1、Umami/MSG: Safety Issues 味精的安全问题,John D. Fernstrom, Ph.D.Professor - University of Pittsburgh School of Medicine 匹兹堡大学 医学院 教授 Scientific Advisor - IGTC IGTC科学顾问,Outline 内容纲要,Brief review of original issues leading to expression of concern in early 1970s简要回顾上世纪70年代初引起关注的安全问题 Brief summary of safety v
2、iews now简单总结当前关于味精安全的观点 Examination of two general issues两大类问题Neurotoxicity神经毒性 General Adverse Effects (e.g., MSG Symptom Complex) 所有不良反应（如味精综合症） Conclusions 结论,Kwok RHM Chinese-Restaurant Syndrome中国餐馆综合症 New Engl J Med 278: 796, 1968 (letter) 1968年 新英格兰医学杂志 （通讯）,First report of adverse symptoms in
3、 humans associated with the ingestion of Chinese food that suggested a possible link to MSG (as well as many other ingredients).首例报道人体摄入中国食品后出现不适症状可能与所添加的味精有关（也可能是其他添加成分） An anecdotal case-report. 单例报告（缺乏足够科学依据）,Schaumberg HH et al. Monosodium L-Glutamate: Its Pharmacology & Role in the Chinese Rest
4、aurant Syndrome Science 163: 826-828, 1969 谷氨酸单钠的药理学及其在中国餐馆并发症中的角色 科学163期，826-828页，1969,Defined MSG “Symptom Triad“ 味精“三种并发症状” 表现为Burning 灼烧感 Facial Pressure 面部紧张 Chest Pain 胸痛,Skeletal stunting骨萎缩 Marked obesity明显肥胖 Sterility 不育 Hypothalamic lesions下丘脑损伤 MSG INJECTED注射味精后,Olney JW. Brain Lesions, O
5、besity and Other Disturbances in Mice Treated with Monosodium Glutamate. SCIENCE 164: 719-721, 1969. 小白鼠注射味精后出现大脑损伤，肥胖以及其他系统紊乱 1969年科学杂志,Conventional Toxicologic database for review by JECFA was very extensive, including acute, subchronic & chronic toxicity studies in rats, mice & dogs, together wit
6、h studies on reproductive toxicity and teratology 供食品添加剂联合专家委员会审查的常规毒性数据资料非常完整，包括大白鼠、小白鼠和狗的急性，亚慢性，慢性毒性研究以及遗传性毒性和畸形学研究。,The Safety Evaluation of Monosodium Glutamate Walker R, Lupien JR Journal of Nutrition 130: 1049S-1052S, 2000. 味精的安全评估 2000年营养学杂志,GLU has very low acute toxicity (15,000+ mg/kg po)
7、in rats and mice 谷氨酸对大、小白鼠具有极低的剧毒性（15000+mg/kg po） No specific adverse effects in chronic and sub-chronic studies up to 2 yr (MSG added to rat and mouse diets up to 4%, to dog diets up to 10%) 两年内，在慢性、亚慢性研究试验中未有明显副作用（大、小白鼠食物中味精占4%，小狗食物中添加10%） Reproductive and teratology studies negative 生殖和畸形研究无异常,W
8、alker R, Lupien JR. J Nutr 130: 1049S-1052S, 2000.,The Safety Evaluation of Monosodium Glutamate 味精的安全评估,The Issues 问题,Neurotoxicity神经毒性研究2. CRS (MSG Symptom Complex)中国餐馆综合症（ 味精综合症）,Neurotoxicity神经毒性研究,Dietary MSG食用味精 Plasma (GLU)血浆（谷氨酸）上升 Brain (GLU)大脑（谷氨酸）上升 Neuronal excitation & death神经兴奋和死亡,Barr
9、iers to Neurotoxicity,Gastrointestinal Tract efficiently uses ingested GLU (MSG) as E-source (95+%). 胃肠道能有效地吸收95%以上的谷氨酸钠作为能源 Gut is thus a barrier to GLU entry into blood. 肠道因此能阻止谷氨酸进入血液中 Blood-Brain Barrier prevents GLU penetration into brain. 血脑屏障阻止谷氨酸渗透到大脑 Only very high oral doses of MSG by gava
