Scientific Opinion on the re‐evaluation of mixed carotenes (E 160a (i)) and beta‐carotene (E 160a (ii)) as a food additive
2012; Wiley; Volume: 10; Issue: 3 Linguagem: Inglês
10.2903/j.efsa.2012.2593
ISSN1831-4732
Tópico(s)Dye analysis and toxicity
ResumoEFSA JournalVolume 10, Issue 3 2593 OpinionOpen Access Scientific Opinion on the re-evaluation of mixed carotenes (E 160a (i)) and beta-carotene (E 160a (ii)) as a food additive EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS), EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS)Search for more papers by this author EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS), EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS)Search for more papers by this author First published: 14 March 2012 https://doi.org/10.2903/j.efsa.2012.2593Citations: 20 Panel members: F. Aguilar, R. Crebelli, B. Dusemund, P. Galtier, J. Gilbert, D.M. Gott, U. Gundert-Remy, J. König, C. Lambré, J-C. Leblanc, A. Mortensen, P. Mosesso, D. Parent-Massin, I.M.C.M. Rietjens, I. Stankovic, P. Tobback, D. H Waalkens-Berendsen, R.A. Woutersen, M. C. Wright Correspondence: [email protected] Acknowledgement: The Panel wishes to thank the members of the Working Group B on Food Additives and Nutrient Sources added to Food: F. Aguilar, R. M. Bakker, Crebelli, B. Dusemund, J. Gilbert, D. Gott, T. Hallas-Møller, J. König, D. Marzin, I. Meyland, A. Mortensen, I. Pratt, D. H. Waalkens-Berendsen and R. A. Woutersen for the preparatory work on this scientific opinion. Adoption date: 16 February 2012 Published date: 14 March 2012 Question number: EFSA-Q-2011-00354, EFSA-Q-2011-00431 On request from: European Commission AboutPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract The Panel on Food Additives and Nutrient Sources added to Food provides a scientific opinion re-evaluating the safety of mixed carotenes [E 160a (i)] and β-carotene [E 160a (ii)] when used as food colouring substances. Mixed carotenes [E 160a (i)] and β-carotene [E 160a (ii)] are authorised as food additives in the EU and have been evaluated previously by the JECFA the latest in 2001 and by the SCF in 1997 and 2000. Both Committees established an Acceptable Daily Intake (ADI) of 0–5 mg/kg bw/day. In this opinion the mixed carotenes are defined according to the Commission Directive 2008/128/EC and consist of two groups of substances: plant carotenes and algal carotenes. β-Carotene comprises (synthetic) β-carotene and β-carotene obtained by fermentation of the fungus Blakeslea trispora. The Panel noted (i) that the specifications of mixed carotenes are inadequate and need to be updated, (ii) that most toxicological studies have been performed with rodents, although rodents, in contrast to humans, very efficiently convert β-carotene to vitamin A. The Panel concluded that based on the presently available dataset, no ADIs for mixed carotenes and β-carotene can be established and that the use of (synthetic) β-carotene and mixed β-carotenes obtained from palm fruit oil, carrots and algae as food colour is not of safety concern, provided the intake from this use as a food additive and as food supplement, is not more than the amount likely to be ingested from the regular consumption of the foods in which they occur naturally (5–10 mg/day). This would ascertain that the exposure to β-carotene from these uses would remain below 15 mg/day, the level of supplemental intake of β-carotene for which