番茄红素

是植物中所含的一种天然色素。主要存在于茄科植物西红柿的成熟果实中。它是目前在自然界的植物中被发现的最强抗氧化剂之一。科学证明，人体内的单线态氧和氧自由基是侵害人体自身免疫系统的罪魁祸首。番茄红素清除自由基的功效远胜于其他类胡萝卜素和维生素E，其淬灭单线态氧速率常数是维生素E的100倍。它可以有效的防治因衰老，免疫力下降引起的各种疾病。因此，它受到世界各国专家的关注。

中文名番茄红素英文名 lycopene from tomato 别称 ψ,ψ-胡萝卜素;茄红素;西红柿红素;蕃茄红素;番茄红素化学式 C40H56 分子量 536.8726 CAS登录号 502-65-8 EINECS登录号 207-949-1 目录 1 相关研究 2 物理性质 ▪ 呈色能力 ▪ 溶解性 3 英文别名 4 生物特性 5 合成途径 6 适用人群 7 药物试验 8 药理作用 9 生理功能 10 制备 11 应用

番茄红素大品牌

1 汤臣倍健汤臣倍健股份有限公司 (电话：4000-916-916) (始于1995年,公众营养与发展中心营养健康倡导产品,营养补充剂专业生产基地,大型上市公司,汤臣倍健股份有限公司) [网店17] 2 自然之宝汤臣倍健股份有限公司 (电话：400-818-9797) (始于1971年美国,全球膳食补充巨头,美国著名的草本和维生素产品制造商,2016年汤臣倍健获得中国市场的永久经营权和商标使用权) [网店10] 3 屯河CofcoTunhe 中粮集团有限公司 (电话：010-85017200) (中粮集团控股子公司,国内知名的全产业链食糖企业和优质番茄制品提供者,大型上市公司,中粮屯河糖业股份有限公司) [网店1] 4 红帆新疆红帆生物科技有限公司 (电话：400-8989-389,0996-6030518) (新疆名牌,自治区著名商标,专业从番茄红素研发/生产/销售,国内较大的天然番茄红素企业,新疆红帆生物科技有限公司) [网店3] 5 中基ChalkiS 中基健康产业股份有限公司 (电话：400-112-1558,0991-8852199) (国内知名番茄红素品牌,集番茄种植/生产/加工/贸易/科研开发为一体的农业产业化企业,中基健康产业股份有限公司)

6 Jamieson健美生上海美深投资管理有限公司 (电话：4008-215-139,027-86695238) (创于1922年加拿大,世界著名维生素制造商,天然营养保健品领先品牌,中国总代:上海美深投资管理有限公司) [网店3] 7 中科ZK 中科健康产业集团股份有限公司 (电话：025-83226666) (始于1984年,江苏省著名商标,主营中药及中药保健品的研制/生产/销售的高新技术企业,中科健康产业集团股份有限公司) [网店3] 8

Swisse(广州市合生元生物制品有限公司) [产品11] 为它投票 (电话：400-883-2490) (源自澳大利亚墨尔本,国际著名的维他命保健品牌,澳洲自然医学疗法的先驱,2015年被合生元收购,合生元国际控股有限公司) 维生素 | 葡萄籽 | 鱼油/深海鱼油 | 番茄红素 | 螺旋藻 | [网店3] 9 GNC健安喜健安喜(上海)贸易有限公司 (电话：400-820-6966) (创立于1935年美国,闻名全球的大型营养保健食品连锁专卖店,膳食补充剂行业领先者,世界著名营养食品公司,健安喜(上海)贸易有限公司) [网店9] 10 修正修正药业集团股份有限公司 (电话：400-707-0777) (始于1995年,旗下拥有斯达舒/修正牌消糜栓/唯达宁喷剂/益气养血口服液等市场著名产品,吉林修正药业集团股份有限公司) [网店13] 11 国珍Guozhen 新时代健康产业(集团)有限公司 (电话：010-64850818) [网店2] 12 金奥力GEEOLE 威海紫光金奥力生物技术有限公司 (电话：400-0631-197,0631-5992055) (山东省著名商标,以营养补充剂为主,集药品/生物制品/保健品等的科研开发/生产销售为一体的现代化高科技企业,威海紫光金奥力生物技术有限公司) [网店5] 13 康恩贝CONBA 浙江康恩贝制药股份有限公司 (电话：400-0572-666,0571-87774811) (始于1969年,集药材种植及药品研发/生产/销售为一体的医药上市企业,康恩贝集团旗下,浙江康恩贝制药股份有限公司) [网店10] 14 红桃K 红桃开集团股份有限公司 (电话：400-736-7177,400-007-8769) (成立于1994年,以现代生物技术为体的大健康产业,高新技术企业,其红桃K生血剂被誉为“中国血健康专家”,红桃开集团有限公司) [网店6] 15 艾兰得aland 江苏艾兰得营养品有限公司 (电话：400-0909-888) (江苏省著名商标,高新技术企业,营养保健品行业领先企业,知名品牌,江苏艾兰得营养品有限公司)

天康齐健新疆天山二母生物科技有限公司（董事长：赵亮电话：0991-5823269，18997904379，18299128095 传真：0991-8877803）

Lycopene

From Wikipedia, the free encyclopedia

Jump to: navigation, search Lycopene

Names IUPAC name (6E,8E,10E,12E,14E,16E,18E,20E,22E,24E,26E)- 2,6,10,14,19,23,27,31-Octamethyldotriaconta-2,6,8,10,12,14,16,18,20,22,24,26,30-tridecaene Other names ψ,ψ-Carotene Identifiers CAS Number 502-65-8 3D model (JSmol) Interactive image ChEBI CHEBI:15948 ChemSpider 394156 ECHA InfoCard 100.007.227 EC Number 207-949-1 E number E160d (colours) PubChem CID 446925 UNII SB0N2N0WV6 InChI [show] SMILES [show] Properties Chemical formula C40H56 Molar mass 536.89 g·mol−1 Appearance deep red solid Density 0.889 g/cm3 Melting point 172–173 °C (342–343 °F; 445–446 K) Boiling point 660.9 °C (1,221.6 °F; 934.0 K) at 760 mmHg[1] Solubility in water insoluble Solubility soluble in CS2, CHCl3, THF, ether, C6H14, vegetable oil insoluble in CH3OH, C2H5OH[1] Solubility in hexane 1 g/L (14 °C)[1] Vapor pressure 1.33·10−16 mmHg (25 °C)[1] Hazards Main hazards Combustible Safety data sheet See: data page NFPA 704

1 0 0 Flash point 350.7 °C (663.3 °F; 623.8 K) [1] Supplementary data page Structure and properties Refractive index (n), Dielectric constant (εr), etc. Thermodynamic data Phase behaviour solid–liquid–gas Spectral data UV, IR, NMR, MS Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). verify (what is ?) Infobox references

Lycopene from the neo-Latin lycopersicum, the tomato species, is a bright red carotene and carotenoid pigment and phytochemical found in tomatoes and other red fruits and vegetables, such as red carrots, watermelons, gac, and papayas, although not in strawberries or cherries.[2] Although lycopene is chemically a carotene, it has no vitamin A activity.[3] Foods that are not red may also contain lycopene, such as asparagus and parsley.[2] In plants, algae, and other photosynthetic organisms, lycopene is an important intermediate in the biosynthesis of many carotenoids, including beta-carotene, which is responsible for yellow, orange, or red pigmentation, photosynthesis, and photoprotection.[3] Like all carotenoids, lycopene is a polyunsaturated hydrocarbon, i.e. an unsubstituted alkene. Structurally, lycopene is a tetraterpene and assembled from eight isoprene units that are composed entirely of carbon and hydrogen.[3] It is insoluble in water. Lycopene's eleven conjugated double bonds give its deep red color and its antioxidant activity in vitro. Owing to the strong color, lycopene is a useful food coloring (registered as E160d) and is approved for usage in the USA,[4] Australia and New Zealand (registered as 160d)[5] and the EU.[6]

Contents [hide] 1 Consumption by humans 2 Structure and physical properties 2.1 Biosynthesis 2.2 Staining and removal 3 Dietary sources 4 Metabolism 4.1 Adverse effects 5 Research and potential health effects 5.1 Regulatory status in Europe and the United States 6 See also 7 References 8 External links

Consumption by humans[edit] Absorption of lycopene requires that it be combined with bile salts and fat to form micelles.[3] Intestinal absorption of lycopene is enhanced by the presence of fat and by cooking.[3] Lycopene dietary supplements (in oil) may be more efficiently absorbed than lycopene from food.[3] Lycopene is not an essential nutrient for humans, but is commonly found in the diet mainly from dishes prepared from tomatoes.[2][3]

Skeletal formula of all-trans lycopene

Ball-and-stick model of all-trans lycopene Structure and physical properties[edit] Lycopene is a symmetrical tetraterpene assembled from eight isoprene units. It is a member of the carotenoid family of compounds, and because it consists entirely of carbon and hydrogen, is also a carotene.[3] Isolation procedures for lycopene were first reported in 1910, and the structure of the molecule was determined by 1931. In its natural, all-trans form, the molecule is long and straight, constrained by its system of eleven conjugated double bonds. Each extension in this conjugated system reduces the energy required for electrons to transition to higher energy states, allowing the molecule to absorb visible light of progressively longer wavelengths. Lycopene absorbs all but the longest wavelengths of visible light, so it appears red.[3] Plants and photosynthetic bacteria naturally produce all-trans lycopene.[3] When exposed to light or heat, lycopene can undergo isomerization to any of a number of cis-isomers, which have a bent rather than linear shape. Different isomers were shown to have different stabilities due to their molecular energy (highest stability: 5-cis ≥ all-trans ≥ 9-cis ≥ 13-cis > 15-cis > 7-cis > 11-cis: lowest).[7] In the human bloodstream, various cis-isomers constitute more than 60% of the total lycopene concentration, but the biological effects of individual isomers have not been investigated.[8]

Lycopene is a key intermediate in the biosynthesis of many carotenoids. Carotenoids like lycopene are important pigments found in photosynthetic pigment-protein complexes in plants, photosynthetic bacteria, fungi, and algae.[3] They are responsible for the bright orange–red colors of fruits and vegetables, perform various functions in photosynthesis, and protect photosynthetic organisms from excessive light damage. Lycopene is a key intermediate in the biosynthesis of many important carotenoids, such as beta-carotene, and xanthophylls.[9] Biosynthesis[edit] The unconditioned biosynthesis of lycopene in eukaryotic plants and in prokaryotic cyanobacteria is similar, as are the enzymes involved.[3] Synthesis begins with mevalonic acid, which is converted into dimethylallyl pyrophosphate. This is then condensed with three molecules of isopentenyl pyrophosphate (an isomer of dimethylallyl pyrophosphate), to give the twenty-carbon geranylgeranyl pyrophosphate. Two molecules of this product are then condensed in a tail-to-tail configuration to give the forty-carbon phytoene, the first committed step in carotenoid biosynthesis. Through several desaturation steps, phytoene is converted into lycopene. The two terminal isoprene groups of lycopene can be cyclized to produce beta-carotene, which can then be transformed into a wide variety of xanthophylls.[3] Staining and removal[edit] Lycopene is the pigment in tomato-containing sauces, turning plastic cookware orange and is insoluble in water. It can be dissolved only in organic solvents and oils. Because of its non-polarity, lycopene in food preparations will stain any sufficiently porous material, including most plastics. To remove this staining, the plastics can be soaked in a solution containing a small amount of household bleach.[10] Dietary sources[edit] Dietary sources of lycopene[3] Source mg wet weight Gac 2,000–2,300 Raw tomato 4.6 per cup Tomato juice 22 per cup Tomato paste 75 per cup Tomato ketchup 2.5 per tablespoon Watermelon 13 per wedge Pink grapefruit 2 per half grapefruit Fruits and vegetables that are high in lycopene include autumn olive, gac, tomatoes, watermelon, pink grapefruit, pink guava, papaya, seabuckthorn, wolfberry (goji, a berry relative of tomato), and rosehip.[3] Ketchup is a common dietary source of lycopene.[3] Although gac (Momordica cochinchinensis Spreng) has the highest content of lycopene of any known fruit or vegetable (multiple times more than tomatoes),[11][12] tomatoes and tomato-based sauces, juices, and ketchup account for more than 85% of the dietary intake of lycopene for most people.[3] The lycopene content of tomatoes depends on species and increases as the fruit ripens.[13] Unlike other fruits and vegetables, where nutritional content such as vitamin C is diminished upon cooking, processing of tomatoes increases the concentration of bioavailable lycopene.[3][14] Lycopene in tomato paste is up to four times more bioavailable than in fresh tomatoes.[15] The reason is that in raw plant foods, lycopene is insoluble in water and is tightly bound to vegetable fiber. Processed tomato products such as pasteurized tomato juice, soup, sauce, and ketchup contain a higher concentration of bioavailable lycopene compared to raw tomatoes.[3][16] Cooking and crushing tomatoes (as in the canning process) and serving in oil-rich dishes (such as spaghetti sauce or pizza) greatly increases assimilation from the digestive tract into the bloodstream. Lycopene is fat-soluble, so the oil is said to help absorption. Gac is a possible commercial source of lycopene for the purposes of extraction and purification, as its seed content of lycopene is high.[17] Another source of lycopene is the fungus Blakeslea trispora.

