome and ingestion of MSG. The LSRO (4) concurred, but acknowledged the possible existence of a small subgroup of healthy people that were sensitive and showed symptoms when exposed to an oral 3-g dose of MSG in the absence of food. More recent studies confirmed the existence of a small MSG-sensitive subgroup (55), and showed that responses did not occur when MSG was given with food (56). Moreover, it was also noted that neither persistent nor serious effects from MSG were observed (56).
Induction of asthma is another adverse reaction to MSG that has been described (4,34,35). However, a review by Stevenson (57) pointed out that although two single-blind studies indicated an association of MSG administration with bronchospasm in a proportion of the patients, the subsequent four studies employing double-blind approaches showed no incidence of bronchospasm after MSG in a total of 109 patients.
Glutamine
In recent years much interest has evolved in the role of glutamine in the maintenance of protein homeostasis, particularly in skeletal muscle, and the potential benefits of glutamine supplementation on the recovery from trauma and infection. Few studies specifically examine adverse effects in healthy animals. However, in the many reports of studies involving glutamine administration to animals, no adverse effects were noted. Similarly, the toxicity of glutamine has not been investigated systematically in healthy humans, although there are many studies to date that seek clinical benefit and few, if any, have reported adverse effects. The most detailed information is given in a summary by Ziegler et al. (58) of a series of experiments in which glutamine was given to volunteers and patients for various periods of time. No adverse effects due to glutamine were reported in four experimental protocols: 34 volunteers monitored for 4 h after receiving oral or i.v. glutamine in doses up to 0.3 g/kg; 7 volunteers monitored for 4 h during i.v. infusion of glutamine at a rate of 0.025 g·kg–1·h–1; 7 volunteers given total parenteral nutrition including glutamine at doses of 0, 0.285, and 0.570 g·kg–1·d–1 over 5 d; and 8 patients with bone marrow transplants given total parenteral nutrition including glutamine at doses of 0, 0.285, and 0.570 g·kg–1·d–1 over 30 d. Other studies that reported safety-related information indicated no adverse effects in 120 surgical patients given alanyl-glutamine for 6 d (59) and 44 preterm neonates given glutamine as 20% of total amino acids for 15 d (60). Therefore, no evidence exists that glutamine supplementation results in adverse effects. However, in view of the widespread and sometimes chronic use of glutamine supplements in both healthy subjects and within the clinical environment, more information is needed, especially from studies that have safety as a primary goal.
Glycine
In an acute study of dogs, i.v. infusion of 1 g/kg glycine over 20 min resulted in neurological changes (61). In more chronic studies of rats, supplementation of low-protein diets with glycine resulted in depression of growth and food intake (1). These effects were moderated with diets that contained more protein or B vitamins (1). In addition, administration of200 mg/d of glycine for 20 wk to Fischer-344 rats increased the incidence of bladder tumors (62). However, the number of treated animals was small, the control group was not described, and the observation does not appear to have been confirmed.
There appear to be no studies of glycine toxicity in humans, but no serious side effects were noted when up to 31 g/d of glycine was given in classic studies of amino acid requirements by Rose et al. (63). Also, glycine is often given as an irrigant during transurethral prostate resection, and nausea, transient blindness, and visual impairment have been reported (64–67). The visual impairment was reported to occur at a plasma glycine concentration >4 mM (64,67), whereas central nervous system symptoms occurred when >0.5 g/kg of glycine was absorbed (65). In children, i.v. infusion of 7.5 g of glycine was proposed as an "innocuous" procedure to detect growth-hormone deficiency (68).
Histidine
Histidine appears to be one of the more toxic amino acids. High dietary histidine levels have been shown to result in potentially serious adverse effects in both animals and humans. In rats, histidine supplementation of low-protein diets leads to depression of growth and food intake; these effects are moderated with higher-protein diets (1). More importantly, high histidine intake in animals resulted in hyperlipidemia, hypercholesterolemia, and enlarged liver (2,69,70). Reduced plasma copper was also reported, and the hypercholesterolemia was reversed by dietary copper supplementation (71).
In human studies, when four overweight/obese subjects were given 24–64 g/d of histidine, increases in urinary zinc, headache, weakness, drowsiness, nausea, anorexia, painful eyes, changed visual acuity, mental confusion, poor memory, and depression occurred (72). However, there were no overt side effects when up to 4.5 g/d of histidine was given as treatment for obesity (72), rheumatoid arthritis (73), and chronic uremia (74,75).
Lysine
Excess dietary lysine leads to reduced growth and feed intake in young animals fed low-protein diets (76). However, no adverse effects were detected in rats given lysine as 3% of the diet for 2 y (77), which is suggestive of low toxicity for this amino acid. When rats were fed diets that contained 5% lysine, accumulation of triglycerides in liver occurred (78,79). This effect was reversed by adding arginine to the diet (1) and is an example of antagonism between the two basic amino acids (1). This might be explained by the competition between these amino acids for processes such as transport (where their structural similarities might be recognized), although the mechanism is clearly quite complex (1).
