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Beta-Carotene and Carotenoids

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Carrots

Introduction:

Beta-carotene is a pigment which produces the orange color in carrots, sweet potatoes and pumpkins but is also found in other fruits and vegetables such as spinach, kale and beet greens. A breakdown in concentration of beta-carotene in foods is represented below from the United States Department of Agriculture (USDA).

Excess beta-carotene may produce a temporary orange coloration of the skin which is not known to be harmful and may improve the healthy appearance of the skin.

Most research not only failed to show any benefit with beta-carotene supplements, but also was associated with certain cancers and increased mortality rates.

Beta-carotene is best consumed from fruit and vegetable sources, has numerous health benefits, and is a safe way to ensure intake of vitamin A since regular vitamin A intake can be associated with liver toxicity.

Beta-carotene is readily converted to vitamin A in the gastrointestinal tract but will not lead to vitamin A toxicity because lesser amounts of beta-carotene is converted to vitamin A as beta-carotene intake increases.

 

Beta-carotene in foods:

For a breakdown of concentration of beta-carotene in foods, please see below or click the following links: Nutritive Value of Foods, United States Department of Agriculture, Agricultural Research Service, Home and Garden Bulletin Number 72. This may be accessed at: https://www.ars.usda.gov/SP2UserFiles/Place/12354500/Data/SR25/nutrlist/sr25w321.pdf  and http://www.nal.usda.gov/fnic/foodcomp/Data/HG72/hg72_2002.pdBeta-carotene in food sources vs. supplements for cardiovascular disease:

 

Beta-carotene in food sources vs. supplements and cardiovascular disease risk:

Intake of vegetables containing beta carotene was associated with a lower risk of cardiovascular mortality and with a lower risk for all causes of death but no benefit was seen with taking beta-carotene supplements. Greenberg ER et al tested beta carotene levels in subjects prior to being randomized for a study. Subjects with an initial beta carotene level of 0.34 to 0.52 micromol/L had a 43% less risk of death from cardiovascular disease when compared to subjects with the lowest intial beta carotene levels of under 0.21 umol/L. Those subjects with an intitial beta carotene level of over 0.52 micromol/L had a lower risk of death from all causes. There was no reduced risk of disease or mortality benefit in subjects who took beta carotene supplements in pill form. (1)

 

Beta-carotene supplements:

Beta-carotene supplements are not advised among healthy individuals, unless they suffer from or are at risk of vitamin A deficiency. Beta-carotene supplementation results in a greater increase of beta-carotene blood concentration than beta-carotene rich foods. A 20 mg/d supplement of beta-carotene can result in blood concentrations high enough to increase a patient\’s risk of lung cancer, while the same quantity obtained from foods was not associated with lung cancer risk. Additionally, 30 mg/d of beta-carotene supplement was associated with blood concentrations 5 times greater than that of 29 mg/d of beta-carotene from carrots. The consumption of 5 or more daily servings of fruits and vegetables is recommended by “National Cancer Institute\’s Five-A-Day for a Better Health program” and “Canada\’s Food Guide for Healthy Eating.” Eating a variety of 5 fruits and vegetables per day provides the individual with about 5.2 to 6 mg/day of food based beta-carotene. This allows plasma carotenoid levels to rise above a range represented in studies which were associated with a lower risk of coronary heart disease and all-cause mortality compared to those with a lower food based carotenoid levels. (2)

 

Establishing beta-carotene levels from food sources:

According to Martini et al in the University of Minnesota Cancer Prevention Research Unit Feeding Studies, an intake of 5 mg per day of beta carotene from food sources was required to establish beta carotene levels to a plasma level of 0.37 umol/L. When food based beta carotene was consumed in amounts over 42 mg per day, levels increased to 0.83 umol/L. (4)

 

The Beta-Carotene and Retinol Efficacy Trial:

The Beta-Carotene and Retinol Efficacy Trial (CARET), showed that among 18,314 men and women who smoked heavily or were exposed to asbestos, daily intake of 30 mg (100,000 IU) of beta-carotene and 25,000 IU vitamin A failed to decrease the risk of heart disease. The study was stopped early because it showed that beta-carotene/vitamin A supplement users who were heavy smokers, ex-smokers or asbestos workers were showing a 28% increased risk of lung cancer in smokers (versus placebo) and a 17% more likely chance of dying, mostly of lung cancer or heart disease.  Results of a 6-year follow-up of study participants showed that compared to the placebo or no intervention group, participants who had taken the intervention had a 12% and 8% increase in relative risk of lung cancer and all-cause mortality among the intervention group, respectively. Researchers also found that after the intervention was stopped relative risk of cardiovascular disease mortality dropped and there was no difference in risk between the two groups. Finally, they found that women were more affected by the supplements with a larger relative risk of cardiovascular disease mortality (1.44 versus 0.93; P = .03), and all-cause mortality (1.37 versus 0.98; P = .001) than males. (3)