10、ge can raise plasma GLU enough to get GLU into brain 只有灌喂大剂量的味精，才会致血浆中的谷氨酸含量升高，而进入到大脑 MSG in food does not have this effect. 食物中添加的味精不会有这种效果,Fernstrom JD et al. J Clin Endocrinol Metab 81: 184-191, 1996. 1996年，临床内分泌代谢杂志,Adult males (80 kg) quickly ingested MSG, 12.7 g (150 mg/kg) in solution.成年男子 （体
11、重约80公斤）能很快吸收溶液中12.7g（约150毫克每公斤）的味精,Tsai P-J, Huang P-C Metabolism 48: 1455-1460, 1999.,Arrows = meal or snack 箭头代表摄取的食物或点心 Meals: 0745, 1215, 1800 h 饮食时间：0745，1215，1800 Daily MSG dose = 100 mg/kg: 每日摄入味精量：100mg/kg Breakfast: 15 mg/kg 早餐：15mg/kg Lunch: 40 mg/kg 午餐: 40mg/kg Dinner 45 mg/kg 晚餐：45mg/kg
12、Data are means sem (n = 10)数据：均值标准差 Black circle: no MSG 黑圈表示不含味精 White circle: MSG. 白圈表示含有味精,GLU injection ip stimulates PRL secretion in ratsDoes GLU (MSG) ingestion stimulate PRL secretion in humans? 腹腔注射谷氨酸钠会刺激小白鼠催乳素的分泌，它会对人体产生同样的作用吗？ 12.7 g oral load of MSG in male subjects 雄性研究对象12.7克口服,Plasma
13、 PRL in rats injected with MSG (1000 mg/kg ip). From: Terry LC et al. Brain Research 217: 129-142, 1981.,Rats,Humans,Placental Barrier to Maternal Glutamate 胎盘屏障母体中的谷氨酸钠Stegink LD et al Am J Obstet Gynecol 122: 70-78 (1975)Monkey study.猴子实验 Highest dose (400 mg/kg iv, open circles) produced plasma G
14、LU 70-times normal.,Battaglia FC. J Nutrition 130: 974S-977S (2000),Effect of oral MSG loading on breast milk free GLU concentrations in lactating women 哺乳妇女食用味精后母乳不会有谷氨酸钠,Lactating women ingested 100 mg/kg MSG in capsules with water, and milk samples were taken at the indicated times thereafter. Th
15、is dose raised plasma GLU from 45 nmol/ml to peak values of about 300 nmol/ml in 30-45 min. From: Baker GL et al., Factors influencing dicarboxylic amino acid content of human milk. In: Glutamic Acid: Advances in Biochemistry & Physiology, Filer LJ et al., ed. New York, Raven Press, 1979 , pp. 111-1
16、23.,哺乳期女性加水摄入 100 mg/kg 的胶囊，对其后特定时间的母乳样品进行检验表明： 这一剂量使得血液谷氨酸浓度在30-45分钟内从45nmol/ml 提高到峰值约300 nmol/ml 。From: Baker GL et al., Factors influencing dicarboxylic amino acid content of human milk. In: Glutamic Acid: Advances in Biochemistry & Physiology, Filer LJ et al., ed. New York, Raven Press, 1979 , p
17、p. 111-123. 影响人体母乳二氨基酸浓度的因素 谷氨酸：生物化学和生理学进展,Brain Issues 大脑问题,Relevance to human MSG ingestion: 有关人体摄入味精 The placenta blocks GLU transfer from maternal into fetal blood: FETAL brain is safe. 胎盘会阻止谷氨酸从母体传递给胎儿：胎儿大脑不会受到影响 Breast milk (GLU) does not rise when mother ingests high-dose MSG: NEWBORN/INFANT
18、brain is safe. 当母体摄入大剂量的味精母乳中的谷氨酸含量不会上升：新生儿的脑发育是安全的 Infant metabolizes GLU at same rate as adult (Stegink et al., Pediatric Res 20: 53-58, 1986). 婴幼儿具有和成年人同样的谷氨酸代谢的能力,Brain Issues大脑问题,The human brain is unaffected by the very high plasma (GLU) following high dose MSG intake 摄入大量的味精导致的血浆中高谷氨酸含量不会对人体大