epidemiological studies did not reveal any increased cancer risk. Furthermore, the Panel could not conclude on the safety in use of mixed carotenes [E 160a (i)] References Abrahamson IA Sr and Abrahamson IA Jr, 1962. Hypercarotenemia. Archives of Ophthalmology 68, 4– 7. Agarwal K, Mukherjee A and Sharma, A, 1993. In vivo cytogenetic studies on male mice exposed to Ponceau 4R and β-carotene. Cytobios 74, 23– 28. Aidoo A, Lyn-Cook LE, Lensing S, Bishop ME and Wamer W, 1995. In vivo antimutagenic activity of in rat spleen. Carcinogenesis 16, 2237– 2241. Abstract only. Alabaster O, Tang Z, Frost A, Shivapurkar N, 1995. Effect of beta-carotene and wheat bran fiber on colonic aberrant crypt and tumor formation in rats exposed to azoxymethane and high dietary fat. Carcinogenesis 16 (1), 127– 32. Alam BS, Alam SQ and Weir JC, 1988. Effects of excess vitamin A and canthaxanthin on salivary gland tumors. Nutrition and Cancer 11, 233– 241. Alam BS, Alam SQ, 1987. The effect of different levels of dietary beta-carotene on DMBA-induced salivary gland tumors. Nutrition and Cancer 9 (2–3), 93– 101. Alam SQ, Alam BS, Chen TW, 1984. Activities of fatty acid desaturases and fatty acid composition of liver microsomes in rats fed beta-carotene and 13-cis-retinoic acid. Biochimica et Biophysica Acta-BBA 792 (2), 110– 7. Alija AJ, Bresgen N, Sommerburg O, Langhans CD, Siems W and Eckl PM, 2006. Beta-carotene breakdown products enhance genotoxic effects of oxidative stress in primary rat hepatocytes. Carcinogenesis 27 (6), 1128– 1133. Alija AJ, Bresgen N, Sommerburg O, Langhans CD, Siems W and Eckl PM, 2005. Cyto- and genotoxic potential of β-carotene and cleavage products under oxidative stress. Biofactors 24 (1–4), 159– 163. Alija AJ, Bresgen N, Sommerburg O, Siems W and Eckl PM, 2004. Cytotoxic and genotoxic effects of beta-carotene breakdown products on primary rat hepatocytes. Carcinogenesis 25 (5), 827– 831. Al-Wadei HA, Takahashi T and Schuller HM, 2006. Growth stimulation of human pulmonary adenocarcinoma cells and small airway epithelial cells by beta-carotene via activation of cAMP, PKA, CREB and ERK1/2. International Journal of Cancer 118 (6), 1370– 1380. Appel MJ, Woutersen RA, 1996. Effects of dietary beta-carotene and selenium on initiation and promotion of pancreatic carcinogenesis in azaserine-treated rats. Carcinogenesis 17 (7), 1411– 6. Appel MF, van Garderen-Hoetmer, Woutersen RA, 1991. Lack of inhibitory effects of p-carotene, vitamin C, vitamin E and selenium on development of ductular adenocarcinomas in exocrine pancreas of hamster. Cancer Letters 103, 157– 162. Aruga F, 1988. Mutagenicity test of Dunaliella bardawil paste with Salmonella typhimurium and Escherichia coli. Nihon Bioresearch Center Inc. Hashima, Gifu, Japan, as submitted to WHO by Nikken Sohonsha Corporation, Hashim-City, Japan. Aruga F, 1987. Acute oral toxicity study on Dunaliella bardawil spray dried powder in mice. Nihon Bioresearch Center Inc. Hashima, Gifu, Japan, as submitted to WHO by Nikken Sohonsha Corporation, Hashim-City, Japan. Astorg P, Gradelet S, Bergès R, Suschetet M, 1996. No evidence for an inhibitory effect of beta-carotene or of canthaxanthin on the initiation of liver preneoplastic foci by diethylnitrosamine in the rat. Nutrition and Cancer 25 (1): 27– 34. Astorg P, 1997. Food carotenoids and cancer prevention: An overview of current research. Trends in Food Science & Technology, December 1997, Vol. 8, 406– 413. ATBC Study group (The Alpha-Tocopherol, β-carotene Cancer Prevention Study Group), 1994. The effects of vitamin E and β-carotene on the incidence of lung cancer and other cancers in male smokers. New England Journal of Medicine. 