In human studies, lysine shows little toxicity and was used as a treatment for herpes virus. In children (10–14 y) no reported ill effects ensued when 14–22-g of lysine hydrochloride was injected i.v. to assess its effect on the urea cycle (80). Infants (aged 4–11 mo) supplemented with up to 1 g of lysine/8 ounces of milk in increments over 3–4 d showed no adverse effects (81). Also, infants (aged 1–5 mo) showed no adverse effects of lysine at a dose of 220 mg/kg (82). In chronic studies, adults given 40 g/d of lysine hydrochloride for 2–5 d (83) or up to 3 g/d for up to 6 mo showed no ill effects except upset stomach (84).
Methionine
Methionine was termed the most toxic amino acid by Harper et al. (1) and Benevenga and Steele (2). A single meal containing 2.7% methionine depressed growth and food intake in animals (2). Moreover, in animals fed 10% casein diets supplemented with 0.5–0.6% methionine (three to four times their requirement), growth stopped and intake was markedly suppressed (85). Continued intake of 2.7% methionine for up to 20 d led to erythrocyte engorgement and hemosiderin accumulation, depression of growth, and liver damage (86). In piglets fed various DL-methionine levels up to 4% of the diet for 27 d, the plasma methionine concentration increased to 100 times the basal level at the highest intake (87). In female rats fed diets with 5% methionine, there were no successful pregnancies (88), whereas animals fed low-protein diets supplemented with DL-methionine for 2 y developed hyper-homocysteinemia and evidence of cardiovascular disease (89). The toxic agent responsible for these effects is believed to be methanethiol-cysteine–mixed disulfides (2).
Human studies also reveal significant adverse effects. Although 5 g/d of methionine for several weeks was reportedly innocuous (90), in two subjects given 30 g i.v., severe nausea, vomiting, and hepatic dysfunction were reported (91). In another study, 8 g/d of methionine was given for 4 d and resulted in decreased serum folate and an increased white cell count (92). Moreover, 10–20 g/d of methionine given orally for 2 wk led to functional psychosis in 7 of 11 patients with schizophrenia (93). As observed in animals, daily 100 mg/kg doses of methionine lead to high plasma methionine, homocysteine, and mixed disulfides (94). Because homocysteinemia is correlated with cardiovascular disease, the long-term use of methionine supplements is a potentially serious concern.
Phenylalanine
Concern for the safety of phenylalanine arises from the abnormal brain development known to occur in humans with phenylketonuria, which results in the buildup of phenylalanine and its metabolites in the blood. Moreover, rats injected with 4 g/kg of phenylalanine from days 8–11 of life show abnormal brain development (95). In animals on normal-protein diets, high dietary phenylalanine levels depress growth, but no more than pair feeding (2). However, in humans given either single oral doses of up to 10 g (96), 30 g i.v. (91), or 3–4 g orally as aspartame (96), no adverse effects were noted. This suggests that in those with a normal ability to metabolize phenylalanine, this amino acid is relatively safe, although there is no information regarding safety during pregnancy and infancy.
Proline
Supplemental proline leads to small depressions of growth and food intake in rats on low-protein diets (1). Administration of proline in the drinking water (50 mg/kg body weight) for 1 mo did not result in any histological changes in liver and kidney (97). The only relevant information for humans is a study that detected no overt side effects when 3–10 g/d proline was given to four patients with gyrate atrophy for 2–4 y (98).
Serine
Growth depression and reduced food intake occur in rats given low-protein diets plus serine (1). The information for humans is sparse. No side effects were reported when up to 15 g of serine was taken orally by healthy subjects, whereas a recurrence of psychotic symptoms ensued in four recovered psychotic patients given the same dose (99). However, a similar study of 12 psychotic patients and 10 controls revealed no changes in self-assessed perceptual or cognitive psychiatric symptomatology (100).
Threonine
Threonine has not been studied extensively but appears to be one of the least toxic of the amino acids. When added to low-protein diets, threonine causes less growth depression than other amino acids (1). Although there was greater inhibition of pup growth than with pair-fed animals when 5% threonine was added to the low-protein diet fed to pregnant rats (1,101), this was less than the growth depression caused by much smaller amounts of tryptophan or histidine (1,102). In human studies there is also little indication of toxicity. No serious side effects were reported when up to 6 g of threonine was given daily for 2 wk to patients with spasticity (103). No data appear to be available for healthy adults, except headaches and backaches occurred when subjects were given up to 22.5 g of threonine i.v. (91). In premature infants, increased formula intake led to increased serum threonine concentrations, particularly in those that consumed whey-based formula (which is especially rich in threonine), but no adverse effects were associated with this (104).