Note that there are some resources which make the mistaken assumption that all red fruits contain lycopene, when in fact many are pigmented by other chemicals. An example is the blood orange, which is colored by anthocyanins,[18] while other red colored oranges, such as the Cara cara navel, and other citrus fruit, such as pink grapefruit, are colored by lycopene.[2][19] In addition, some foods that do not appear red also contain lycopene, e.g., asparagus, which contains approximately 30μg of lycopene per 100 gram serving[2] (0.3μg/g) and dried parsley and basil, which contain approximately 3.5-7 μg of lycopene per gram.[2] Metabolism[edit] Distribution of lycopene[citation needed] Tissue nmol/g wet weight Liver 1.28–5.72 Kidney 0.15–0.62 Adrenal 1.9–21.6 Testes 4.34–21.4 Ovary 0.25–0.28 Adipose 0.2–1.3 Lung 0.22–0.57 Colon 0.31 Breast 0.78 Skin 0.42 Adverse effects[edit]

Test tube containing a dichloromethane solution of lycopene Lycopene is non-toxic and commonly found in the diet, mainly from tomato products. There are cases of intolerance or allergic reaction to dietary lycopene, which may cause diarrhea, nausea, stomach pain or cramps, gas, and loss of appetite.[20] Lycopene may increase the risk of bleeding when taken with anticoagulant drugs.[20] Because lycopene may cause low blood pressure, interactions with drugs that affect blood pressure may occur. Lycopene may affect the immune system, the nervous system, sensitivity to sunlight, or drugs used for stomach ailments.[20] Research and potential health effects[edit] Lycopene is under a variety of basic and clinical research, including primarily its potential effects on cardiovascular diseases and prostate cancer.[21][22][23] A 2011 review shows insufficient evidence to support the use of lycopene for the prevention of prostate cancer.[22] Regulatory status in Europe and the United States[edit] In a review of literature on lycopene and its potential role as a dietary antioxidant, the European Food Safety Authority concluded that there was insufficient evidence for lycopene having this effect in humans, particularly as it may affect skin, heart function or vision protection from ultraviolet light.[24] Lycopene from tomatoes has been tested in human studies in the United States and other countries for cardiovascular diseases and prostate cancer. These studies, however, did not attain sufficient scientific agreement to conclude an effect on any disease.[25] The US Food and Drug Administration (FDA), in rejecting manufacturers' requests in 2005 to allow "qualified labeling" for lycopene and the reduction of various cancer risks, provided a conclusion remaining in effect in 2017: "...no studies provided information about whether lycopene intake may reduce the risk of any of the specific forms of cancer. Based on the above, FDA concludes that there is no credible evidence supporting a relationship between lycopene consumption, either as a food ingredient, a component of food, or as a dietary supplement, and any of these cancers." See also[edit] Nutrition Tocopherol Tocotrienol Tomatine Lycopene (data page) References[edit] ^ Jump up to: a b c d e "Lycopene". PubChem, US National Library of Medicine. 2016. Retrieved 13 October 2016. ^ Jump up to: a b c d e f "Foods highest in lycopene, Nutrition Data, USDA Nutrient Database, version SR-21". nutritiondata.com. Conde Nast. 2014. Retrieved 2014-08-19. ^ Jump up to: a b c d e f g h i j k l m n o p q r s "Carotenoids: α-Carotene, β-Carotene, β-Cryptoxanthin, Lycopene, Lutein, and Zeaxanthin". Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis, OR. July 2016. Retrieved 29 May 2017. Jump up ^ "21 CFR 73.585. Tomato lycopene extract" (PDF). US Food and Drug Administration. 26 July 2005. Jump up ^ Australia New Zealand Food Standards Code"Standard 1.2.4 - Labelling of ingredients". Retrieved 2011-10-27. Jump up ^ UK Food Standards Agency: "Current EU approved additives and their E Numbers". Retrieved 2011-10-27. Jump up ^ Chasse et al. Journal of Molecular Structure: THEOCHEM, Volume 571, Number 1, 27 August 2001 , pp. 27-37(11)[1] Jump up ^ Erdman Jr, J. W. (2005). "How do nutritional and hormonal status modify the bioavailability, uptake, and distribution of different isomers of lycopene?". The Journal of nutrition. 135 (8): 2046S–7S. PMID 16046737. Jump up ^ NDSU Agriculture. "What Color is Your Food?". Retrieved 10 May 2012. Jump up ^ Barnes, Chris (11 October 2011). "How To Clean Tomato Sauce Stains From Plastic Storage Containers". The Huffington Post. Retrieved 29 May 2017. Jump up ^ Tran, X. T.; Parks, S. E.; Roach, P. D.; Golding, J. B.; Nguyen, M. H. (2015). "Effects of maturity on physicochemical properties of Gac fruit (Momordica cochinchinensis Spreng.)". Food Science & Nutrition. 4 (2): 305–314. PMC 4779482 . doi:10.1002/fsn3.291. Jump up ^ Ishida BK, Turner C, Chapman MH, McKeon TA (January 2004). "Fatty acid and carotenoid composition of gac (Momordica cochinchinensis Spreng) fruit". Journal of Agricultural and Food Chemistry. 52 (2): 274–9. PMID 14733508. doi:10.1021/jf030616i. Jump up ^ Ilahy, R; Piro, G; Tlili, I; Riahi, A; Sihem, R; Ouerghi, I; Hdider, C; Lenucci, M. S. (2016). "Fractionate analysis of the phytochemical composition and antioxidant activities in advanced breeding lines of high-lycopene tomatoes". Food Funct. 7 (1): 574–83. PMID 26462607. doi:10.1039/c5fo00553a. Jump up ^ Perdomo F, Cabrera Fránquiz F, Cabrera J, Serra-Majem L (2012). "Influence of cooking procedure on the bioavailability of lycopene in tomatoes". Hospital Nutrition (Madrid). 27 (5): 1542–6. PMID 23478703. doi:10.3305/nh.2012.27.5.5908 (inactive 2017-05-29). Jump up ^ Kamiloglu, S.; Demirci, M.; Selen, S.; Toydemir, G.; Boyacioglu, D.; Capanoglu, E. (2014). "Home processing of tomatoes (Solanum lycopersicum): Effects onin vitrobioaccessibility of total lycopene, phenolics, flavonoids, and antioxidant capacity". Journal of the Science of Food and Agriculture. 94 (11): 2225–33. PMID 24375495. doi:10.1002/jsfa.6546. Jump up ^ Yamaguchi, Masayoshi (2010). Carotenoids : Properties, Effects and Diseases. New York: Nova Science Publishers. p. 125. ISBN 9781612097138. Jump up ^ Aoki, H; Kieu, N. T.; Kuze, N; Tomisaka, K; Van Chuyen, N (2002). "Carotenoid pigments in GAC fruit (Momordica cochinchinensis SPRENG)". Bioscience, Biotechnology and Biochemistry. 66 (11): 2479–82. PMID 12506992. doi:10.1271/bbb.66.2479. Jump up ^ Hillebrand, S; Schwarz, M; Winterhalter, P (2004). "Characterization of anthocyanins and pyranoanthocyanins from blood orange Citrus sinensis (L.) Osbeck juice". Journal of Agricultural and Food Chemistry. 52 (24): 7331–8. PMID 15563216. doi:10.1021/jf0487957. Jump up ^ Alquezar, B; Rodrigo, M. J.; Zacarías, L (2008). "Regulation of carotenoid biosynthesis during fruit maturation in the red-fleshed orange mutant Cara Cara". Phytochemistry. 69 (10): 1997–2007. PMID 18538806. doi:10.1016/j.phytochem.2008.04.020. ^ Jump up to: a b c "Lycopene". Mayo Clinic. 2017. Retrieved 29 May 2017. Jump up ^ Cheng, H. M.; Koutsidis, G; Lodge, J. K.; Ashor, A; Siervo, M; Lara, J (2017). "Tomato and lycopene supplementation and cardiovascular risk factors: A systematic review and meta-analysis". Atherosclerosis. 257: 100–108. PMID 28129549. doi:10.1016/j.atherosclerosis.2017.01.009. ^ Jump up to: a b Ilic, D.; Forbes, KM.; Hassed, C. (2011-11-09). "Lycopene for the prevention of prostate cancer". Cochrane Database of Systematic Reviews (11): CD008007. PMID 22071840. doi:10.1002/14651858.CD008007.pub2. Jump up ^ Rowles Jl, 3rd; Ranard, K. M.; Smith, J. W.; An, R; Erdman Jr, J. W. (2017). "Increased dietary and circulating lycopene are associated with reduced prostate cancer risk: A systematic review and meta-analysis". Prostate Cancer and Prostatic Diseases. PMID 28440323. doi:10.1038/pcan.2017.25. Jump up ^ "Scientific Opinion on the substantiation of health claims related to lycopene and protection of DNA, proteins and lipids from oxidative damage (ID 1608, 1609, 1611, 1662, 1663, 1664, 1899, 1942, 2081, 2082, 2142, 2374), protection of the skin from UV-induced (including photo-oxidative) damage (ID 1259, 1607, 1665, 2143, 2262, 2373), contribution to normal cardiac function (ID 1610, 2372), and maintenance of normal vision (ID 1827) pursuant to Article 13(1) of Regulation (EC) No 1924/2006". EFSA Journal. 9 (4). 2011. doi:10.2903/j.efsa.2011.2031/epdf (inactive 2017-05-29). Jump up ^ "Qualified Health Claims: Letter Regarding Tomatoes and Prostate Cancer (Lycopene Health Claim Coalition) (Docket No. 2004Q-0201)". US Food and Drug Administration. 8 November 2005.