330, 1029– 1356. Auckland G, 1952. A case of carotinaemia. British Medical Journal 2, 267– 268. Azuine MA, Goswami UC, Kayal JJ, Bhide SV, 1992. Antimutagenic and anticarcinogenic effects of carotenoids and dietary palm oil. Nutrition and Cancer 17 (3), 287– 95. Bagdon RE, Zbinden G and Studer A, 1960. Chronic toxicity studies of beta-carotene. Toxicology and Applied Pharmacology 2, 223– 236. Baron JA, Cole BF, Mott L, Haile R, Grau M, Church TR, Beck GJ and Greenberg ER, 2003. Neoplastic and antineoplastic effects of beta-carotene on colorectal adenoma recurrence: results of a randomized trial. Journal of the National Cancer Institute 95 (10), 717– 722. Bauernfeind JC, Adams CR and Marusich WL, 1981. Carotenes and other vitamin A precursors in animal feed. In: Carotenoids as colorants and vitamin A precursors, ed. J.C. Bauernfeind, New York, Academic Press, pp. 563– 743. Beems RB, 1987. The effect of β-carotene on BP-induced respiratory tract tumors in hamsters. Nutrition and Cancer 10, 197– 204. Ben-Amotz A, Mokady S and Avron M, 1988. The β-carotene-rich alga Dunaliella bardawil as a source of retinol in a rat diet. British Journal of Nutrition 59, 442– 449. Ben-Amotz A, Edelstein S and Avron M, 1986. Use of the β-carotene rich alga Dunaliella bardawil as a source of retinol. British Poultry Science 27, 613– 619. Bernhard K, 1963. Wiss. Veröff. Dtsch. Gesellsch. Ernährung, 9, 169. BIBRA, 1996. British Industrial Biological Research Association working group. Toxicity profiles, beta-apo-8'-carotenal, ethyl-beta-apo-8'-carotenal, ethyl-beta-apo-8'-carotenoat and methyl beta-apo-8'-carotenoate. Blot WJ, Li JY, Taylor PR, Guo W, Dawsey S et al., 1993. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. Journal of the National Cancer Institute 85, 1483– 91. Bohlke K, Spiegelma D, Trichopoulou A, Katsouyanni K and Trichopoulos D, 1999. Vitamins A, C and E and the risk of breast cancer: results from a case-control study in Greece. British Journal of Cancer 79, 23– 29. Boon CS, McClements DJ, Weiss J and Decker E, 2010. Factors Influencing the Chemical Stability of Carotenoids in Foods. Critical Reviews in Food Science and Nutrition, Volume 50, 515– 532. Buser SM and Arceo RG, 1995. Subchronic (13-week) oral study with β-carotene as a feed admixture in the rat. Unpublished Report No. B-161'158. Buser S and Hummler H, 1983. The Effect of Beta-Carotene in a combined Tumorigenicity and Toxicity Study in Rats. Unpublished Report No. B-104 701. ChemIDplus Advanced (via Internet, 2008). Accessible via: chem.sis.nlm.nih.gov/chemidplus/ Cifone MA, 1987. Mutagenicity test on EK 87–0048 B-CAT in the rat primary hepatocyte unscheduled DNA synthesis assay. Unpublished report of Hazleton Laboratories America Inc. Submitted to WHO by Eastman Kodak Co., Rochester, NY, USA. Colacchio TA, Memoli VA, Hildebrandt L, 1989. Antioxidants vs. carotenoids. Inhibitors or promoters of experimental colorectal cancers. Archives of Surgery 124 (2), 217– 21. Colacchio TA and Memoli VA, 1986. Chemoprevention of colorectal neoplasms. Ascorbic acid and beta-carotene. Archives of Surgery 121 (12), 1421– 4. Cooper DA, Eldridge AL, Peters JC, 1999. Dietary carotenoids and certain