 

Antioxidants and mortality:

A meta-analysis that included 78 randomized clinical trials was conducted to determine the relationship of oral antioxidant supplementation (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) and mortality. Mean duration of supplementation was 3 years. When all of the trials were combined, and the analysis that is typically used when similarity is present was conducted (fixed-effect model), antioxidant use did slightly increase mortality. When the trials with low risks of bias were considered, the patients consuming the antioxidants had a 4% higher risk of death compared to those taking placebo or no intervention (relative risk [RR]=1.04). The increased risk of mortality was significantly associated with use of beta-carotene (death rate: 13.8% on supplement vs 11.1% on placebo; RR=1.05) and vitamin E (12.0% vs 10.3%; RR=1.03) and possibly vitamin A, though the relationship was not significant with a 14.0% death rate among those taking vitamin A compared to a 13.6% death rate among placebo subjects. The current evidence does not support the use of these antioxidant supplements in the general population or in patients with various diseases. (5).

 

Lutein and zeaxanthin carotenoid vitamins:

Elderly individuals with specifically low lutein and zeaxanthin (which are carotenoid vitamins similar to beta-carotene), may face an increased risk of atrial fibrillation (an irregular heartbeat) according to a study that included 1,847 participants aged 61-82 years. The study calculated hazard ratios after adjusting for systolic bp, diabetes, age, smoking, diabetes, alcohol use, use of bp medication, gender, congestive heart failure, recurring atrial fibrillation, and myocardial infarction. The hazard ratio for lutein was 1.70 and for zeaxanthin it was 1.99. Lycopene, β-cryptoxanthin, α-carotene and total carotenoids were not found to be associated with the risk of atrial fibrillation. (14)

 

Beta-carotene and cancer:

Cancer risk and beta-carotene:

Cancer risk may be lower in those who consume beta-carotene containing foods. High blood concentrations of beta-carotene and other carotenoids, (plant pigments found in carrots, sweet potatoes, spinach, kale, collard greens, papaya, bell peppers, tomatoes), have been linked to a lower risk of cancer, especially lung, mouth, throat, and cervical cancers. A blood beta-carotene concentration less than 0.28 micromol/L has been linked with a higher risk of several cancers, while a concentration of more than 0.28 to 0.37 micromol/L have been associated with a reduced risk of several cancers in prospective blood concentration studies. However, three other large randomized studies reported no cancer benefit from beta-carotene supplements given at 20, 30, or 50 mg/d for 4 to 12 years. (2)

Beta-carotene supplements are not advised: Beta-carotene supplements are not advised among healthy individuals, unless they suffer from or are at risk of vitamin A deficiency. Beta-carotene supplementation results in a greater increase of beta-carotene blood concentration than beta-carotene rich foods. A 20 mg/d supplement of beta-carotene is associated with blood concentrations high enough to increase a patient\’s risk of lung cancer, while the same quantity obtained from foods was not associated with lung cancer risk. Additionally, 30 mg/d of beta-carotene supplement was associated with blood concentrations 5 times greater than that of 29 mg/d of beta-carotene from carrots. The consumption of 5 or more daily servings of fruits and vegetables is recommended by “National Cancer Institute\’s Five-A-Day for a Better Health program” and “Canada\’s Food Guide for Healthy Eating.” Eating a variety of 5 fruits and vegetables per day provides the individual with about 5.2 to 6 mg/day of food based beta-carotene. This allows plasma carotenoid levels to rise above a range represented in studies which were associated with a lower risk of cancer and all-cause mortality compared to those with a lower food based carotenoid levels. (2)

 

Intake of vegetables, beta-carotene, and risk of death:

Intake of vegetables containing beta carotene was associated with a lower risk for all causes of death including cancer but no benefit was seen with taking beta-carotene supplements. Greenberg ER et al tested beta carotene levels in subjects prior to being randomized to take beta carotene supplements. Subjects with an intial beta carotene level of 0.34 to 0.52 umol/L had a 51% less risk of dying from cancer when compared to subjects with the lowest intial beta carotene levels of under 0.21 umol/L. Those subjects with an intitial beta carotene level of over 0.52 umol/L had a lower risk of death from all causes. There was no reduced risk of disease or mortality benefit in subjects who took beta carotene supplements in pill form (1).