番茄红素 2014-08-21 11:05阅读：728 概述番茄红素分子式为C40H56，属于类胡萝卜素的一种。其抗氧化性能在所有类胡萝卜素中是最强的，它清除单线态氧的能力是常用抗氧化剂维生素E的100倍，是β-胡萝卜素的2倍以上；它的保健功能覆盖了延缓衰老、预防癌症、增强肌体免疫能力、改善动脉粥样硬化以及美容、美肤、防紫外线辐射等多个方面。不仅如此，人体内番茄红素的含量过低，容易衰老、容易发生某些慢性器质性疾病和癌症。人体各组织器官中番茄红素含量见表一。表一人体各组织中番茄红素含量(nmol/L) 肾上腺睾丸肝脏脂肪乳房肾皮肤结肠 21.60 21.36 5.72 1.30 0.78 0.62 0.42 0.31 人体不能自行合成番茄红素，必须从外源食品中获得。各蔬菜水果中番茄红素含量不等（详见表二），其中尤以番茄中含量最高。番茄又因产地、品种等差异，其中的番茄红素含量各异，欧美各国产的番茄酱中番茄红素含量为40mg/kg左右，而中国新疆产番茄酱中番茄红素的含量可达60mg／kg。有些研究表明新疆番茄中番茄红素含量可达130mg/kg 表二常见蔬菜、水果中番茄红素含量（mg/kg）番茄番石榴红色葡萄柚西瓜木瓜李子 50~120 54 34 23~72 20~53 0.05~0.1 国际市场批准概况欧洲经济共同体(EEC)和英国许可使用的食用色素中包括了番茄红素。联合国食品添加剂专家委员会(JECFA)认定番茄红素为A类营养素并为50多个国家和地区作为营养着色双重作用的食品添加剂番茄红素目前已经获得了欧洲“新颖食品”品准和美国的“GRAS”身份。目前还未能获得美国“FDA”的认证。FDA目前认为番茄红素可能是减少前列腺癌、高血压和心脏的风险的抗氧剂中的一种或者在上述过程中起综合作用，但是未承认番茄红素有抗癌作用，理由是研究不足。目前很多针对番茄红素抗癌等方面的研究正在进行。欧洲“新颖食品” 欧洲“ 新颖食品” 执行的是1997年颁布的《欧盟新颖食品法》，其中规定：原属于国外特定人群使用的传统食品或或市面上新流通的新技术新食品均可视为新颖食品（Novel food）,于上市前须依据欧盟新颖食品法规向会员国主管机关提出申请，并提交安全性评估资料。由会员国评估机构进行评估。美国“GRAS” Generally Recognized As Safe（GRAS）'公认安全'.GRAS是美国食品法律中的一个非常重要、独特和庞杂的食物/食物成分类别.在美国食品法律和法规的位阶上,GRAS介于常规食物/食物成分和食品添加剂之间. 市场概况 2003年全球番茄红素总销量约为3万kg(5％含量)，总销售额为900～1000万美元。据CMR估计，番茄红素产品销售额将以每年35％的速度增长，将达到4～5亿美元的销售量。 2006年全世界番茄红素的总用量接近1800吨，据有关机构预测番茄红素产量在未来数年仍将以约10%的速度增长，2009年的市场用量将超过2300吨。应用番茄红素的新产品层出不穷。从2003年到2009年全球市场总共新推出了大约400只含番茄红素的产品。各国（地区）市场推出的番茄红素新产品数量详见表三。从推向市场的产品统计数据来看，美国仍然是全球最富活力的番茄红素产品市场，过去5年来，这一市场的活跃度一直处于稳定状态。2003年至2009年，美国已经推出了143只含有番茄红素的新产品，而第二位的加拿大只有32只含有番茄红素的新产品上市。由市场调研机构Mintel公司提供的数据表明，番茄红素这种原料在美国市场上的人气稳步攀升。表三各国（地区）市场2003年至2009年推出的番茄红素新产品美国加拿大日本巴西法国阿根廷台湾越南英国荷兰 143 32 20 20 19 19 17 12 11 10 单位：支数据来源：医药经济报2009-7-30报道。报道中数据来源于Mintel公司的“全球新产品数据库”(GNPD) 随着番茄红素功能特性日益被人所知，广泛的用于膳食补充剂、某些食品和饮料产品之中。各类别产品的数量详见表四。其中，含番茄红素补充剂是最受欢迎的产品，2003年至2009年，全球推出了177只含有番茄红素的补充剂新产品。护肤品和彩妆产品位列第二和第三，分别为81只和51只。番茄红素在食品和饮料领域的应用有点滞后，整个大类只有67只新产品，该领域市场对番茄红素仍然犹豫不决。表四 2003年至2009年新推出的各类别含番茄红素产品数量总计补充剂护肤产品彩妆非酒精饮料面包、麦片加工肉类奶制品糖果、巧克力酱料、调味料甜点、冰激凌 418 177 81 51 20 17 7 7 6 5 5 单位：支数据来源：医药经济报2009-7-30报道。报道中数据来源于Mintel公司的“全球新产品数据库”(GNPD) 生产概况目前国外番茄红素的开发生产方式有：从番茄酱中提取、化学合成、生物工程生产等方法。生物工程和化学合成方法的方法优势在：产量高，成本低；天然植物提取的优势在于产品完全为自然状态，存在天然异构体组分，大众接受度高。植物提取以色列、日本、印度等国从番茄中提取番茄红素。以色列的Lycored　Natuial　Indusuies　Ltd. 公司，最早进行番茄红素的工业化提取，在相关生产领域技术处于世界先进水平，拥有世界最大的天然番茄红素生产工厂，是世界最大番茄红素供应商。化学合成拜耳公司、罗氏公司、巴斯夫公司以合成法生产番茄红素。其中最成功的是巴斯夫公司和帝斯曼公司(原罗氏)。德国巴斯夫公司在1997年8月完成了合成工艺开发并在欧洲提出专利申请。帝斯曼公司于1997年l0月完成了工艺开发并在欧洲提出专利申请。该工艺是进行烯化反应，制得番茄红素收率65％。生物工程利用生物工程菌，靠微生物发酵的方法生产番茄红素。主要是药厂生产用，产品直接用于药品的生产。因为消费者在选择保健品、功能性食品时，天生具有倾向自然的特点。而且天然番茄红素拥有70多种同分异构体，有初步的研究表明其同番茄红素各分异构体的组份含量很可能跟抗癌等作用有关，因此在食品、保健品领域的应用中，植物提取产品具有不可替代的优势。应用现状目前，国外已将这一产品广泛用于食品添加剂、功能性食品、医药原料和高级化妆品等行业。以下是整理出的国际上番茄红素的主要应用方向和典型的产品。 1 防止紫外线灼伤的护肤产品典型的产品有澳大利亚Bullivant S Natural Heath Products Pty．Ltd生产的防晒霜LYC—O—MATO Sunscreen factor 8#125mL等。 2 预防前列腺疾病的保健产品典型的产品有美国Waku．nage of America CO，Ltd生产的Lycosoy Postrate Protector。 3 用于类胡萝b素复合产品主要与一胡萝卜素、B一胡萝卜素、叶黄素等其它类胡萝卜素复合的功能性食品。 4 用于美容和延缓衰老的产品番茄红素为脂溶性物质，一般可用于美容和延缓衰老的乳霜类产品中。典型的产品如Kie—hlg契尔氏生产的番茄红素保湿乳液等产品，具有美白和抗衰老效果。 5 生产防病、治病药品。目前，美国Henkel Corporation，Makhteshim Chemical Woeks Limited等公司及日本Makhtshi公司等几家公司相继生产出以番茄红素为主要原料的药品，其主要作用包括降低血压，治疗高胆固醇高血脂。国内市场市场综述我国番茄红素的研究和生产还处于刚刚起步阶段。2006年产量80吨，市场需求平稳增长，估计今后数年仍会以每年10-20%的增幅持续增长。2006年全世界番茄红素的总用量接近1800吨，据有关机构预测番茄红素产量在未来数年仍将以约10%的速度增长，2009年的市场用量将超过2300吨【来源：上海证券报华北制药股份有限公司2007年第三季度报告】工业品按照含量，一般为5%或12%，其中5%含量的产量最大。市场参考价格：5%含量 750元/kg；12%含量 1200元/kg 生产厂家国内番茄红素大多数采用溶媒法和超临界萃取法从番茄酱中提取，少部分制药厂商采用发酵法生产番茄红素。主要生产企业如下：新疆红帆生物科技有限公司国内最早从植物提取番茄红素的是新疆红帆生物科技有限公司。2003年成立，当年其研发的番茄红素制备技术通过自治区科技成果鉴定。采用超临界流体萃取技术和分子蒸馏技术，国家发改委批准为高技术产业化示范工程。目前为止是全球范围专业生产天然番茄红素的第二大生产企业。产品包括脂溶性的番茄红素油树脂、水溶性番茄红素制剂及番茄红素包埋粉剂型原料，其中“番茄红素水分散性溶液的制备方法”是该公司专利。2006年1月，红帆番茄红素软胶囊获得“国食健字号”批文。中粮屯河和新中基是国内番茄行业的两大巨头，已占到国内番茄市场90%的市场份额，主要业务都是番茄酱出口。由于番茄酱市场近几年波动较大，两公司都已涉足番茄红素的提取。生产采用超临界萃取法和溶媒法，从番茄酱中提取番茄红素。主要产品为番茄红素油树脂和番茄红素包埋粉剂型原料。终端产品均为番茄红素软胶囊。华北制药生产采用发酵法（生物工程）。目前该公司番茄红素已占国内市场份额30％，占中国出口份额的80％，其中90％的产品出口到美国，是中国发酵法番茄红素产品最大的生产供应商。目前计划上马年产350吨番茄红素工程。该项目的说明称投资收益率为37％（税后），投资回收期为2.7年（税后）。终端产品终端产品中，获得国食健字批文的目前有20只，全部为番茄红素软胶囊。具体品牌及生产企业见下：【数据来源：国家食品药品监督管理局 http://www.sfda.gov.cn/WS01/CL0001/】 1.科卫牌番茄红素软胶囊 (山东省金卫医学科技开发有限公司国食健字G20090524) 2.中科牌番茄红素胶囊 (南京中科药业有限公司国食健字G20060480) 3.国珍牌番茄红素软胶囊 (成都中科生物技术开发有限公司国食健字G20030031) 4.太极牌番茄红素软胶囊 (太极集团·四川天诚制药有限公司北京桐君阁大药房有限责任公司国食健字G20040251) 5.利氏牌番茄红素软胶囊 (广州优宝工业有限公司国食健字G20040812) 6.盈康牌番茄红素软胶囊 (济南生命力生物科技有限公司国食健字G20050103) 7.红鑫牌番茄红素软胶囊 (常州市红健生物制品有限公司卫食健字(2003)第0217号) 8.艾兰得牌天然番茄红素软胶囊 (江苏江山制药有限公司国食健字G20090498) 9.丰德天元牌番茄红素软胶囊 (北京丰德天元药业科技有限公司国食健字G20090412) 10.康即福尔牌番茄红素玉米胚芽油 (南京康吉福食用油有限公司国食健字G20060773) 11.莱泊新牌番茄红素软胶囊 (广西北生药业股份有限公司广西北生集团科技开发有限公司国食健字G20070089) 12.中基牌天然番茄红素软胶囊 (新疆中基天然植物纯化高新技术研究院有限公司国食健字G20060668) 13.红帆R牌番茄红素软胶囊 (新疆红帆生物科技有限公司国食健字G20060110) 14.西红为生牌番茄红素胶囊 (四川省天然药物研究所成都三勒浆药业集团四川华美制药有限公司国食健字G20050152) 15.安格德牌番茄红素软胶囊 (北京安格德科技发展有限责任公司国食健字G20050360) 16.神谷牌蜂胶番茄红素软胶囊 (大连神谷生物科技发展有限公司国食健字G20041223) 17.亿生康牌番茄红素软胶囊 (北京金蓝鲨生物医药科技有限公司国食健字G20040129) 18.健生宁牌番茄红素软胶囊 (广东太阳神集团有限公司国食健字G20040223) 19.美通牌番茄红素多烯酸乙酯软胶囊 (天津美通药业有限公司国食健字G20040388) 20.天之素牌番茄红素软胶囊 (北京京研益农科技发展中心卫食健字(2003)第0239号) 预期国际市场目前产量和交易量都在上升。番茄红素抑制肿瘤生长以及减少肿瘤发生的研究目前是国际科学界的一个研究热点。已有研究中番茄红素均表现出一定的防癌或者抗癌作用（尤其是前列腺癌），随着研究的不断进展，FDA批准番茄红素为“抗癌”的几率将增加。预计届时将出现番茄红素国际需求量的激增。国内对于番茄红素市场的培育也有了两年左右的时间，主要是以番茄红素预防前列腺癌科普宣传的角度。国际市场上化妆品对于番茄红素的需求量也很大，尤其那些“美在内”类型的产品。国内化妆品还未搜索到有添加番茄红素为有效成分的。食品添加剂领域，由于成本问题，番茄粉或者番茄提取物可能更有优势。

分享我的博客微博

我来说两句...

番茄红素是一种胡萝卜素类的天然色素，除了番茄之外，西瓜、葡萄柚、胡萝卜、南瓜、红薯等蔬菜、水果中都含有这种成分。其中，红番茄所含的番茄红素比例最高。近年来，不少学者热衷于进行番茄红素与抗癌作用的研究。有研究发现，番茄红素作为一种抗氧化剂，具有预防前列腺癌的作用。因此，很多生产番茄酱、番茄调味品的厂商为了促销，都强调其产品中含有番茄红素。例如，美国市场上广泛销售的亨氏番茄酱，其包装上就明确写有“富含具有抗氧化作用的番茄红素”，并以此作为宣传重点。但FDA认为，目前掌握的证据并无法证明番茄红素具有抗癌效果。日前，这些番茄类产品的生产商提出，要将番茄红素的抗癌作用用于其产品宣传和包装之上。因此，FDA发布公告并对这些公司提出警告，其中还包括生产各种营养制品和营养补充剂的公司，此外还有“番茄红素健康联盟”，该联盟包括生产番茄酱产品的亨氏集团。这些公司对FDA的决定均表示强烈的不满。亨氏集团表示，还将寻找更多的证据，以证明番茄红素具有肯定的抗癌作用。

【题　名】美国FDA不承认番茄红素抗癌【作　者】伟光【机　构】不详【刊　名】粮油食品科技, 2006(2): 69-69 【关键词】番茄红素美国食品抗癌效果 FDA 预防癌症食品添加剂营养补充剂发布公告抗氧化剂前列腺癌【文　摘】《食品添加剂市场》讯，美国食品和药品管理局（FDA）近日发布公告称，由于番茄红素的作用目前并不肯定，因此番茄、番茄酱等产品的生产者及番茄红素营养补充剂的生产商，不能在其产品上标注“具有预防癌症”等字样。近年来，有研究发现，番茄红素作为一种抗氧化剂，具有预防前列腺癌的作用。因此，很多生产番茄酱、番茄调味品的厂商为了促销，都强调其产品中含有番茄素。FDA认为，目前掌握的证据无法证明番茄红素具有抗癌效果

多氢番茄红素

多氢番茄红素，是一种源自以色列特种RET番茄品种提取的天然番茄产物，含有番茄红素、六氢番茄红素、八氢番茄红素以及天然维生素E、植物固醇、类胡萝卜素的番茄混合物。以色列LycoRed公司是这种多氢番茄红素的研究者、创造者以及全球最大供应商。目前这种多氢番茄红素“以撒宁Lyco-ISN”已经登录中国，成为国内唯一的多氢番茄红素品牌。分享多氢番茄红素，是一种含有番茄红素（C40H56）、八氢番茄红素（C40H64）、六氢番茄红素（C40H62）等天然来源的多种番茄红素混合物。番茄红素分子结构番茄红素分子结构番茄红素，是一种源自番茄提取物的红色素，它是一种类胡萝卜素类物质，具有吸收可见光、清除自由基、抗氧化、抗细胞老化的功能。分子结构为除分子两端有连续单间之外，分子结构中间完全是单双键交替的规律结构。八氢番茄红素，是番茄红素在脱氢过程中的中间产物，它的分子结构比番茄红素（C40H56）多了4个单键，所以多了8个氢原子。六氢番茄红素则多了3个单键，所以表现为多了6个氢原子。这种多出来的氢原子与碳原子的结合处于不稳定状态，在细胞中率先脱氢而产生更多的游离氢离子，从而增加了番茄红素淬灭单线太氧自由基的能力，因而它比C40H56 具有更强的抗氧化特性。目前中国市场上出现的多氢番茄红素，是来自以色列LycoRed公司的产品，该公司是全球番茄红素行业的领导者，其多氢番茄红素的研究及应用处于世界领先地位。多氢番茄红素分子结构多氢番茄红素分子结构以色列多氢番茄红素登陆中国 2012年，以色列LycoRed公司与中国企业签约，在中国大陆推广其多氢番茄红素原来生产的终端产品——仙本多氢番茄红素。目前，这种由以色列原装进口的多氢番茄红素产品已在中国市场有售。这种产品与其他番茄红素产品的不同之处，在与其采用以色列LycoRed公司的原来在以色列生产，每一粒胶囊含有八氢番茄红素与六氢番茄红素，总计每粒胶囊含有7.5毫克多氢番茄红素，这是非常特别的产品。多氢番茄红素的独特作用 1、双倍的抗氧化作用——不稳定氢原子双倍捕获O- 2、更明确的靶向作用——能在肝脏、肾脏、前列腺、乳腺、卵巢中更好地富集 3、超强的协同作用——大量研究发现，单一番茄红素作用有限，而番茄红素与八氢番茄红素、六氢番茄红素的联合使用，解决了番茄红素起效慢的问题。多氢番茄红素抗癌药、前列腺药物的临床——以色列率先发现并成功提取到八氢番茄红素与六氢番茄红素，多国将其用于临床药物的开发，研究发现，这种多氢番茄红素的联合作用，其抗氧化活性、抗衰老活性、吸收可见光及紫外线，减少日光性损伤，具有更为显著的作用。番茄红素的一般药理作用 1、抗氧化延缓衰老。

一般人体有清除自由基的酶类（如辅酶Q12）。但自由基产生太多或人体清除能力不足时，就需从外界补充抗氧化剂来维持细胞平衡。一个番茄红素分子可猝灭上万个自由基，抗氧化能力是维生素E的100倍，维生素C的1000倍。是自然界最强的延缓衰老的抗氧化剂。

2、防癌抗癌，辅助抑制肿瘤。

环境、饮食、遗传、职业、心理等原因使人体产生自由基，侵入细胞膜，攻击DNA，激活封闭静止的癌基因，产生癌细胞，繁殖裂变、分裂复制直至永久性破坏某器官或癌细胞转移。番茄红素有效猝灭自由基，达到预防的作用。对已形成的肿瘤，可促进细胞间隙传输信号，接触抑制、分化诱导癌细胞，使肿瘤缩小。以色列番茄红素进入中国以色列番茄红素进入中国

3、前列腺保健，提高男性生育能力。

番茄红素通过人体脂蛋白运输到全身各器官，在睾丸、前列腺浓度最高。猝灭自由基，清除侵入前列腺的毒素，从而有效防止前列腺发生病变。番茄红素还可调节前列腺液，使pH值保持在6-6.5，为精子提供舒适的活动环境，增强精子活性，提高男性生育能力。

4、调节血脂，预防心脑血管疾病。

番茄红素可深入清除血管垃圾，调节血浆胆固醇浓度，保护LDL不受氧化。还可修复完善被氧化的细胞，促进细胞间胶质形成，增强血管柔韧度。

5、抗辐射，美容美肤。

日常生活中辐射、日晒可加速皮肤氧化衰老，衍生皱纹、色斑。实验证明，辐射后的皮肤中，番茄红素含量减少31%-46%，其它成分含量几乎不变。番茄红素通过猝灭侵入人体的自由基，在肌肤表层形成一道天然屏障，有效阻止外界紫外线、辐射对肌肤的损害。并可促进血液中胶原蛋白和弹性蛋白的结合，使肌肤充满弹性，娇媚动人。