Tryptophan
High intake levels of tryptophan depress food intake and growth in animals fed low-protein but not higher-protein diets (1,2). In addition, adult rats fed 20% casein diets supplemented with 28.5% tryptophan showed rapid weight loss (105). However, pigs given tryptophan as 1% of diet showed no effects on growth or intake (106). In biochemical studies, rats given 5% tryptophan in diet for 6 wk showed increases in serotonin and 5-hydroxyindole acetic acid in the lower brain stem (107). Moreover, behavioral effects that are mediated through serotonergic neurons, e.g., reduced sleep latency, reduced food intake, depressed motor activity, and improved maze-test performance were observed in animal studies (108). Despite these reported effects in animals, no evidence exists of serious adverse effects attributable directly to tryptophan in humans, and some potentially beneficial effects, e.g., sleep enhancement (109), have been reported, so tryptophan is widely sold as a sleep aid. The most important negative evidence is the outbreak of eosinophlia-myalgia syndrome in the 1980s that occurred in subjects taking tryptophan supplements (110). However, this is now believed to be unrelated to tryptophan itself; rather, the syndrome appears to have resulted from a contaminant in the tryptophan produced by a single supplier (5).
Tyrosine
In young rats on low-protein diets, depression of growth and food intake occur when additional tyrosine is given, which is followed by death at higher tyrosine intake levels. A unique effect of this amino acid is to induce corneal and paw lesions in rats fed low-protein diets with 3–5% tyrosine, but histopathological changes also occur in a variety of other tissues (1). These effects are moderated with time and higher levels of dietary protein or by limiting amino acids (1). The eye lesions were shown to consist of tyrosine crystals resulting from the high concentration and low solubility of tyrosine in tissue fluids (111,112). In addition, changes in catecholamine-mediated functions, e.g., blood pressure, were reported (113). After female rats were given additional tyrosine during gestation, neurological and behavioral changes were detected in the pups (114).
The genetic disorder tyrosinemia II is associated with very high plasma tyrosine levels due to the deficiency of hepatic tyrosine aminotransferase. It results in mental retardation and lesions of the eye and soles of the feet that are analogous to those reported in animal studies (4). However, experimental studies of high tyrosine intake in humans have not in general reproduced these effects or the adverse effects seen in animals. Oral doses of 100 mg/kg in adults did not change blood pressure or pulse rate, and there were no other reported side effects (115,116). Although a 14-g dose resulted in increases in plasma epinephrine, norepinephrine, and dopamine concentrations, no physical or psychological effects were detected (117). Moreover, a single 100 mg/kg dose of tyrosine led to improvement in cognitive and performance tasks at high altitude (118). During these studies, no side effects were reported. However, in babies there may be some cause for concern. A follow-up study of premature infants who had suffered transient neonatal tyrosinemia revealed an association between elevated plasma tyrosine in infancy, impaired perceptual function, and reduced achievement scores when they reached 7–8 y of age (119). Also, in a study of transient neonatal tyrosinemia attributed to a high-protein formula plus a lack of supplemental vitamin C, children whose tyrosinemia persisted for >45 d showed lower scores on some tests of intellectual ability (120). This suggests that supplemental tyrosine should be avoided by pregnant women and infants.
General conclusions
Adverse effects are apparent in animals when most (if not all) amino acids are taken in amounts that are disproportionate to the normal diet composition. In growing animals, this is generally apparent as a reduction in growth rate, but the magnitude of this effect and the ability of the animal to compensate vary widely. Also, large variation exists in the incidence and nature of adverse effects that are observed with different amino acids in adults. Moreover, no general rule or mechanism appears to account for the effects of all amino acids or even groups of amino acids. Neurological effects occur with a range of amino acids, but there appears to be no uniform mechanism. The most toxic amino acids for both animals and humans appear to be methionine, cysteine, and histidine. Not only do these amino acids have acute adverse effects, but evidence exists that they can cause tissue damage and increase homocysteine and/or cholesterol levels and so may be associated with chronic diseases if taken over long periods of time. However, in general, there is little evidence of serious adverse effects in humans from most amino acid supplements. Nonetheless, for many amino acids, the data relevant to humans are very limited, so unanticipated adverse consequences of consuming large amounts cannot be ruled out. In particular, there are no data that would enable an upper level of safe intake to be established with confidence for any amino acid.
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FOOTNOTES |
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3 Abbreviations used: BCAA, branched-chain amino acid; FNB, Food and Nutrition Board of the Institute of Medicine; JECFA, Joint WHO/FAO Expert Committee on Food Additives; LSRO, Life Sciences Research Office; MSG, monosodium glutamate.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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1. Harper, A. E., Benevenga, N. J. & Wohlheuter, R. M. (1970) Effects of ingestion of disproportionate amounts of amino acids. Physiol. Rev. 50: 428–558.
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