cancers, heart disease, and age-related macular degeneration: a review of recent research. Nutrition Rewiew 57, 201– 214. Cozzi R, Ricordi R, Aglitti T, Gatta V, Perticone P and De Salvia R, 1997. Ascorbic acid and β-carotene as modulators of oxidative damage. Carcinogenesis 18, 223– 228. Cyanotech, 1988. Ten-day Konatene (TM) feeding study: effects on serum beta-carotene levels. Unpublished summary report submitted to WHO by Cyanotech Corporation, Woodinville, Washington, USA. Druesne-Pecollo N, Latino-Martel P, Norat T, Barrandon E, Bertrais S, Galan P and Hercberg S, 2010. Beta-carotene supplementation and cancer risk: a systematic review and metaanalysis of randomized controlled trials. International Journal of Cancer 127, 172– 184. European Commission, 2001. Commission of the European Communities (COM). 542 final. Report from the Commission on dietary food additive intake in the European Union. Brussels. eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=iOM:2001:0542:FIN:EN:PDF European Commission, 1997. Food Science and Techniques. Reports on Tasks for Scientific Cooperation (SCOOP). Report of Experts participating in task 4.2. Report on the Methodologies for the Monitoring of Food Additive Intake across the European Union. Directorate General Industry. December 1997. Elmadfa I, 2009. European Nutrition and Health Report 2009. Forum of Nutrition Vol 62, Karger, Basel. Ernst, H. 2002. Recent advances in industrial carotenoid synthesis. Pure Applied Chemistry Vol. 74, 11, 2213– 2226. Expert Group on Vitamins and Minerals (EVN). Safe upper levels of vitamins and minerals. Food Standards Agency, United Kingdom, 2003. Fraps GS and Meinke WW, 1945. Archives of Biochemistry 6, 323. Furuhashi T, 1989. Twenty-eight-day oral subacute toxicity study on Dunaliella bardawil. Nihon Bioresearch Center Inc., Hashima, Gifu, Japan, as submitted to WHO by Nikken Sohonsha Corporation, Hashima-City, Japan. Furukawa F, Nishikawa A, Kasahara K, Lee IS, Wakabayashi K, Takahashi M and Hirose M, 1999. Inhibition by β-carotene of upper respiratory tumorigenesis in hamsters receiving diethylnitrosamine followed by cigarette smoke exposure. Japanese Journal of Cancer Research 90, 154– 161. Fuster A, Picó C, Sánchez J, Oliver P, Zingaretti MC, Murano I, Morroni M, Hoeller U, Goralczyk R, Cinti S, Palou A, 2008. Effects of 6-month daily supplementation with oral beta-carotene in combination or not with benzo[a]pyrene on cell-cycle markers in the lung of ferrets. Journal of Nutritional Biochemistry 19, 295– 304. Gallandre F, 1979. Mutagenicity studies with Ro 01–8300 in Mammalian Systems. Unpublished Report N. B-90-155. Gärtner C, Stahl W, Sies H, 1996. Preferential increase in chylomicron levels of the xanthophylls lutein and zeaxanthin compared to beta-carotene in the human. International Journal for Vitamin and Nutrition Research 66 (2), 119– 25. Ghazi A, De Lumen B and Oswald WJ, 1992. Comparative bioavailability of beta-carotene from Dunaliella salina, Dunaliella salina extract, carrot extract and synthetic beta-carotene. Report submitted to WHO by Microbio Resources, Inc., San Diego, CA USA. Graffin B, Genty I, Cretel E, Rodolphe J and Durand JM, 2002. Case report – Carotene-induced hepatic fibrosis. Digestive Diseases Science 47, 793. Greenberg ER, Baron JA, Tosteson TD, Freeman DH Jr, Beck GJ et al., 1994. A clinical trial of antioxidant vitamins to prevent colorectal adenoma. New England