6、乳房子宫保健。

番茄红素在体外培养液中对乳房癌细胞MCF7抑制能力比β-胡萝卜素强一倍以上。若和其它抗氧化剂（如维生素E、维生素C、β-胡萝卜素）合理运用，可促进女性乳房健康发育，减少乳腺癌发生几率。美国依利诺斯大学对比研究发现，体内番茄红素含量低的女性比含量高的女性宫颈癌发病率高五倍以上。

7、改善皮肤过敏症，消除因皮肤过敏而引起的皮肤干燥和瘙痒感，令人感觉轻松愉快。

8、番茄红素大量存在于体内各种黏膜组织，长期服用可以改善各种因体内黏膜组织破坏而引发的各种不适。如干咳、眼睛干涩，口腔溃疡，保护胃肠道黏膜组织等。

9、番茄红素具有极强的解酒作用。酒精在人体内的代谢过程主要是氧化还原反应，会产生大量的自由基。平时服用番茄红素，可以增加酒量；喝酒前服用，解酒效果显著，可以减轻酒精对肝脏的损伤；而醉酒后服用，可以减轻头痛、呕吐等醉酒症状。

10、番茄红素还具有预防骨质疏松、降血压、减轻运动引起的哮喘等多种生理功能。

11、番茄红素有助男性减少中风风险，血液里番茄红素水平最高者比这一成分最低者中风几率降低55% 。

多氢番茄红素具有更强抗氧化、抗病防病作用研究人员给雄性大鼠喂食30天的以色列公司提供的番茄提取物。之后他们在前列腺和肝脏中分析化合物积累，发现除了普通的番茄红素，六氢番茄红素与八氢番茄红素也在两种腺体中有积累。

肝脏中八氢番茄红素积累量的要比番茄红素与六氢番茄红素多，反之番茄红素集中在前泪腺，其次是八氢番茄红素与六氢番茄红素。仙本番茄红素仙本番茄红素

在后续的试验中，研究人员对的大鼠喂食以色列八氢番茄红素或六氢番茄红素两组对照。在两个对照组中，所有组织中的化合物浓度都有所增加。

首席研究员杰西卡·坎贝尔告诉我们：“从这些结果可以提供更好的理解八氢番茄红素和六氢番茄红素相对比番茄红素在组织中的积累”。

番茄红素是公认的预防前列腺癌的角色，同时也是一种男女均适用的强效抗氧化和抗衰老物质。前列腺癌是美国及西方白种人最常见癌症，仅次于最致命的肺癌之后。在全球范围内每年因前列腺癌被夺去生命的就有20万人，同时还有50万例新发病例。在过去的15年，前列腺癌的发病率已经增长了1.7%。

美国FDA已经批准声称番茄提取物可以降低胃、卵巢癌、胰腺癌和前列腺癌的风险。但就单一番茄红素预防癌症的有效性而言，FDA质疑并提出现有证据不能支持这一说法。相反,他们认为西红柿的保护作用来源于一组化合物,如八氢番茄红素或六氢番茄红素,或者不同物质之间的协同作用。

全球多氢番茄红素研究的领先者是以色列，他们采用地中海沿岸与沙漠边缘地区独特地理环境种植的优质番茄品种，提取出了含有六氢番茄红素与八氢番茄红素成分的多氢番茄红素原料，目前这一优质番茄红素产品已经成为继美国受到追捧之外在全球热销的产品。

番茄红素被公认为是前列腺疾病的克星番茄红素被公认为是前列腺疾病的克星

热门评论 0 以撒宁 2013-08-07 19:45:27 以色列科学家在细胞培养中，发现番茄红素可以抑制胆固醇的合成，增大巨噬细胞低密度脂蛋白(LDL)受体。 BenGurion大学及Seroka医学中心的体外实验显示，番茄红素可以抑制包括乳腺疾病及内皮组织增生细胞的生长。查看更多评论

关注百科官方微信： hudong_baike 第一时间获取更多百科资讯保存二维码

Puritan's Pride，中文译为普丽普莱，是一家1960年创建于美国纽约长岛的美国保健品公司，全球最大的营养素生产企业，属下产品全部通过美国FDA认证。也是美国三大保健品牌之一，同维他命世界、GNC齐名。

这款普丽普莱的番茄红素，每粒含量高达40mg，算是同类型产品中含量很高的了。关于番茄红素，是成熟番茄的主要色素，是一种不含氧的类胡萝卜素，具有优越的生理功能，它不仅具有抗癌抑癌的功效，而且对于预防心血管疾病、动脉硬化、前列腺慢性疾病等各种成人病、增强人体免疫系统以及延缓衰老等都具有重要意义。上班族、老年人都可以有针对性的服用。

目前普丽普莱对这款番茄红素进行促销，每瓶60粒，一次购买五瓶的价格是52.65美元，结算时输入优惠码“BUYNOW4”后的价格为47.39美元包邮。

要说的是，普丽普莱每次大特价，都有销售临期保健品的可能，这次是否也是这样无从查知，所以最好跟小伙伴们拼单购买。海淘链接

赞0 收藏2 分享到

https://www.fda.gov/Food/IngredientsPackagingLabeling/LabelingNutrition/ucm072767.htm FDA回复

Qualified Health Claims: Letter Regarding Tomatoes and Prostate Cancer (Lycopene Health Claim Coalition) (Docket No. 2004Q-0201) SHARE TWEET LINKEDIN PIN IT EMAIL PRINT Back to Qualified Health Claims: Letters of Enforcement Discretion November 8, 2005

F. Kerr Dow, Ph.D. Vice President Nutrition and Technical Affairs H. J. Heinz Company P.O. Box 57 Pittsburgh, Pennsylvania 15230-0057

RE: Qualified Health Claim Petition - Tomato Lycopene, Tomatoes and Tomato Products, which Contain Lycopene, Lycopene in Tomatoes and Tomato Products, Lycopene in Fruits and Vegetables, including Tomatoes and Tomato Products and Reduced Risk of Prostate Cancer (Docket No. 2004Q-0201)

Dear F. Kerr Dow:

This letter responds to the qualified health claim petition received on May 17, 2004, by the Food and Drug Administration (FDA or the agency), submitted by the Lycopene Health Claim Coalition,[1] pursuant to Section 403(r)(4) or 403(r)(5)(D) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. §§ 343(r)(4) or 343(r)(5)(D)). The petition proposed the following qualified health claims:

1) "Although the evidence is not conclusive, tomato lycopene may reduce the risk of prostate cancer." 2) "Although the evidence is not conclusive, tomato lycopene may reduce the risk of prostate cancer when consumed as part of a healthy diet." 3) "Although the evidence is not conclusive, tomato products, which contain lycopene, may reduce the risk of prostate cancer." 4) "Although the evidence is not conclusive, tomatoes and tomato products, which contain lycopene, may reduce the risk of prostate cancer." 5) "Although the evidence is not conclusive, tomato products, which contain lycopene, may reduce the risk of prostate cancer when consumed as part of a healthy diet." 6) "Although the evidence is not conclusive, tomatoes and tomato products, which contain lycopene, may reduce the risk of prostate cancer when consumed as part of a healthy diet." 7) "Although the evidence is not conclusive, lycopene in tomato products may reduce the risk of prostate cancer." 8) "Although the evidence is not conclusive, lycopene in tomatoes and tomato products may reduce the risk of prostate cancer." 9) "Although the evidence is not conclusive, lycopene in tomato products may reduce the risk of prostate cancer when consumed as part of a healthy diet." 10) "Although the evidence is not conclusive, lycopene in tomatoes and tomato products may reduce the risk of prostate cancer when consumed as part of a healthy diet." 11) "Although the evidence is not conclusive, lycopene in fruits and vegetables, including tomatoes and tomato products, may reduce the risk of prostate cancer." In a letter dated May 27, 2004, FDA informed you that the petition was undergoing initial review and that we would follow the interim procedures for qualified health claim petitions as described in the FDA publication entitled "Consumer Health Information for Better Nutrition Initiative" Task Force Final Report, more specifically, the agency's guidance for procedures on qualified health claims.[2] Thus, FDA filed the petition on June 30, 2004 and posted it on the FDA website for a 60-day comment period. The agency received a total of five comments pertaining to this docket, which included petitions submitted on behalf of Heinz and American Longevity, Inc. The petition submitted on behalf of American Longevity, Inc., requested that the agency authorize health claims or allow qualified health claims characterizing the relationship between consumption of lycopene, tomatoes, and lycopene-containing tomato-based foods, and reduction in the risk of certain forms of cancer, prostate cancer, lung cancer, gastric cancer, colorectal cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, and pancreatic cancer. Three of the comments were from individuals and two were from industry. The three comments from individuals supported the proposed claims but did not provide any data to support their conclusions and were not directed to any specific petition. One of the comments from industry was directed specifically to your petition and the other was directed to the petition submitted on behalf of American Longevity, Inc. The comment directed to your petition did not support many of the claims as presented and provided substantial data to support their conclusions. FDA considered all relevant comments in its evaluation of the petition.

This letter sets forth the basis of FDA's determination that the current scientific evidence for the proposed qualified health claim related to consumption of tomatoes and/or tomato sauce, and a reduced risk of prostate cancer is appropriate for consideration as a qualified health claim on conventional foods. This letter also sets forth the basis for FDA's determination that there is no credible evidence to support claims about consumption of tomato lycopene; tomatoes and tomato products which contain lycopene; lycopene in tomatoes and tomato products, or lycopene in fruits and vegetables, including tomatoes and tomato products and a reduced risk of prostate cancer. Finally, this letter sets forth the factors that FDA intends to consider in the exercise of its enforcement discretion for a qualified health claim with respect to consumption of tomatoes and/or tomato sauce and a reduced risk in prostate cancer.

I. Overview of Data and Eligibility for a Qualified Health Claim

A health claim characterizes the relationship between a substance and a disease or health-related condition (21 CFR 101.14(a)(1)). The substance must be associated with a disease or health-related condition for which the general U.S. population, or an identified U.S. population subgroup is at risk (21 CFR 101.14(b)(1)). Health claims characterize the relationship between the substance and a reduction in risk of contracting a particular disease.[3] In a review of a qualified health claim, the agency first identifies the substance and disease or health-related condition that is the subject of the proposed claim and the population to which the claim is targeted.[4] FDA considers the data and information provided in the petition, in addition to other written data and information available to the agency, to determine whether the data and information could support a relationship between the substance and the disease or health-related condition.[5] The agency then separates individual reports of human studies from other types of data and information. FDA focuses its review on reports of human intervention and observational studies.[6] In addition to individual reports of human studies, the agency also considers other types of data and information in its review, such as meta-analyses,[7] review articles,[8] and animal and in vitro studies. These other types of data and information may be useful to assist the agency in understanding the scientific issues about the substance, the disease or health-related condition, or both, but cannot by themselves support a health claim relationship. Reports that discuss a number of different studies, such as meta-analyses and review articles, do not provide sufficient information on the individual studies reviewed for FDA to determine critical elements, such as the study population characteristics and the composition of the products used. Similarly, the lack of detailed information on studies summarized in review articles and meta-analyses prevents FDA from determining whether the studies are flawed in critical elements, such as design, conduct of studies, and data analysis. FDA must be able to review the critical elements of a study to determine whether any scientific conclusions can be drawn from it. Therefore, FDA uses meta-analyses, review articles, and similar publications[9] to identify reports of additional studies that may be useful to the health claim review and as background about the substance-disease relationship. If additional studies are identified, the agency evaluates them individually.

FDA uses animal and in vitro studies as background information regarding mechanisms of action that might be involved in any relationship between the substance and the disease. The physiology of animals is different than that of humans. In vitro studies are conducted in an artificial environment and cannot account for a multitude of normal physiological processes, such as digestion, absorption, distribution, and metabolism that affect how humans respond to the consumption of foods and dietary substances (Institute of Medicine, National Academies of Science, 2005). Animal and in vitro studies can be used to generate hypotheses or to explore a mechanism of action but cannot adequately support a relationship between the substance and the disease.

FDA evaluates the individual reports of human studies to determine whether any scientific conclusions can be drawn from each study. The absence of critical factors, such as a control group or a statistical analysis, means that scientific conclusions cannot be drawn from the study (Spilker et al., 1991, Federal Judicial Center, 2000). Studies from which FDA cannot draw any scientific conclusions do not support the health claim relationship, and these are eliminated from further review.

Because health claims involve reducing the risk of a disease in people who do not already have the disease that is the subject of the claim, FDA considers evidence from studies in individuals diagnosed with the disease that is the subject of the health claim only if it is scientifically appropriate to extrapolate to individuals who do not have the disease. That is, the available scientific evidence must demonstrate that: (1) the mechanism(s) for the mitigation or treatment effects measured in the diseased populations are the same as the mechanism(s) for risk reduction effects in non-diseased populations; and (2) the substance affects these mechanisms in the same way in both diseased people and healthy people. If such evidence is not available, the agency cannot draw any scientific conclusions from studies that use diseased subjects to evaluate the substance-disease relationship.

Next, FDA rates the remaining human intervention and observational studies for methodological quality. This quality rating is based on several criteria related to study design (e.g., use of a placebo control versus a non-placebo controlled group), data collection (e.g., type of dietary assessment method), the quality of the statistical analysis, the type of outcome measured (e.g., disease incidence versus validated surrogate endpoint), and study population characteristics other than relevance to the U.S. population (e.g., selection bias and whether important information about the study subjects -- e.g., age, smoker vs. non-smoker -- was gathered and reported). For example, if the scientific study adequately addressed all or most of the above criteria, it would receive a high methodological quality rating. Moderate or low quality ratings would be given based on the extent of the deficiencies or uncertainties in the quality criteria. Studies that are so deficient that scientific conclusions cannot be drawn from them cannot be used to support the health claim relationship, and these are eliminated from further review.

Finally, FDA evaluates the results of the remaining studies. The agency then rates the strength of the total body of publicly available evidence.[10] The agency conducts this rating evaluation by considering the study type (e.g., intervention, prospective cohort, case-control, cross-sectional), the methodological quality rating previously assigned, the quantity of evidence (number of the various types of studies and sample sizes), whether the body of scientific evidence supports a health claim relationship for the U.S. population or target subgroup, whether study results supporting the proposed claim have been replicated[11], and the overall consistency[12] of the total body of evidence.[13] Based on the totality of the scientific evidence, FDA determines whether such evidence is credible to support the substance/disease relationship, and, if so, determines the ranking that reflects the level of comfort among qualified scientists that such a relationship is scientifically valid.