19、脑产生影响 No dose of MSG has yet been given to humans high enough to induce CNS effects. 至今亦未发现食用味精会影响人体中枢神经系统,CRS/Allergy (MSG Symptom Complex),中国餐馆综合症/过敏症 味精综合症,Studying MSG Symptom Complex 味精综合症研究,Can reproducible symptoms be defined? 能定义这些重复性的症状么？ Are reproducible symptoms dose-related? 这些重复性症状与摄入剂量
20、有关吗? Do MSG-sensitive individuals exist? 对味精敏感的个体存在吗？,SYMPTOMS ATTRIBUTED TO MSG:味精所致症状,Burning, tightness, numbness in upper chest, neck and face. 发烧，身体发紧，胸腔上部发闷，脖子、面部发麻 Dizziness, headache 眩晕，头疼 Chest pain, palpitation 胸口痛，心悸 Weakness 乏力 Nausea, vomiting 反胃呕吐 Bronchospasm (asthmatics)哮喘 Hives (urt
21、icaria)麻疹MECHANISMS UNKNOWN 机制未知,Multicenter, double-blind, placebo-controlled, multiple-challenge evaluation of reported reactions to monosodium glutamate.Geha RS et al. J Allergy Clin Immunol 106:973-80, 2000味精反应的多中心、双盲、安慰剂控制、多重治疗评估报告2000年 过敏与临床免疫学 杂志,Protocol A: 130 self-styled MSG-sensitive indi
22、viduals. Fasted, challenge blind with placebo or MSG (5 g in liquid). 实验A：130例自认为MSG过敏者，禁食，以安慰剂或MSG(5克液体)进行盲试。Protocol B: Subjects had positive response of 2 symptoms toeither or both treatments in A (i.e., placebo responderstoo). Fast, blind challenge with 0, 1.25, 2.5 or 5 gMSG (in liquid). 实验B: 对
23、A中，出现阳性反应的实验对象，超过2种症状（例如：对安慰剂反应也一样）。禁食，以0，1.25，2.5或5克MSG(液体)进行盲试。,Geha RS et al., J Allergy Clin Immunol 106:973-80, 2000,Protocol C: Subjects had positive response of 2 symptoms to 5g MSG but not placebo in A or B. Fast, placebo (suc-rose) or MSG (5 g), in capsules (blind). Do twice. 实验C: 对A和B中阳性反应
24、的实验对象-对5克MSG出现超过2种症状（对安慰剂没有），禁食，以胶囊性的安慰剂（蔗糖）或MSG(5克)，进行盲试。重复实验。Protocol D: Subjects had positive response to both MSG chal-lenges in C. Fast, breakfast & placebo (sucrose)or MSG (5 g), in capsules (blind). Do three times. 实验D: 对C中MSG治疗出现阳性反应的实验对象，禁食，早餐加胶囊性安慰剂（蔗糖）或MSG(5克)，进行盲试。重复3次实验,Geha RS et al.,
25、J Allergy Clin Immunol 106:973-80, 2000,SYMPTOMS RATED:症状表现 General Weakness虚弱 Muscle Tightness肌肉紧张 Muscle Twitching肌肉酸痛 Flushing脸颊发红 Sweating盗汗 Burning Sensation灼感 Headache-migraine偏头痛 Chest pain胸闷 Palpitations心悸 Numbness-Tingling发麻,Geha RS et al., J Allergy Clin Immunol 106:973-80, 2000,Protocol A
26、 Results:实验A结果,n=50: 2 symptoms with MSG & 0/1 with placebo.MSG组超过2种症状出现+安慰剂组1个 n=19: 2 symptoms with MSG & placebo.超过2种症状出现，味精和安慰剂 n=17: 2 symptoms with placebo & 0/1 with MSG.安慰剂组超过2种症状出现+MSG组1个 n=44: 0 or 1 symptoms with MSG & placebo.没有或1种症状出现：MSG+安慰剂,Geha RS et al., J Allergy Clin Immunol 106:9
27、73-80, 2000,Protocol B Results:实验B结果,n=86 from A had 2 symptoms with a treatment (blinded: placebo or MSG), and included in B. 69 completed. 对2种症状进行治疗（双盲：安慰剂或MSG） Overnight fast, challenge with 0, 1.25, 2.5 or 5 g MSG. 禁食过夜，按0，1.25，2.5或5克MSG看结果,Geha RS et al., J Allergy Clin Immunol 106:973-80, 2000