Journal of Medicine 331, 141– 147. Greenberg ER, Baron JA, Stukel TA, Stevens MM, Mandel JS et al., 1990. A clinical trial of β-carotene to prevent basal-cell and squamous-cell cancers of the skin. New England Journal of Medicine 323, 789– 795. Greenberg R, Cornbleet T and Joffay AI, 1959. Accumulating and excretion of vitamin a-like fluorescent material by sebaceous glands after the oral feeding of various carotenoids. Journal of Investigative Dermatology 32, 599– 604. Gregory JR, Foster K, Tyler H and Wiseman M, 1990. The Dietary and Nutritional Survey of British Adults, London, Her Majesty's Stationery Office. Gugger ET, Bierer TL, Henze TM, White WS and Erdman JW, 1992. β-Carotene uptake and tissue distribution in ferrets (Mustela putorius furo). The Journal of Nutrition 122, 115– 119. Hansgeorg E, 2002. Recent advances in industrial carotenoid synthesis. Pure Applied Chemistry, 74, 11, 2213– 2226. IARC, 1998. International Agency for Research on Cancer; Working group on the Evaluation of Cancer Preventive Agents. IARC: Handbooks of cancer prevention, Vol. 2: carotenoids. IARC press, Lyon, France. Ivett JL, 1987. Mutagenicity test on EK 87–0047, corn oil control and EK 87–0048, B-CAT in the in vivo mouse micronucleus assay. Unpublished report of Hazleton Laboratories America Inc. submitted to WHO by Eastman Kodak Co., Rochester, NY, USA. Jagannath DR, 1987. Mutagenicity test on EK 87–0048 B-CAT in the Ames Salmonella/microsome reverse mutation assay. Unpublished report of Hazleton Laboratories America Inc. submitted to WHO by Eastman Kodak Co., Rochester, NY, USA. JECFA (Joint FAO/WHO Expert Committee on Food Additives), 2006. Combined compendium of food additive specifications - all specifications monographs from the 1st to the 65th meeting (1956–2005). FAO JECFA Monographs Series, No. 1 Volume 1–3, 2006. JECFA, 2001. WHO/FAO Joint Expert Committee on Food Additives. Safety evaluation of certain food additives and contaminants. WHO Food additives series, 48. JECFA, 1993. WHO/FAO Joint Expert Committee on Food Additives. Toxicological evaluation of certain food additives and contaminants. WHO Food additives series, 32. JECFA, 1975. WHO/FAO Joint Expert Committee on Food Additives. Toxicological evaluation of some food colours, enzymes, flavour enhancers, thickening agents and certain food additives. WHO Food additives series, 6. Jensen CD, Howes TW, Spiller GA, Pattison TS, Whittam JH and Scala J, 1987. Observations on the effects of ingesting cis- and trans-beta-carotene isomers on human serum concentrations. Nutrition Reports International 35, 413– 422. Jensen CD, Spiller GA, Pattison TS, Whittam JH and Scala J, 1986. Acute effects of dietary carotenes on serum alpha and beta carotene in humans. Nutrition Reports International 33, 117– 122. Jensen CD, Pattison TS, Spiller GA, Whittam JH and Scala J, 1985. Repletion and depletion of serum alpha and beta carotene in humans with carrots and an algae-derived supplement. Acta Vitaminologica et Enzymologica 7, 189– 198. Jones RC, Sugie S, Braley J, Weisburger JH, 1989. Dietary beta-carotene in rat models of gastrointestinal cancer. Journal of Nutrition 119 (3), 508– 14. Jonker, 1997. Sub-acute oral toxicity study with beta-carotene in rats. TNO report V96.889 Kalariya NM, Ramana KV, Srivastava SK, van Kuijk FJ, 2009. Genotoxic effects of carotenoid breakdown products in human retinal pigment epithelial cells. Current Eye Research 34 (9): 737– 47. Kim Y, Liu XS, Liu C, Smith DE, Russell RM, Wang XD, 2006. Induction of pulmonary neoplasia in the smoke-exposed ferret by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK): a model for human lung cancer. Cancer Letters 234 (2), 209– 19. Kistler A, 1982. Embryotoxicity study in rabbits with oral administration of Ro 01–8300, beta-carotene. Phase II – Teratological study. Unpublished Report Nr. B-46 351. Kistler A, 1981. Embryotoxicity study in rats with oral administration of Ro 01–8300, beta-carotene. Phase II – Teratological study with postnatal evaluation. Unpublished Report Nr. B-94 683. Klipstein-Grobusch K, Geleijnse JM, den Breeijen JH, Boeing H, Hofman A, Grobbee DE and Witteman JC, 1999. Dietary antioxidants and risk of myocardial infarction in the elderly: the Rotterdam study. American Journal of Clinical Nutrition 69, 261– 266. Kluifthoof JD, 2001. Unpublished data submitted to WHO by DSM Food Specialties. Komatsu S, 1971. Teratogenic effects of vitamin A: effect of β-carotene. Shika Gakuho 71, 2067– 1074. Krinsky NI, Mathews-Roth MM, Welankiwar S, Sehgal PK, Lausen NCG, Russett M, 1990. The metabolism of [14-C]β-carotene and the presence of other carotenoids in rats and monkeys. Journal of Nutrition 120, 81– 87. Kübler W, 1963. Wiss. Veröff. Dtsch. Gesellsch. Ernährung. 9, 222. Kuroiwa Y, Nishikawa A, Imazawa T, Kitamura Y, Kanki K, Ishii Y, Umemura T and Hirose M, 2006. A subchronic toxicity study of Dunaliella carotene in F344 rats. Food and Chemical Toxicology 44 (1), 138– 145. Lahiri M, Maru GB and Bhide SV, 1993. Effect of plant phenols, β-carotene and a-tocopherol on benzo[a]pyrene-induced DNA damage in mouse forestomach mucosa (target organ) and bone marrow polychromatic erythrocytes (non-target organ). Mutation Research 303, 97– 100. Langouët S, Mican AN, Müller M, Fink S P, Marnett JL, Muhle SA and Guengerich FP, 1998. Biochemistry 37, 5184– 5193. Leo MA and Lieber CS, 1999. Alcohol, vitamin A, and beta-carotene: adverse interactions, including hepatotoxicity and carcinogenicity. American Journal of Clinical Nutrition 69 (6), 1071– 1085. Li JY, Taylor PR, Li B, Dawsey S, Wang GQ et al., 1993. Nutrition intervention trials in Linxian, China: multiple vitamin/mineral supplementation, cancer incidence and disease specific mortality among adults with esophageal dysplasia. Journal of the National Cancer Institute 85, 1492– 1498. Liu C, Russell RM, Wang XD, 2004. Alpha-tocopherol and ascorbic acid decrease the production of beta-apo-carotenals and increase the formation of retinoids from beta-carotene in the lung tissues of cigarette smoke-exposed ferrets in vitro. Journal of Nutrition 134 (2), 426– 30. Liu C, Russell RM, Wang XD, 2003. Exposing ferrets to cigarette smoke and a pharmacological dose of beta-carotene supplementation enhance in vitro retinoic acid catabolism in lungs via induction of cytochrome P450 enzymes. Journal of Nutrition 133 (1), 173– 9. Liu C, Wang XD, Bronson RT, Smith DE, Krinsky NI, Russell RM, 2000. Effects of physiological versus pharmacological beta-carotene supplementation on cell proliferation and histopathological changes in the lungs of cigarette smoke-exposed ferrets. Carcinogenesis 21 (12), 2245– 53. Lock S, 1985. Fourteen days oral rat testing using dried Dunaliella cells. BioMed No. 4476. Unpublished summary report of Biomed Research Laboratories Inc. submitted to WHO by Cyanotech Corporation, Woodinville, Washington, USA. Lowe