A. Substance

A health claim characterizes the relationship of any substance and a disease or health-related condition (21 CFR 101.14(a)(1)). A substance means a specific food or component of a food, regardless of whether the food is in conventional form or a dietary supplement (21 CFR 101.14(a)(2)). The petition identified tomatoes and tomato products, which contain lycopene; lycopene in tomatoes and tomato products; lycopene in fruits and vegetables, including tomatoes and tomato products; and "tomato lycopene" as the substances of the qualified health claim petition. The petition does not define "tomato lycopene"; however, the agency assumes that the petitioner meant this term to mean lycopene extracted from tomato or tomato products to be used as an ingredient for food or as an ingredient in dietary supplements, as described in an article by Don Hartal and Lorri Danzig provided with the petition and the petitioner's request for a qualified health claim under section 403(r)(5) of the Act (21 U.S.C. 343(r)(5)), which applies to dietary supplements. Tomatoes and tomato products are foods within the definition of food under the Act (21 U.S.C. § 321(f)(1)). Similarly, fruits and vegetables are foods within the definition of food under the Act.[14] Lycopene is an ingredient of foods such as red tomatoes, red tomato-based foods, red or pink grapefruit, watermelon, red sweet peppers, papaya, and pink guava. Lycopene is also a member of the carotenoid family that is marketed as a dietary supplement. Therefore, lycopene is both a food ingredient and a component of food and thus meets the definition of food under the Act (21 U.S.C. § 321(f)(3)). Therefore, the agency concludes that tomatoes, tomato products, and lycopene meet the definition of substance in the health claim regulation (21 CFR 101.14(a)(2)). B. Disease or Health-Related Condition

A disease or health-related condition means damage to an organ, part, structure, or system of the body such that it does not function properly or a state of health leading to such dysfunctioning (21 CFR 101.14(a)(5)). The petition has identified prostate cancer as the disease that is the subject of the proposed qualified health claim. Cancer is a constellation of more than 100 different diseases, each characterized by the uncontrolled growth and spread of abnormal cells (American Cancer Society, 2004). Therefore, the agency concludes that prostate cancer is a disease as defined in 21 CFR 101.14(a)(5). C. Safety Review

Under 21 CFR 101.14(b)(3)(ii), if the substance is to be consumed at other than decreased dietary levels, the substance must be a food or a food ingredient or a component of a food ingredient whose use at the levels necessary to justify the claim must be demonstrated by the proponent of the claim, to FDA's satisfaction, to be safe and lawful under the applicable food safety provisions of the Act. FDA evaluates whether the substance is "safe and lawful" under the applicable food safety provisions of the Act. For conventional foods, this evaluation involves considering whether the ingredient that is the source of the substance is generally recognized as safe (GRAS), approved as a food additive, or authorized by a prior sanction issued by FDA (see 21 CFR 101.70(f)). For dietary supplements, the applicable safety provisions require, among other things, that the dietary ingredient not present a significant or unreasonable risk of illness or injury under conditions of use recommended or suggested in labeling or, if no conditions of use are suggested or recommended in the labeling, under ordinary conditions of use (section 402(f)(1)(A) of the Act (21 U.S.C. 342(f)(1)(A))). Further a dietary supplement must not contain a poisonous or deleterious substance which may render the supplement injurious to health under the conditions of use recommended or suggested in the labeling (section 402(f)(1)(D) of the Act (21 U.S.C. 342(f)(1)(D))).

As discussed in section I.A., the substances requested by the petitioner are (1) tomatoes, (2) tomatoes and tomato products, which contain lycopene, (3) lycopene in tomatoes and tomato products, (4) lycopene in fruits and vegetables, including tomatoes and tomato products, and (5) tomato lycopene.

Tomatoes and Tomato Products

For purposes of the health claim regulation, tomatoes and tomato products are not ingredients that are the source of the substance; rather tomatoes and tomato products are the substance. Tomatoes are also a primary ingredient in many tomato products. Tomato products can thus be a source of tomatoes. Tomatoes are foods of natural biological origin that have been widely consumed in the United States for their nutrient properties prior to January 1, 1958, without known detrimental effects, which are subject only to conventional processing as practiced prior to January 1, 1958, and for which no known safety hazard exists. Tomatoes themselves and tomatoes as a food ingredient in tomato products are consistent with FDA's definition of food ingredients ordinarily regarded as "generally recognized as safe" (GRAS) (21 CFR 170.30(d)). The limited scientific evidence describing the effects of tomatoes and tomato products on prostate cancer, suggests that consumption of one-half to one cup of tomatoes and/or tomato sauce per week may reduce the risk of prostate cancer (discussed in section IV C). Therefore, FDA concludes under the preliminary requirements of 21 CFR 101.14(b)(3)(ii), that the use of tomatoes and/or tomato sauce[15] at the level necessary to justify the claim is safe and lawful.

Fruits and Vegetables

It is not necessary for FDA to make any determination about the safety or lawfulness of fruits and vegetables in this letter, because the agency is denying the proposed claim related to "fruits and vegetables" for lack of credible evidence, as discussed in sections II and III.

Lycopene

The petition asserts that there is no reason to believe that lycopene consumption would result in harm. Lycopene and other carotenoids serve as a key source of antioxidants. Antioxidants are substances that can prevent or delay the oxidation of other substances and may protect against chronic disease (Institute of Medicine, 2000 p 35-57). There are no specific intake quantities for lycopene proposed in the petition. Instead, the petition cites various articles in the scientific literature stating that, to be effective, lycopene supplementation must be at daily doses of at least 15 mg. No Dietary Reference Intakes (DRIs) have been established for the carotenoid lycopene. However, the Institute of Medicine supports existing recommendations for increased consumption of carotenoid-rich fruits and vegetables (Institute of Medicine, 2000 p 325). FDA has received two GRAS notifications concerning lycopene, one submitted by LycoRed for tomato lycopene extract 6 percent, tomato lycopene extract 1.5 percent, and crystallized tomato lycopene extract, (GRAS notification number 000156), and the other submitted by BASF corporation for synthetic lycopene (GRAS notification number 000119). In the "Agency Response Letter" to the GRAS notifications for the above listed subjects, the agency stated it had no questions at this time regarding the conclusions that tomato lycopene extract 6 percent, tomato lycopene extract 1.5 percent, and crystallized tomato lycopene extract or synthetic lycopene are GRAS under their intended conditions of use. FDA further stated that the agency had not made its own determination regarding the GRAS status of the use of tomato lycopene extract 6 percent, tomato lycopene extract 1.5 percent, and crystallized tomato lycopene extract or synthetic lycopene and, as always, it is the continuing responsibility of manufacturers to ensure that the food ingredients they market are safe, and are otherwise in compliance with all applicable legal and regulatory requirements (Agency Response Letters to GRAS notifications # 000156 and 000119; (http://www.cfsan.fda.gov/~rdb/opa-g156.html and http://www.cfsan.fda.gov/~rdb/opa-g119.html). Additionally, FDA has received a GRAS notification for lycopene from Blakeslea trispora the review of which is still pending (GRAS notification number 000173). FDA has also recently amended its color additive regulations to provide for the safe use of tomato lycopene extract and tomato lycopene concentrate as color additives in foods (70 FR 43043; July 26, 2005). The action was in response to a petition filed by LycoRed Natural Products Industries.

It is not necessary for FDA to make any determination about the safety or lawfulness of lycopene either as a food ingredient, a component of food or as a dietary supplement in this letter because the agency is denying the proposed claims for tomato lycopene; tomatoes and tomato products, which contain lycopene; lycopene in tomatoes and tomato products, and lycopene in fruits and vegetables, including tomatoes and tomato products for lack of credible evidence, as discussed in section II.

II. The Agency's Consideration of a Qualified Health Claim

FDA has identified the following markers to use in identifying risk reduction for purposes of a health claim evaluation involving cancer: incident cases of the particular cancer being studied, and recurrent colon/rectal polyps for colon/rectal cancer. Colon/rectal polyp recurrence has been used as a surrogate marker for colon/rectal cancer and has been used by the National Cancer Institute as a surrogate marker for colon cancer prevention (Schatzkin et al., 1994). To evaluate the potential effects of tomato lycopene; tomatoes and tomato products, which contain lycopene; lycopene in tomatoes and tomato products; lycopene in and fruits and vegetables, including tomatoes and tomato products consumption on cancer risk, FDA considered these markers as indicators or predictors of the disease prostate cancer. The petition cited 177 publications and or websites as evidence to substantiate the relationship for the claims. These publications consisted of 38 review articles; three abstracts; 13 in vitro studies; ten animal studies; 63 articles that did not measure lycopene, tomatoes or tomato products and/or a type of cancer, the substance and disease that are subject of the proposed claims, (i.e., studies on lycopene bioavailability, transport, relationship to other diseases, other substance (β-carotene[16]); one federal report; one power point presentation from a scientific meeting, eight book chapters; nine websites (i.e., government databases, medical dictionary, general health information); and 31 studies on cancer and lycopene/tomato/tomato products foods (see docket # 2004Q-0201 for bibliography), of which five were intervention studies and 26 were observational studies.

In addition to the studies in your petition, the agency considered two additional intervention studies for prostate cancer (Clinton et al., 1996; Matalaga et al., 2001) and three additional observational studies (Grant et al., 1999; Meyer et al., 1997; Jian et al., 2005).

A. Assessment of Review Articles, Meta-Analyses and Abstracts

Although useful for background information, the review articles, meta-analysis, and abstracts do not contain sufficient information on the individual studies that they reviewed and, therefore, FDA could not draw any scientific conclusions from this information. FDA could not determine factors such as the study population characteristics or the composition of the products used (e.g., food, dietary supplement). Similarly, the lack of detailed information on studies summarized in review articles and meta-analyses prevents FDA from determining whether the studies are flawed in critical elements such as design, conduct of studies, and data analysis. FDA must be able to review the critical elements of a study to determine whether any scientific conclusions can be drawn from it. As a result, the review articles, meta-analysis, and abstracts supplied by the petitioner do not provide information from which scientific conclusions can be drawn regarding the substance-disease relationships claimed by the petitioner. B. Assessment of Animal and In Vitro Studies

FDA uses animal and in vitro studies as background information regarding mechanisms of action that might be involved in any relationship between the substance and the disease, and they can also be used to generate hypotheses or to explore a mechanism of action, but they cannot adequately support a relationship between the substance and the disease in humans. FDA did not consider the animal or in vitro studies submitted with the petition as providing any supportive information about the substance - disease relationship because such studies cannot mimic the normal human physiology that may be involved in the risk reduction of any type of cancer, nor can the studies mimic the human body's response to the consumption of tomato lycopene; tomatoes and tomato products, which contain lycopene; lycopene in tomato and tomato products or lycopene in fruits and vegetables, including tomatoes and tomato products. Therefore, FDA cannot draw any scientific conclusions from the animal or in vitro studies regarding tomato lycopene; tomatoes and tomato products, which contain lycopene; lycopene in tomato and tomato products or lycopene in fruits and vegetables, including tomatoes and tomato products and the reduction of risk of prostate cancer. C. Assessment of Intervention Studies

Five intervention studies (Chen et al., 2001; Bowen et al., 2002; Van Breemen et al., 2002; Kucuk et al., 2001; Ansari et al., 2003) were submitted by the petitioner and two studies (Matlaga et al., 2001; Clinton et al., 1996) were identified by the Agency to evaluate the relationship between tomato lycopene; tomatoes or tomato products, which contain lycopene; lycopene in tomatoes and tomato products; and/or lycopene in fruits and vegetables, including tomatoes and tomato products and prostate cancer. However, all seven of these studies used tomatoes or tomato products (e.g., tomato sauce) and/or lycopene as a treatment for men diagnosed with prostate cancer. Health claims characterize the relationship between the substance and a reduction in risk of contracting a particular disease.[17] These claims involve reducing the risk of a disease in people who do not already have the disease that is the subject of the claim. As a result, FDA considers evidence from studies in individuals already diagnosed with prostate cancer only if it is scientifically appropriate to extrapolate to individuals who do not have the disease. That is, the available scientific evidence must demonstrate that: (1) the mechanism(s) for the mitigation or treatment effects measured in the diseased populations are the same as the mechanism(s) for risk reduction effects in non-diseased populations; and (2) the substance affects these mechanisms in the same way in both diseased people and healthy people. Given that such evidence was not available, the agency cannot draw any scientific conclusions from these seven studies. D. Assessment of Observational Studies

Lycopene

A total of 17 studies[18] evaluated the relationship of lycopene and prostate cancer. The studies can be categorized into three groups: 1) Studies that evaluated lycopene from dietary sources and assessed the risk of cancer based on dietary lycopene intake; 2) Prospective observational and cross-sectional studies that used a single measure of serum lycopene concentration for determining the relationship between serum lycopene and risk of cancer; and 3) Studies that evaluated serum lycopene levels in subjects diagnosed with cancer. Nine observational studies cited in the petition[19] calculated lycopene intake from estimated dietary intake. The proposed claims regarding lycopene are for a relationship between lycopene as a dietary supplement or lycopene as an ingredient or component of food, tomatoes and tomato products, which contain lycopene, lycopene in tomatoes and tomato products, and lycopene in fruits and vegetables, including tomatoes and tomato products. In observational studies that calculate nutrient intake from conventional food, measures of lycopene intake are based on recorded dietary intake methods such as food frequency questionnaires, diet recalls, or diet records, in which the type and amount of foods consumed are estimated. Estimated lycopene concentration values are then added to the data using typical lycopene concentration values for the food product category based on the USDA National Nutrient Database for Standard Reference, SR 16. A common weakness of observational studies is the limited ability to ascertain the actual food or nutrient intake for the population studied. Furthermore, the lycopene content of foods can vary significantly (e.g., due to food variety, ripening stage of the food, food processing/cooking procedures, or storage (duration, temperature) (Giovannucci et al., 1999; Gartner et al., 1997; Boileau et al., 2002; Shi et al., 2000). Thus, it is difficult to ascertain an accurate amount of the nutrient consumed based on reports of dietary intake of foods.

In addition, lycopene-containing foods contain not only lycopene, but also other nutrients that may be associated with the metabolism of lycopene or the pathogenesis of certain cancers. Because lycopene-containing foods consist of many nutrients and substances, it is difficult to study the nutrient or food components in isolation (Sempos et al., 1999). For studies based on recorded dietary intake of such foods, it is not possible to accurately determine whether any observed effects of lycopene on cancer risk were due to: 1) lycopene alone; 2) interactions between lycopene and other nutrients; 3) other nutrients acting alone or together; or, 4) decreased consumption of other nutrients or substances contained in foods displaced from the diet by the increased intake of lycopene-rich foods.