28、,n=19/69 reported 2 symptoms to 5 g MSG but not placebo. 19/69例报道，5克MSG下有超过2种症状出现，没有安慰剂 n=14/19 the same symptoms occurred in B as in A. 14/19例中同样症状出现，类似于A实验 Hence, 14/130 showed reproducible response to 5 g MSG. 因此， 14/130表现出对5克MSG的可重复性反应,Protocol C Results:实验C结果,Geha RS et al., J Allergy Clin Immu
29、nol 106:973-80, 2000,1995 FASEB MSG Panel: 3 placebo-MSG challenges must give same positive response to MSG, no response to placebo. Give MSG in capsules. 1995年美国实验生物学联合会味精组：3种安慰剂-味精治疗必须引起同样的对味精的阳性反应，对安慰剂没有反应，味精应该以胶囊的形式给予。 n=19 had 2 symptoms in A & B with MSG & no symptoms with placebo. n=12 agreed
30、 to be studied. N=19时，实验A和B的味精组都有超过2种症状出现，安慰剂组没有症状出现，n=12时，实验一致。,Protocol C Results:实验C结果,Geha RS et al., J Allergy Clin Immunol 106:973-80, 2000,Two separate tests of MSG (5 g) vs placebo. 分开测试味精（5克）和安慰剂 n=2/12 had 2 symptoms with MSG but symptoms were not the same. n=2/12，味精组超过2种症状出现，安慰剂组没有症状出现，但症
31、状不同。 n=0/130 met FASEB criteria for MSG sensitivity n=0/130 时符合FASEB的MSG过敏性实验标准,Geha RS et al., J Allergy Clin Immunol 106:973-80, 2000,CONCLUSION: Using criteria established by the 1995 FASEB panel, none of the individuals who claimed a sensitivity to MSG actually showed this sensitivity when teste
32、d under blinded conditions.结论：根据1995年美国实验生物学联合会（FASEB）制定的标准，对那些声称味精过敏的个体进行双盲试验表明他们未表现出敏感性。,CRS Symptoms in Humans 人体的MSG症状,Asthma: Early studies claiming that MSG induces asthma in asthma patients have not been confirmed in recent studies involving greater numbers of patients.哮喘：早期研究声称味精会导致哮喘病人病情发作，
33、但近期众多数量病人的研究中未得到证实,Stevenson DD. Monosodium glutamate and asthma. J Nutr 130: 1067S-1073S, 2000 味精和哮喘 2000年 营养学杂志.,MSG Symptoms in Humans 人体的MSG症状,Urticaria: 65 subjects with idiopathic urticaria; single- and double-blind studies using 2.5 g MSG challenges vs placebo (capsules). 荨麻疹：使用2.5g味精和安慰剂（胶囊）
34、治疗65例特发性荨麻疹，单盲和双盲研究 “ MSG is a distinctly uncommon cause or exacerbant of chronic urticaria, if it induces urticaria at all. We were certainly unable to demonstrate MSG-induced urticaria in any of our chronic urticaria patients, even those who believed MSG provoked their urticaria in the past.” 即使味精
35、会引发荨麻疹，那也很少会引起或加剧慢性荨麻疹。我们无法确证慢性麻疹病人中多少是由味精所致的，尽管有些人认为是因为过去食用味精所致病。,Simon RA. Additive-induced urticaria: Experience with monosodium glutamate (MSG). J Nutr 130: 1063S-1066S, 2000.,Bazzano G, DElia JA, Olson RE Science 169: 1208-1209, 1970.,Adult human subjects ingested a chemically-de-fined diet sup
36、plying all of the essential amino acids in optimum amounts, plus glutamic acid as the sole source of non-essential nitrogen, for 14-42 days. No subjects developed the Chinese restaurant syndrome. No changes in weight, irrita-bility, appetite or mentation were noted.,给予成人研究对象适量的化学性饮食包含所有必须氨基酸，并以谷氨酸作为非必须氮源，14-42天后，没有发现中国餐馆综合症，体重、情绪、胃口以及智力都没有变化。,