G.M., Booth LA, Young AJ and Bilton RF, 1999. Lycopene and beta carotene protect against oxidative damage in HT29 cells at low concentrations but rapidly lose this capacity at higher doses. Free Radical Research 30, 141– 151. Majnarich JJ, 1988. Subchronic oral toxicity (12 week) study of algal beta carotene fed to male and female Sprague-Dawley rats. Unpublished report of Biomed Research Laboratories Inc. submitted to WHO by Cyanotech Corporation, Woodinville, Washington, USA. Manoharan K and Banerjee MR, 1985. Beta-carotene reduces sister chromatid exchanges induced by chemical carcinogens in mouse mammary cells in organ culture. Cell Biology International Report 9, 783– 789. Marques SA, Loureiro AP, Gomes OF, Garcia CC, Di Mascio P and Medeiros MH, 2004. Induction of 1,N2-etheno-2'-deoxyguanosine in DNA exposed to β-carotene oxidation products. FEBS Letters 560 (1–3), 125– 130. Mathews-Roth MM, 1993. Carotenoids in erythropoietic protoporphyria and other photosensitivity diseases. Annals of the New York Academy of Sciences 691, 127– 138. Mathews-Roth MM, Lausen N, Drouin G, Richter A, Krinsky NI, 1991. Effects of carotenoid administration on bladder cancer prevention. Oncology 48 (3), 177– 9. Mathews-Roth MM, Krinsky NI, 1987. Carotenoids affect development of UV-B induced skin cancer. Photochemistry and Photobiology 46 (4), 507– 9. Mayne ST, 1996. Beta-carotene, carotenoids, and disease prevention in humans. FASEB J. 10, 690– 701. McLarty JW, 1992. An intervention trial in high risk asbestos exposed persons. Advances in Experimental Medicine and Biology 320, 141– 149. Merck Index, 2006. 14th Edition. Published by Merck Research Laboratories, Division of Merck & Co. Inc., Whitehouse Station, NJ, USA. Merkle J, Kirsch P, Dèckardt K, Freisberg KO, Hempel K-J, 1980. Bericht über die Prüfung der Toxizität von beta-carotin-Trockenpulver im 4-Wochen-Fütterungsversuch an der ratte. BASF-report 25698n 5M 7107. Meyers DG, Maloley RA and Weeks D, 1996. Safety of antioxidant vitamins. Archives of Internal Medicine. 156, 925– 935. Mokady S, Abramovici A and Cogan U, 1989. The safety evaluation of Dunaliella bardawil as a potential food supplement. Food and Chemical Toxicology 27, 221– 226. Moon RC, 1994. Chemoprevention of respiratory tract neoplasia in the hamster by oltipraz, alone and in combination. International Journal of Oncology 4, 661– 667. Mordi RC, Walton JC, Burton GW, Hughes L, Ingold KU and Lindsay DA, 1991. Exploratory study of β-carotene autoxidation. Tetrahedron Letters, Vol. 32, 33, 4203– 4206. Moreno FS, Wu TS, Penteado MV, Rizzi MB, Jordão Júnior AA, Almeida-Muradian LB, Dagli ML, 1995. A comparison of beta-carotene and vitamin A effects on a hepatocarcinogenesis model. International Journal for Vitamin and Nutrition Research 65 (2), 87– 94. Moreno FS, Rizzi MB, Dagli ML, Penteado MV, 1991. Inhibitory effects of beta-carotene on preneoplastic lesions induced in Wistar rats by the resistant hepatocyte model. Carcinogenesis. 