In fact, evidence demonstrates that in a number of instances, epidemiological studies based on the recorded dietary intake of conventional foods may indicate a benefit for a particular nutrient with respect to a disease but it is subsequently demonstrated in an intervention study that the nutrient-containing dietary supplement does not confer a benefit or actually increases risk of the disease (Lichtenstein and Russell, 2005). For example, previous epidemiological studies reported an association between fruits and vegetables high in beta-carotene and a reduced risk of lung cancer (Peto et al., 1981). However, subsequent intervention studies, the Alpha-Tocopherol and Beta Carotene Prevention Study (ATBC) and the Carotene and Retinol Efficiency Trial (CARET), demonstrated that beta-carotene supplements increase the risk of lung cancer in smokers and asbestos-exposed workers, respectively (The Alpha-Tocopherol and Beta Carotene Cancer Prevention Study Group, 1994; Omenn et al., 1996).[20] These studies illustrate that the effect of a nutrient provided as a dietary supplement exhibits different health effects compared to when it is consumed among many other food components. Furthermore, these studies demonstrate the potential public health risk of relying on results from epidemiological studies, in which the effect of a nutrient is based on recorded dietary intake of conventional foods as the sole source for concluding that a relationship exists between a specific nutrient and disease risk; the effect could actually be harmful.[21]

Evidence is also now available that epidemiological studies based on the recorded dietary intake of conventional foods may suggest a benefit for a particular nutrient in that food with respect to a disease but it is subsequently demonstrated in an intervention study that the nutrient itself, when isolated from other nutrients in the food, does not confer a benefit ("Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acid," Institute of Medicine of the National Academies, 2002). For example, previous epidemiological studies (38 out of 48) reported an association between dietary fiber and reduced risk of colon cancer (Lanza 1990; Kromhout et al, 1982). Despite these and other positive findings, three recent clinical intervention trials found no association between dietary fiber and reduced risk of colon cancer (Alberts et al., 2000; Bonithon-Kopp et al., 2000; Schatzkin et al., 2000).

Furthermore, the observational studies that calculated lycopene intake from estimated dietary intake did not specify whether the tomato and/or tomato product intake reported was derived from red tomatoes. There are three varieties of tomatoes (red, green, and yellow) and only red tomatoes contain lycopene (USDA Nutrient Database, http://www.nal.usda.gov/fnic/foodcomp/). Thus, it is not possible to know whether the tomatoes in the studies actually contained lycopene. Nor, for the reasons discussed above, would it be possible to know whether, even if the tomatoes contained lycopene, that the lycopene had any relation to the reported effects. Moreover, the only data on lycopene in fruits and vegetables derived from two observational studies calculating lycopene intake from estimated dietary intake that included pink grapefruit and watermelon. The data on tomatoes and tomato-based products and the data on pink grapefruit and watermelon were combined in these studies. Therefore, it is impossible for FDA to determine whether any reported effects were from the tomatoes or tomato products, which may or may not have contained lycopene, or from the watermelon and pink grapefruit.

For the above reasons, FDA concludes that scientific conclusions cannot be drawn from observational studies on foods for the proposed claims for lycopene as a food ingredient, a component of food, or as a dietary supplement.[22]

Four observational studies evaluated serum lycopene levels and prostate cancer risk.[23] Numerous studies have shown that dietary lycopene intake and serum lycopene levels are poorly correlated; correlation coefficient range r = 0.11-0.45 (Campbell et al., 1994; Michaud et al., 1998; Casso et al., 2000; Neuhouser et al., 2001).[24] In addition, many factors can affect the serum lycopene levels including age, basal metabolic index (BMI), smoking, serum cholesterol levels, and season of the year (Casso et al., 2000; Mayne et al., 1999; Neuhouser et al., 2001). Since serum lycopene levels and dietary levels are poorly correlated and many factors (e.g., BMI, serum cholesterol, smoking, time of year) can alter the serum lycopene measures at a given point in time, scientific conclusions cannot be drawn from these four studies about the relationship between lycopene intake and risk reduction of any type of cancer.

Four studies[25] evaluated serum lycopene levels in subjects with cancer. In addition to the problem that serum lycopene levels are poorly correlated with dietary intake (see above), these studies used subjects diagnosed with different forms of cancer. Health claims characterize the relationship between the substance and a reduction in risk of contracting a particular disease.[26] These claims involve reducing the risk of a disease in people who do not already have the disease that is the subject of the claim. As a result, FDA considers evidence from studies in individuals already diagnosed with prostate cancer only if it is scientifically appropriate to extrapolate to individuals who do not have the disease. That is, the available scientific evidence must demonstrate that: (1) the mechanism(s) for the mitigation or treatment effects measured in the diseased populations are the same as the mechanism(s) for risk reduction effects in non-diseased populations; and (2) the substance affects these mechanisms in the same way in both diseased people and healthy people. Given that such evidence was not available, the agency cannot draw any scientific conclusions from these studies.

Tomatoes and Tomato Products

There were 19 observational studies on tomato and/or tomato product consumption and risk of prostate cancer, consisting of three prospective cohort studies[27], one sub-cohort study[28], 13 case-control studies[29], and two ecological studies.[30] Three studies were a republication of studies already being used in evaluating the proposed claim.[31] One study compared insulin-like growth factors (IGF) and tomato intake.[32] IGF is not a surrogate endpoint for prostate cancer. Therefore, the agency could not draw any scientific conclusions from this study. Finally, two case-control studies provided no information as to whether the food frequency questionnaires in the studies, which were used for the collection of tomato consumption data from study subjects, had been appropriately validated.[33] Validation of the food frequency questionnaire method is essential in order to be able to draw conclusions from the scientific data, as the failure to validate may lead to false associations between dietary factors and diseases or disease-related markers.[34] As a result, these studies provided no information on the accuracy of how tomato intake was measured, and hence, no scientific conclusions could be drawn from them.[35] Thus, there were 13 observational studies evaluating the relationship between tomatoes or tomato products and prostate cancer. Two large cohort studies conducted in the United States evaluated tomato/tomato sauce intake and prostate cancer risk (Giovannucci et al., 2002; Mills et al., 1989). Both studies received a high methodological quality rating. Giovannucci et al. (2002) used the Health Professionals Follow-Up Study cohort that contained 47,365 males followed for approximately 12 years. In this cohort 2,481 prostate cancer cases were identified during follow-up. Tomato sauce intake was evaluated using three different food frequency questionnaires given at the beginning of the study and at four-year intervals. Consuming one, or greater than one, serving of tomato sauce per week was associated with significant decreased risk of prostate cancer; relative risk 0.80 (95% Confidence Interval (CI) of 0.70-0.91) and 0.77 (95% CI of 0.66-0.90)[36], respectively. Mills et al. (1989) followed a cohort of 14,000 Seventh Day Adventist males for six years, 180 prostate cancer cases were identified during the follow-up. Consuming tomatoes one to four times per week, or greater than five times per week was associated with a significant decrease in prostate cancer incidence; relative risk 0.62 (95% CI of 0.40-0.96) and 0.57 (95% CI of 0.35-0.93), respectively.

One sub-cohort study evaluated tomatoes and prostate cancer risk in 642 prostate cancer cases and 1,668 random healthy subjects from a cohort in the Netherlands (Schuurman et al., 1998). This study was of high methodological quality. Tomato intake (per 25 grams tomatoes) was not associated with prostate cancer, with a relative risk of 1.05 (95% CI of 0.90-1.22). Tomato juice intake (per 25 grams) was not associated with prostate cancer incidence; relative risk of 1.12 (95% CI of 0.96-1.29).

Eight case-control studies evaluated tomatoes and prostate cancer risk and all of the studies received high to moderate methodological quality ratings. Jain et al. (1999) reported that consuming greater than 109 grams of tomatoes per day was associated with a reduced risk of prostate cancer; odds ratio of 0.64 (95% CI of 0.45-0.91). This case-control study was conducted in Canada with 617 prostate cancer cases and 636 controls. Bosetti et al. (2000) conducted a case-control study that included 320 prostate cancer cases and 246 controls in Greece. Decreased intake of cooked tomatoes was associated with an increased risk of prostate cancer; odds ratio of 1.91 (95% CI of 1.20-3.04). However, there was no association between raw tomato intake and prostate cancer risk. Jian et al. (2005) conducted a case-control study in 130 prostate cancer cases and 274 controls from China. Tomato intake was associated with a reduced risk of prostate cancer; odds ratio of 0.16 (95% CI of 0.07-0.38).

Five of the eight case-control studies found no association between tomato consumption and prostate cancer risk (Villeneuve et al., 1999; Key et al., 1997; Hayes et al., 1999; Kolonel et al., 2000; LeMarchand et al., 1991). One case-control study conducted in Canada included 1,623 prostate cancer cases and controls and found no association between prostate cancer and tomatoes or tomato juice consumption; odds ratio of 1.0 (95% CI of 0.7-1.3) (Villeneuve et al., 1999). Another case-control study conducted in England included 328 prostate cancer cases and controls and found no association between prostate cancer and raw or cooked tomato intake; odds ratio of 1.06 (95% CI of 0.55-1.62) and 0.92 (0.59-1.42), respectively (Key et al., 1997). Hayes et al. (1999) conducted a case-control study in the United States with 932 prostate cancer cases and 1,201 controls. Tomato juice and raw/cooked tomato consumption had no association with prostate cancer risk. Kolonel et al. (2000) conducted a case-control study using 1,619 prostate cancer cases and 1,618 controls from a multi-ethnic population from the United States and Canada. There was no association between tomatoes or cooked tomato consumption and prostate cancer risk. Le Marchand et al. (1991) conducted a case-control study in Hawaii with 452 prostate cancer cases and 899 controls. Tomato consumption had no association with prostate cancer risk.

Two ecological studies of moderate methodological quality evaluated tomato consumption and prostate cancer risk (Grant., 1999; Ganmaa et al., 2002). Grant (1999) compared prostate cancer mortality data from 41 countries to the tomato supply for each country. Of the 28 countries that consumed more than five kilocalories per day from tomatoes, there was a strong protective correlation between tomato intake and prostate cancer mortality. Ganmaa et al. (2002) evaluated prostate cancer incidence rates and tomato consumption (based on country intake) for 44 countries. There was no correlation between tomato consumption and prostate cancer.

III. Strength of the Scientific Evidence

Below, the agency rates the strength of the total body of publicly available evidence. The agency conducts this rating evaluation by considering the study type (e.g., intervention, prospective cohort, case-control, cross-sectional), the methodological quality rating previously assigned, the quantity of evidence (number of the various types of studies and sample sizes), whether the body of scientific evidence supports a health claim relationship for the U.S. population or target subgroup, whether study results supporting the proposed claim have been replicated[37], and the overall consistency[38] of the total body of evidence. Based on the totality of the scientific evidence, FDA determines whether such evidence is credible to support the substance/disease relationship, and, if so, determines the ranking that reflects the level of comfort among qualified scientists that such a relationship is scientifically valid. Lycopene

As discussed in Section II of this letter, no studies provided information about whether lycopene may reduce the risk of prostate cancer. Based on the above, FDA concludes that there is no credible evidence supporting a relationship between lycopene consumption, either as a food ingredient, a component of food, or a dietary supplement, and prostate cancer.[39] Tomatoes and Tomato Products

As discussed in Section II of this letter, there were 13 observational studies that evaluated the relationship between the consumption of tomatoes or tomato products and prostate cancer: two cohort studies, one sub-cohort study, eight case-control studies, and two ecological studies. Both cohort studies reported a significant reduction in prostate cancer risk with increased consumption of tomato sauce or tomatoes, respectively (Giovannucci et al., 2002; Mills et al., 1989). Furthermore, prospectively designed studies provide stronger evidence for an association than case-control studies since there are fewer forms of bias.[40] The cohort studies were conducted in the United States, received high methodological quality ratings, and contained a large number of subjects (greater than 14,000 per study). Two case-control studies (Jain et al., 1999; Bosetti et al., 2000) and one ecological study (Grant, 1999) also reported a protective association between tomatoes and prostate cancer risk. However, five case-control studies (Villeneuve et al., 1999; Key et al., 1997; Hayes et al., 1999; Kolonel et al., 2000; and LeMarchand et al., 1991), one sub-cohort study (Schuurman et al., 1998) and one ecological study (Ganmaa et al., 2002) found no association between tomato intake and prostate cancer risk. Several of these case-control studies were conducted in the United States, received high methodological quality ratings, and each study contained greater than 1,000 subjects. Based on the above, FDA finds that there is very limited credible evidence for a qualified health claim. FDA concludes that there is a very low level of comfort that a relationship exists between tomatoes and/or tomato sauce and prostate cancer.[41]

IV. Other Enforcement Discretion Factors

For the purposes of this section of the letter, the term "tomato" includes raw, cooked, dried, or canned tomatoes. FDA has not established a standard of identity for tomato sauce, however, the agency's policy on tomato sauce is that it should consist of a spiced tomato product concentrated to contain not less than 8.37 percent salt-free tomato solids, and that it can be made by adding spices to tomato puree (CPG 7109.21). For the purposes of this letter the term "tomato sauce" means a spiced or not spiced tomato product that contains at least 8.37% of salt-free tomato solids. Factors that FDA intends to consider in the exercise of its enforcement discretion for qualified health claims about tomatoes and/or tomato sauce and prostate cancer used on the label or in the labeling of tomatoes and/or tomato sauce are discussed below.