12 (10), 1817– 22. Mukherjee A, Agarwal K, Aguilar MA and Sharma A, 1991. Anticlastogenic activity of β-carotene against cyclophosphamide in mice in vivo. Mutation Research 263, 41– 46. Murakoshi M, Nishino H, Satomi Y, Takayasu J, Hasegawa T, Tokuda H, Iwahima A, Okuzumi J, Okabe H, Kitano H and Iwasaki R, 1992. Potent preventive action of a-carotene against carcinogenesis: spontaneous liver carcinogenesis and promoting stage of lung and skin carcinogenesis in mice are suppressed more effectively by a-carotene than by β-carotene. Cancer Research 52, 6583– 6587. Nabae K, Ichihara T, Hagiwara A, Hirota T, Toda Y, Tamano S, Nishino M, Ogasawara T, Sasaki Y, Nakamura M and Shirai T, 2005. A 90-day oral toxicity study of beta-carotene derived from Blakeslea trispora, a natural food colorant, in F344 rats. Food and Chemical Toxicology 43 (7), 1127– 1133. Nagasawa H, Fuji Y, Yamamoto K, Konoshi R and Ben-Amotz A, 1989. No deleterious side-effects on mammary growth and endocrine parameters of chronic ingestion of beta-carotene-rich alga Dunaliella bardawil in virgin mice in comparison with synthetic all- trans beta-carotene. The Cancer Journal 2, 391– 394. Ni R, Leo MA, Zhao J and Lieber CS, 2001. Toxicity of beta-carotene and its exacerbation by acetaldehyde in HepG2 cells. Alcohol and Alcoholism 36 (4), 281– 285. Nieman C and Obbink HJ, 1954. The biochemistry and pathology of hypervitaminosis A. Vitamins and Hormones 12, 69– 99. Nishino H, 1995. Cancer chemoprevention by natural carotenoids and their related compounds. Journal of Cellular Biochemistry - Supplement 22, 231– 235. Olmedilla B, Granado F, Blanco I, Rojas-Hidalgo E, 1994. Seasonal and sex related variations in six serum carotenoids, retinol, and $aL-tocopherol. The American Journal of Clinical Nutrition 60, 106– 110. Olmos J, Ochoa L, Paniagua-Michel J, Contrera R, 2009. DNA fingerprinting differentiation between β-carotene hyperproducer strains of Dunaliella from around the world. Saline Systems 5. Omenn GS, 1998. Chemoprevention of lung cancer: the rise and demise of β-carotene. Annual Review of Public Health 19, 73– 99. Omenn GS, Goodman GE, Thornquist M, Balmes J, Cullen MR, Glass A, Keogh JP, Meyskens FL, Valanis B, Williams JH, Barnhart S and Hammar S, 1996a. Effects of a combination of β-carotene and vitamin A on lung cancer incidence, total mortality, and cardiovascular mortality in smokers and asbestos-exposed workers. The New England Journal of Medicine 334, 1150– 1155. Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, Keogh JP, Meyskens FL, Valanis B, Williams JH, Barnhart S, Cherniack MG, Brodkint CA and Hammar S, 1996b. Risk factors for lung cancer and for intervention effects in CARET, the beta-carotene and retinol efficiency trial. Journal of the National Cancer Institute 88, 1550– 1559. Paolini M, Antelli A, Pozzetti L, Spetlova D, Perocco P, Valgimigli L, Pedulli GF and Cantelli-Forti G, 2001. Induction of cytochrome P450 enzymes and over-generation of oxygen radicals in beta-carotene supplemented rats. Carcinogenesis 22 (9), 1483– 1495. Pedersen AN, Fagt S, Velsing Groth M, Christensen T, Biltoft-Jensen A, Matthiessen J, Andersen NL, Kørup K, Hartkopp H, Hess Ygil K, Hinsch HJ, Saxholt E, Trolle E, 2010. Danskernes kostvaner 2003–2008. Danmarks Tekniske Universitet, Søborg, Denmark. Pedrick MS, Turton JA, Hicks RM, 1990. The incidence of bladder cancer in carcinogen-treated rats is not substantially reduced by β-carotene (BC). Eight Eur. Fat Soluble Vitamins Group Meeting (Abstract) p. 189. Ph. Eur., 2008. European Pharmacopoeia, 6th edition, Govi Verlag, Eschborn, Germany. Poor CL, Bierer TL, Merchen NR, Fahey GC, Murphy M, Erdman JW, 1992. Evaluation of the preruminant calf as a model for the study of human carotenoid metabolism. Journal of Nutrition 122, 262– 268. Raj AS and Katz M, 1985. Beta-carotene as an inhibitor o
Referência(s)