A. Disqualifying Nutrient Levels

Under the general requirements for health claims (21 CFR 101.14(e)(3)), a food may not bear a health claim if that food exceeds any of the disqualifying nutrient levels for total fat, saturated fat, cholesterol, or sodium established in § 101.14(a)(4). Disqualifying total fat levels for individual foods are above 13.0 g per reference amount customarily consumed (RACC), per label serving size, and, for foods with a RACC of 30 g or less or 2 tablespoons or less, per 50 g. Disqualifying saturated fat levels for individual foods are above 4.0 g per RACC, per label serving size, and, for foods with a RACC of 30 g or less or 2 tablespoons or less, per 50 g. Disqualifying cholesterol levels for individual foods are above 60 mg per RACC, per label serving size, and, for foods with a RACC of 30 g or less or 2 tablespoons or less, per 50 g. Disqualifying sodium levels for individual foods are above 480 mg per RACC, per label serving size, and, for foods with a RACC of 30 g or less or 2 tablespoons or less, per 50 g. Tomatoes and most tomato sauces would not exceed the disqualifying levels for total fat, saturated fat, and cholesterol as specified in 21 CFR 101.14(a)(4). However, some tomatoes or tomato sauces may be disqualified based on their sodium level. FDA intends to consider the exercise of its enforcement discretion for qualified health claims about consumption of tomatoes and/or tomato sauce and reduced risk of prostate cancer on the label or in the labeling of tomatoes, tomato sauce, when the food does not exceed any disqualifying nutrient levels (i.e., total fat, saturated fat, cholesterol and sodium) as specified in 21 CFR 101.14(a)(4).

B. 10 Percent Minimum Nutrient Content Requirement

Under the general requirements for health claims, a conventional food may not bear a health claim unless it contains, prior to any nutrient addition, at least 10 percent of the Daily Value (DV) for vitamin A, vitamin C, iron, calcium, protein, or dietary fiber per RACC (21 CFR 101.14(e)(6)). The purpose of this provision is to prevent the use of health claims on foods with minimal nutritional value. FDA notes that most tomatoes and tomato sauces will contain at least 10 percent of vitamin A, vitamin C, or both. Therefore, FDA intends to consider the exercise of its enforcement discretion for qualified health claims about tomatoes and/or tomato sauce and prostate cancer, used on the label or in the labeling of tomatoes and/or tomato sauce when the food complies with the 10 percent minimum nutrient contribution requirement as specified in 21 CFR 101.14(e)(6).

C. Minimum Effective Amount of Tomatoes Eligible for the Claim

The general requirements for health claims require that, if the claim is about the effects of consuming the substance at other than decreased dietary levels, the level of the substance must be sufficiently high and in the appropriate form to justify the claim. Where no definition of high has been established, the claim must specify the daily dietary intake necessary to achieve the claimed effect (see 21 CFR 101.14(d)(2)(vii)). After considering the available scientific evidence, the agency determined that the minimum effective amount of tomatoes and/or tomato sauce that may result in a reduced risk of prostate cancer is one-half to one cup per week. V. Agency's Consideration of Disclaimers or Qualifying Language

We considered but rejected use of a disclaimer or qualifying language to accompany the proposed claim for which we found no credible evidence for tomato lycopene; tomatoes and tomato products, which contain lycopene; lycopene in tomatoes and tomato products, lycopene in fruits and vegetables, including tomatoes and tomato products, and lycopene as a food ingredient, a component of food, or as a dietary supplement and prostate cancer. We concluded that neither a disclaimer nor qualifying language would suffice to prevent consumer deception in these instances, where there is no credible evidence to support the claims. Adding a disclaimer or incorporating qualifying language that effectively characterizes the claim as baseless is not a viable regulatory alternative because neither the disclaimer nor the qualifying language can rectify the message conveyed by the unsubstantiated claim. See, e.g., In re Warner-Lambert Co., 86 F.T.C. 1398, 1414 (1975), aff'd, 562 F.2d 749 (D.C. Cir. 1977) (pro forma statements of no absolute prevention followed by promises of fewer colds did not cure or correct the false message that Listerine will prevent colds); Novartis Consumer Health, Inc. v. Johnson & Johnson-Merck Consumer Pharms. Co., 290 F.3d 578, 598 (3d Cir. 2002) ("We do not believe that a disclaimer can rectify a product name that necessarily conveys a false message to the consumer."); Pearson v. Shalala, 164 F.3d 650, 659 (D.C. Cir. 1999) (the court stated that, where the weight of the evidence was against the claim, FDA could rationally conclude that the disclaimer "The FDA has determined that no evidence supports this claim" would not cure the misleadingness of a claim). In such a situation, adding a disclaimer or qualifying language does not provide additional information to help consumer understanding but merely contradicts the claim. Resort Car Rental System, Inc. v. FTC, 518 F.2d 962, 964 (9th Cir.) (per curiam) (upholding FTC order to excise "Dollar a Day" trade name as deceptive because "by its nature [it] has decisive connotation for which qualifying language would result in contradiction in terms."), cert denied, 423 U.S. 827 (1975); Continental Wax Corp. v. FTC, 330 F.2d 475, 480 (2d Cir. 1964) (same); Pasadena Research Labs v. United States, 169 F.2d 375 (9th Cir. 1948) (discussing "self-contradictory labels"). In the FDA context, courts have repeatedly found such disclaimers ineffective. See, e.g., United States v. Millpax, Inc., 313 F.2d 152, 154 & n.1 (7th Cir. 1963) (disclaimer stating that "no claim is made that the product cures anything, either by the writer or the manufacturer" was ineffective where testimonials in a magazine article promoted the product as a cancer cure); United States v. Kasz Enters., Inc., 855 F. Supp. 534, 543 (D.R.I.) ("The intent and effect of the FDCA in protecting consumers from . . . claims that have not been supported by competent scientific proof cannot be circumvented by linguistic game-playing."), judgment amended on other grounds, 862 F. Supp. 717 (1994). VI. Conclusions

Based on FDA's consideration of the scientific evidence submitted with your petition, and other pertinent scientific evidence, FDA concludes that there is no credible evidence to support a qualified health claim for tomato lycopene; tomatoes and tomato products, which contain lycopene; lycopene in tomatoes and tomato products; lycopene in fruits and vegetables, including tomatoes and tomato products, and lycopene as a food ingredient, a component of food, or as a dietary supplement and reduced risk of prostate cancer. Thus, FDA is denying these claims. However, FDA concludes that there is very limited credible evidence for qualified health claims for tomatoes and/or tomato sauce, and prostate cancer provided that the qualified claim is appropriately worded so as to not mislead consumers. Thus, FDA intends to consider exercising its enforcement discretion for the following qualified health claim: Prostate Cancer "Very limited and preliminary scientific research suggests that eating one-half to one cup of tomatoes and/or tomato sauce a week may reduce the risk of prostate cancer. FDA concludes that there is little scientific evidence supporting this claim." FDA intends to consider exercising its enforcement discretion for the above qualified health claim when all factors for enforcement discretion identified in Section IV of this letter are met. Please note that scientific information is subject to change, as are consumer consumption patterns. FDA intends to evaluate new information that becomes available to determine whether it necessitates a change in this decision. For example, scientific evidence may become available that will support significant scientific agreement, that will support a qualified health claim for those claims that were denied, that will no longer support the use of the above qualified health claim, or that may raise safety concerns about the substance that is the subject of the claim. Sincerely yours, Barbara O. Schneeman, Ph.D. Director Office of Nutritional Products, Labeling and Dietary Supplements Center for Food Safety and Applied Nutrition

Appendix 1 (Heinz Letter)

See petition (docket #2004Q-0201) for complete reference citation Observational Studies that evaluated lycopene from dietary sources Giovannucci et al., 2002 Key et al., 1997 Hayes et al., 1999 Norrish et al., 2000 Cohen et al., 1999 Schuurman et al., 2002 Meyer et al., 1997 Deneo-Pellegrini et al., 1999 Jian et al., 2005

Lycopene serum levels from prospective studies Gann et al., 1999 Huang et al., 2003 Hsing et al., 1990 Nomura et al., 1997

Serum lycopene measures in subjects diagnosed with cancer Lu et al., 2001 Vogt et al., 2002 Rao et al, 1999 Cinton et al., 1996

Republication Giovannucci et al., 1995 Norrish et al., 2000 Tzonou et al, 1999

Used non validated endpoints of cancer Mucci et al., 2001

Food Frequency Questionnaire Validation not Verified in Study Norrish et al., 2000 Cohen et al., 1999

References:

Alberts DS., Martinez ME., Roe DJ., Guillen-Rodriguez JM., Marshall JR., van Leeuwen JB., Reid ME., Ritenbaugh C., Vargas PA., Bhattacharyya AB., Earnest DL., Sampliner RE. "Lack of effect of a high-fiber cereal supplement on the recurrence of colorectal adenomas. Phoenix Colon Cancer Prevention Physicians' Network." New England Journal of Medicine, 342: 1156-1162, 2000. Ansari, M.S., Gupta, N.P. "A comparison of lycopene and orchidectomy vs orchidectomy alone in the management of advanced prostate cancer." British Journal of Urology, 92: 375-378, 2003.

Boileu TWM., Boileau AC., Erdman JW. "Bioavailability of all-trans and cis-isomers of lycopene." Experimental Biology and Medicine, 227: 914-919, 2002.

Bonithon-Kopp C., Kronborg O., Giacosa A., Rath U., Faivre J. "Calcium and fibre supplementation in prevention of colorectal adenoma recurrence: A randomized intervention trial." Lancet, 356: 1300-1306, 2000.

Bowen, P., Chen L., Stacewicz-Sapuntzakis, M., Duncan, C., Sharifi, R., Ghosh, L., Kim, H, Christov-Tzelkow, K, Van Breemen, R. "Tomato sauce supplementation and prostate cancer: lycopene accumulation and modulation of biomarkers of carcinogenesis." Experimental Biology and Medicine, 227: 886-893, 2002.

Bosetti, C. Tzonou, A., Lagiou, P., Negri, E., Tricholpoulos, D., Hsieh, C.C. "Fraction of prostate cancer incidence attributed to diet in Athens, Greece." European Journal of Cancer Prevention, 9: 119-123, 2000.

Cade, J., Thompson, R., Burley, V., and Warm, D. "Development, Validation and Utilization of Food-Frequency Questionnaires-A Review." Public Health Nutrition, 5: page 573, 2002.

Campbell, D.R., Gross, M.D., Martini, M.C., Grandits, G.A., Slavin, J.L., and Potter, J.D. "Plasma carotenoids as biomarkers of vegetable and fruit intake." Cancer Epidemiology, Biomarkers, and Prevention, 3: 493-500, 1994.

Casso, D., White, E., Patterson, R.E., Agurs-Collins, T., Kooperberg, C., Haines, P.S. "Correlates of serum lycopene in older women." Nutrition and Cancer, 36: 163-169, 2000.

Chen, L., Stacewicz-Sapuntzakis, M., Duncan, C., Sharifi, R., Ghosh, L., Van Breemen, R., Ashton, D., Bowen, P.E. "Oxidative DNA damage in prostate cancer patients consuming tomato sauce-based entrees as a whole food intervention." Journal of the National Cancer Institute, 93: 1872-1879, 2001.

Clinton, S.K., Emenhiser, C., Schwartz, S.J., Bostwick, D.G., Williams, A.W., Moore, B.J., Erdman, J.W. "cis-trans lycopene isomer, carotenoids, and retinol in the human prostate." Cancer, Epidemiology, Biomarkers, and Prevention, 5: 823-833, 1996.

Deneo-Pellegrini, H., De Stefani, E., Ronco, A., Mendilaharsu M. "Foods, nutrients and prostate cancer: a case-control study in Uruguay." British Journal of Cancer, 80: 591-597, 1999.

Federal Judicial Center, Reference Manual on Scientific Evidence, Second Edition, 2000, page 93.

Ganmaa D., Li X.M., Wang J., Qin L.Q., Wang P.Y., Sato A. "Incidence and mortality of testicular and prostatic cancers in relation to world dietary practices." International Journal of Cancer, 98: 262-267, 2002.

Gartner C., Stahl W., Sies H. "Lycopene is more bioavailable from tomato paste than fresh tomatoes." American Journal of Clinical Nutrition, 66: 116-122, 1997.

Giovannucci E., "Tomatoes, tomato-based products, lycopene and cancer: review of the epidemiological literature." Journal of the National Cancer Institute, 91: 317-331, 1999.

Giovannucci, E., Rimm, E.B., Liu Y., Stampfer, M.J., Willett, W.C. "A prospective study of tomato products, lycopene, and prostate cancer risk." Journal of the National Cancer Institute, 94: 391-398, 2002.

Grant, W.B. "An ecologic study of dietary links to prostate cancer." Alternative Medicine Review, 4: 162-169, 1999.

Hayes, R.B., Ziegler, R.G., Gridley, G., Swanson, C., Greenberg, R.S., Swanson, G.M., Schoenberg, J.B., Silverman, D.T., Brown, L.M, Pottern, L.M, Liff, J., Schwartz, A.G., Fraumeni, J.F., Hoover, R.N. "Dietary factors and risks for prostate cancer among blacks and whites in the United States." Cancer, Epidemiology, Biomarkers, and Prevention, 8: 25-34, 1999.

Hill A.B. "The environment and disease: association or causation?" Proc R Soc Med, 58:295-300, 1965.

Institute of Medicine, National Academy of Sciences. Dietary Supplements: A Framework for Evaluating Safety. Chapter 7, Categories of Scientific Evidence - In Vitro Data. National Academy Press. Washington, D.C. 2005.

Jain, M.G., Hislop, G.T., Howe, G.R., Ghardirian, P. "Plant foods, antioxidants, and prostate cancer risk: findings from case-control studies in Canada." Nutrition and Cancer, 34: 173-184, 1999.

Jian L., Du C., Lee A.H., Binns C.W. "Do dietary lycopene and other carotenoids protect against prostate cancer?" International Journal of Cancer, 113: 1010-1014, 2005.

Key, T.J.A., Silcocks, P.B., Davey, G.K., Appleby, P.N., Bishop, D.T. "A case-control study of diet and prostate cancer." British Journal of Cancer, 76: 678-687, 1997.

Kolonel, L.N., Hankin, J.H., Whittemore, A.S., Wu, A.H., Gallagher, R.P., Wilkens, L.R., John, E.M., Howe, G.R., Dreon, D.M., West, D.W., Paffenbarger, R.S. "Vegetables, fruits, legumes and prostate cancer: a multiethnic case-control study." Cancer Epidemiology, Biomarkers, and Prevention, 9: 794-804, 2000.

Kromhurt D., Bosschieter EB., de Lezenne Coulander C. " Dietary fiber and 10-year mortality rate from coronary heart disease, cancer, and all causes. The Zutphen study." Lancet, 2: 518-522, 1982.

Kucuk, O., Sarkar, F.H., Sakr, W., Djuric, Z., Pollak, M.N., Khachick, F., Li, Y., Banerjee, M., Grignon, D., Bertram, J.S., Crissman, J.D., Pontes, E.J., Wood, D.P. "Phase II randomized clinical trial of lycopen supplementation before radical prostatectomy." Cancer, Epidemiology, Biomarkers, and Prevention, 10: 861-869, 2001.

Lanza E., National Cancer Institute Satelite Symposium on Fiber and colon cancer. In Krischevsky D., Bonfield C., Anderson JW., eds., Dietary Fiber: Chemistry Physiology and Health Effects. New York, Plenom Press., pages 383-387, 1990.

Le Marchand, L., Hankin, J.H., Kolonel, L.N., Wilkens, L.R. "Vegetable and fruit consumption in relation to prostate cancer risk in Hawaii: a reevaluation of the effect of dietary beta-carotene." American Journal of Epidemiology, 133: 215-219, 1991.

Lichtenstein AH., Russell RM. "Essential nutrients: food or supplements? Where should the emphasis be? "Journal of the American Medical Association," 294: 351-358, 2005

Matlaga, B.R., Hall, M.C., Stindt, D., Torti, F.M. "Response of hormone refractory prostate cancer to lycopene." Journal of Urology, 166: 613, 2001.

Mayne, S.T., Cartmel, B., Silva, F., Kim, C.S., Fallon, B.G., Briskin, K., Zheng, T., Baum, M., Shor-Posner, G., Goodwin, W.J. "Plasma lycopene concentrations in humans are determined by lycopene intake, plasma cholesterol concentrations, and selected demographic factors." Journal of Nutrition, 129: 849-854, 1999.

Michaud, D.S., Giovannucci, E.L., Ascherio, A., Rimm, E.B., Forman, M. R., Sampson, L., Willett, W.C. "Associations of plasma carotenoid concentrations and dietary intake of specific carotenoids in samples of two prospective cohort studies using a new carotenoid database." Cancer, Epidemiology, Biomarkers, and Prevention, 7: 283-290, 1998.

Mills, P.K., Beeson, L., Phillips, R.L., Fraser, G.E. "Cohort study of diet, lifestyle, and prostate cancer in Adventist men." Cancer, 64: 598-604, 1989.

Neuhouser, M.L., Rock, C.L., Eldridg, A.L, Kristal, A.R., Patterson, R.E., Cooper, D.A., Neumark-Sztainer, D., Cheskin, L.J., Thornquist, M.D. "Serum concentrations of retinol, α-tocoperol and the carotenoids are influenced by diet, race, and obesity in a sample of healthy adolescents." Journal of Nutrition, 131: 2184-2191, 2001.

Omenn GS., Goodman GE., Thornquist MD. "Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease." New England Journal of Medicine, 334: 1150-1155, 1996.

Peto R., Doll R., Buckley JD., Sporn MB. "Can dietary beta-carotene materially reduce human cancer rates?" Nature, 290: 201-208, 1981.

Schatzkin A., Freedman LS., Dawsey SM., Lanza E. "Interpreting precursor studies: what polyp trials tell us about large bowl cancer." Journal of the National Cancer Institute, 86: 1053-1057, 1994.

Schatzkin A., Lanza E., Corle D., Lance P., Iber F., Caan B., Shike M., Weissfeld J., Burt R., Cooper MR., Kikendall JW., Cahill J. "Lack of effect of a low-fat, high-fiber diet on the recurrence of colorectal adenomas. Polyp Prevention Trial Study Group." New England Journal of Medicine, 342: 1149-1155, 2000.

Schuurman, A.G., Goldbohm, R.A., Dorant, E., van den Brandt, P.A. "Vegetable and fruit consumption and prostate cancer risk: a cohort study in the Netherlands." Cancer, Epidemiology, Biomarkers, and Prevention, 7: 673-680, 1998.

Sempos CT., Liu K., Ernest MD. "Food and nutrient exposures: what to consider when evaluating epidemiologic evidence." American Journal of Clinical Nutrition, 69: 1330S-1338S, 1999.

Shi J. and Le Maguer M. "Lycopene in tomatoes: chemical and physical properties affected by food processing." Critical Reviews in Biotechnology, 20: 293-334, 2000.

Spilker, B. Guide to Clinical Studies. Raven Press, New York, New York, 1991. Subar, A.F., Thompson, F.E., Kipnis, V., Midthune, D., Hurwitz, P., McNutt, S., McIntosh, A., and Rosenfeld, S. "Comparative validation of the block, Willett, and National Cancer Institute food frequency questionnaires." American Journal of Epidemiology, 154: 1089-1099, 2001.

Szklo, M. and Nieto, F.J. Epidemiology Beyond the Basics, Aspen Publishing, 2000.

The Alpha-Tocopherol: beta-Carotene Cancer Prevention Study Group. " The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers." New England Journal of Medicine, 330: 1029-1035, 1996.

Van Breemen, R.B., Xu, X., Viana, M.A., Chen, L., Stacewicz-Sapuntzakis, M., Duncan, C., Bowen, P.E., Sharifi, R. "Liquid chromatograph-mass spectrometry of cis- and all-trans-lycopene in human serum and prostate tissue after dietary supplementation with tomato sauce." Journal of Agriculture, Food, and Chemistry, 50: 2214-2219, 2002.

Villeneuve, P.J., Johnson, K.C., Keiger, N., Mao, Y. "Risk factors for prostate cancer: results from the Canadian national enhanced cancer surveillance system." Cancer Causes, and Control, 10: 355-367, 1999.

Wilson, E.B. An Introduction to Scientific Research, pages 46-48, Dover Publishing, 1990.

Wright, M.E., Mayne, S.T., Swanson, C.A., Sinha, R., Alavanja, M.C. "Dietary carotenoids, vegetables, and lung cancer risk in women: the Missouri women's health study (United States)." Cancer Causes and Control, 14: 85-96, 2003.

Notes

[1] This coalition consists of the H.J. Heinz Company, LycoRed Natural Products Industries, Ltd., The Morningstar Company, and The Prostate Cancer Foundation. [2] Interim Procedures for Qualified Health Claims in the Labeling of Conventional Human Food and Human Dietary Supplements, (Attachment E) July 10, 2003. (http://www.cfsan.fda.gov/~dms/nuttf-e.html).

[3] See Whitaker v. Thompson, 353 F.3d 947, 950-51 (D.C. Cir 2004) (upholding FDA's interpretation of what constitutes a health claim), cert. denied, 125 S.Ct. 310 (2004). [125 S.Ct. 310 (2004).

[4] See guidance entitled "Interim Evidence-based Ranking System for Scientific Data," July 10, 2003. [http://www.cfsan.fda.gov/~dms/hclmgui4.html]

[5] For brevity "Disease" will be used as shorthand for "disease or health-related condition" in the rest of the section.

[6] In an intervention study, subjects similar to each other are randomly assigned to either receive the intervention or not to receive the intervention, whereas in an observational study, the subjects (or their medical records) are observed for a certain outcome (i.e., disease). Intervention studies provide the strongest evidence for an effect. See Guidance entitled "Significant Scientific Agreement in the Review of Health Claims for Conventional Foods and Dietary Supplements" (December 22, 1999). [http://www.cfsan.fda.gov/~dms/ssaguide.html]

[7] A meta-analysis is the process of systematically combining and evaluating the results of clinical trials that have been completed or terminated (Spilker, 1991).

[8] Review articles summarize the findings of individual studies.

[9] Other examples include book chapters, abstracts, letters to the editor, and committee reports.

[10] See supra, note 4.

[11] Replication of scientific findings is important for evaluating the strength of scientific evidence (An Introduction to Scientific Research, E. Bright Wilson Jr., pages 46-48, Dover Publications, 1990).

[12] Consistency of findings among similar and different study designs is important for evaluating causation and the strength of scientific evidence (Hill A.B. The environment and disease: association or causation? Proc R Soc Med 1965;58:295-300); See also Systems to rate the scientific evidence, Agency for Healthcare Research and Quality http://www.ahrq.gov/clinic/epcsums/strengthsum.htm#Contents, defining "consistency" as "the extent to which similar findings are reported using similar and different study designs."

[13] See supra, note 4.

[14] In this instance, it is not necessary for FDA to determine whether it would be appropriate to consider the broad food category of fruits and vegetables as a substance for purposes of a health claim (see "QHC ANPRM," 68 FR 66040, Nov. 25, 2003), because even if they were considered to be a substance FDA finds that there is no credible evidence to support the claim concerning "fruits and vegetables." Nonetheless, FDA has evaluated information the petitioner submitted concerning fruits and vegetables.

[15] Since there were no other tomato products identified that purported to show an effect, the substance "tomato products" is in effect limited, in this case, to tomato sauce.

[16] While both lycopene and β-carotene are classified as carotenoids, they are structurally different from each other and exhibit different physiological effects.

[17] See supra, note 3.

[18] See Appendix 1

[19] See Appendix 1

[20] Β-carotene and lycopene are both members of the carotenoid family ("Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids," A Report of the Panel on Dietary Antioxidants and Related Compounds, Food and Nutrition Board of the Institute of Medicine, 2000).

[21] With regard to dietary supplements, in Pearson v. Shalala, the D.C. Circuit noted that FDA had "logically determined" that the consumption of a dietary supplement containing antioxidants could not be scientifically proven to reduce the risk of cancer where the existing research had examined only foods containing antioxidants as the effect of those foods on reducing the risk of cancer may have resulted from other substances in those foods. 164 F.3d 650, 658 (D.C. Cir 1999). The D.C. Circuit, however, concluded that FDA's concern with granting antioxidant vitamins a qualified health claim could be accommodated by simply adding a prominent disclaimer noting that the evidence for such a claim was inconclusive given that the studies supporting the claim were based on foods containing other substances that might actually be responsible for reducing the risk of cancer. Id. The court noted that FDA did not assert that the dietary supplements at issue would "threaten consumer's health and safety." Id. at 656. There is, however, a more fundamental problem with allowing qualified health claims for nutrients in dietary supplements based solely on studies of foods containing those nutrients than the problem the D.C. Circuit held could be cured with a disclaimer. As noted above, even if the effect of the specific component of the food constituting the dietary supplement could be determined with certainty, recent scientific studies have shown that nutrients in food do not necessarily have the same beneficial effect when taken in the form of a dietary supplement. See Lichtenstein and Russell (2005). Indeed, not only have studies on single nutrient supplements established that the benefits associated with the dietary intake of certain nutrients do not materialize when the nutrients are taken as a supplement, but some of these studies have actually indicated an increased risk for the very disease the nutrients were predicted to prevent. Id. Thus, an observational study based on food provides no information from which scientific conclusions may be drawn for the single nutrient supplement.

[22] Therefore, observational studies in foods do not provide any credible evidence for a claim for risk reduction for a single food component because, in fact, the single food component form may decrease, have no effect, or actually increase risk of the disease or health related condition. Additionally, such studies do not provide credible evidence for the single food component as discussed above. For the reasons set forth in Section V, we have concluded that neither a disclaimer nor qualifying language would suffice to prevent consumer deception in these instances because observational studies in food do not provide credible evidence for the proposed claims for tomato lycopene, tomatoes and tomato products, which contain lycopene, lycopene in tomatoes and tomato products, or lycopene in fruits and vegetables, including tomatoes and tomato products and there is no other credible evidence to support these claims.

[23] See appendix 1

[24] Correlation coefficients range from -1 (negative correlation) through +1 (positive correlation). The closer to 1 the coefficient the stronger the correlation; the closer to zero the weaker the correlation.

[25] See appendix 1

[26] See supra, note 3.

[27] In a cohort study, a group of healthy people or cohort is identified and followed up for a certain time period to ascertain the occurrence of disease and or health related events. (Epidemiology Beyond the Basics, page 24, Aspen Publishers, 2000).

[28] A sub-cohort study uses subjects from a defined cohort study. Cases are subjects diagnosed with the disease (i.e. cancer) in the cohort and controls are subjects selected randomly from a sample of the entire cohort at baseline. (Epidemiology Beyond the Basics, Aspen Publishers, 2000.)

[29] In a case-control study, a group of cases are identified as the individuals in whom the disease of interest was diagnosed during a given year and controls are selected from individuals who do not have the disease in the same time period (Epidemiology Beyond the Basics, page 29 Aspen Publishers, 2000).

[30] An ecological study examines a possible association between aggregate measure of exposure and disease or mortality (Epidemiology Beyond the Basics, page 17, Aspen Publishing 2000).

[31] See Appendix 1.

[32] See Appendix 1.

[33] See Appendix 1.

[34] "Validation of the food frequency questionnaire method is essential, as incorrect information may lead to false associations between dietary factors and disease or disease-related markers." Cade, J., Thompson, R., Burley, V., and Warm D. Development, Validation and Utilization of Food-Frequency Questionnaires-A Review. Public Health Nutrition, 5: page 573, 2002. See, also, Subar, A., et al., Comparative validation of the Block, Willett, and National Cancer Institute Food Frequency Questionnaires, American Journal of Epidemiology, 154: 1089-1099, 2001.

[35] "Food frequency questionnaires require validation prior to or as a part of dietary research. The approach taken in most studies is to examine the concordance of food frequency responses with reference instruments such as multiple 24 hour recalls or diet records using measurement error models to estimate the correlations between nutrient intakes measured by food frequency questionnaires and truth." Subar, A., et al., Comparative validation of the Block, Willett, and National Cancer Institute Food Frequency Questionnaires, American Journal of Epidemiology, 154: 1089-1099, 2001.

[36] Relative risk is expressed as the ratio of the risk (incidence) in exposed individuals to that in unexposed individuals (Epidemiology Beyond the Basics, page 93, Aspen Publishers, 2000). It is calculated in prospective studies by measuring exposure (e.g. lycopene intake) in subjects with and without disease (e.g. specific type of cancer). An adjusted relative risk controls for potential confounders. Confidence intervals provide a statistical analysis (p value) of relative risk. 95% Confidence intervals that include 1.0 are not statistically significant. "CI" stands for a Confidence interval.

[37] See supra, note 11.

[38] See supra, note 12.

[39] FDA also notes that there were no studies that evaluated the relationship between the consumption of a group of lycopene-containing fruits and vegetables and prostate cancer.

[40] See supra, note 4.

[41] See supra, note 4.

huangblue / life

番茄红素 #150

番茄红素

番茄红素大品牌

Lycopene

https://www.fda.gov/Food/IngredientsPackagingLabeling/LabelingNutrition/ucm072767.htm FDA回复

https://www.fda.gov/Food/IngredientsPackagingLabeling/LabelingNutrition/ucm072767.htm FDA回复