 

The Beta-Carotene and Retinol Efficacy Trial (CARET):

The CARET trial showed that among 18,314 men and women who smoked heavily or were exposed to asbestos, daily intake of 30 mg (100,000 IU) of beta-carotene and 25,000 IU vitamin A failed to decrease the risk of cancer. The study was stopped early because it showed that beta-carotene/vitamin A users who were heavy smokers, ex-smokers or asbestos workers were showing a 28% increased risk of lung cancer in smokers (versus placebo) and a 17% more likely chance of dying, mostly of lung cancer or heart disease.  Results of a 6-year follow-up of study participants showed that compared to the placebo or no intervention group, participants who had taken the intervention had a 12% and 8% increase in relative risk of lung cancer and all-cause mortality among the intervention group, respectively. They found that women were more affected by the supplements with a larger relative risk of lung cancer mortality (1.33 versus 1.14; P = .36), and all-cause mortality (1.37 versus 0.98; P = .001) than males. (3)

 

Beta-carotene supplements and cancer:

A review of 9 randomized controlled trials found that beta-carotene supplementation was not protective against primary cancer and may increase risk of lung and stomach cancers in smokers and asbestos workers. There was no statistically significant difference between the beta-carotene group and the placebo or no treatment group in the incidence of all-site cancer and of stomach, pancreas, colon-rectum, prostate, breast and skin cancers. However, the risk of lung cancer and stomach cancer were significantly higher in the beta-carotene at 20-30 mg day(-1)than the placebo group (relative risk [RR]=1.16 and RR=1.34, respectively). In subgroup analyses, among smokers and asbestos workers beta-carotene significantly increased the risk of all-site cancer (RR 1.08), lung cancer (RR 1.20) and stomach cancer (RR 1.54). In conclusion, beta-carotene supplementation should not be recommended for healthy individuals for the prevention of cancer. (10)

 

Beta-carotene and breast cancer:

According to a large prospective study of 83,234 women (aged 33-60 years old), consumption of foods rich in specific carotenoids (plant pigments found in carrots, sweet potatoes, spinach, kale, collard greens, papaya, bell peppers, tomatoes) and vitamins A, C, and E may reduce the risk of breast cancer among premenopausal women. Increased intake of lutein and zeaxanthin (both carotenoids), and vitamin A supplements, as well as beta-carotene from food were found to lower the risk of breast cancer in premenopausal women, but the link was found to be weak. However among women with a family history of breast cancer, this association was strong. Researchers reported that higher intake of beta-carotene was associated with a moderately reduced risk of breast cancer among women consuming 15 g/d of alcohol or more. Furthermore, premenopausal women eating at least 5 servings of fruits and vegetables per day had a significant reduction of breast cancer risk compared to women who had less than 2 servings per day. Premenopausal women with a family history of breast cancer who consumed more than 5 servings of fruits and vegetables per day received the greatest benefit from carotenoids with a moderately reduced risk of breast cancer. (11)

 

Beta-carotene, other antioxidants, and mortality:

A meta-analysis that included 78 randomized clinical trials was conducted to determine the relationship of oral antioxidant supplementation (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) and mortality. Mean duration of supplementation was 3 years. When all of the trials were combined, and the analysis that is typically used when similarity is present was conducted (fixed-effect model), antioxidant use did slightly increase mortality. When the trials with low risks of bias were considered, the patients consuming the antioxidants had a 4% higher risk of death compared to those taking placebo or no intervention (relative risk [RR]=1.04). The increased risk of mortality was significantly associated with use of beta-carotene (death rate: 13.8% on supplement vs 11.1% on placebo; RR=1.05) and vitamin E (12.0% vs 10.3%; RR=1.03) and possibly vitamin A, though the relationship was not significant with a 14.0% death rate among those taking vitamin A compared to a 13.6% death rate among placebo subjects. The current evidence does not support the use of these antioxidant supplements in the general population or in patients with various diseases. (5)

 

Mortality risk and beta-carotene from food vs. supplements:

The studies mentioned suggest a lower risk of mortality stems from beta-carotene intake from food sources rather than supplements which provides evidence that other phytonutrients contained in the food sources are translating to the benefits. It is also possible that high levels increase mortality. A similar effect is seen when vitamin D levels become high which results in an increased mortality rate. The benefit may also come from other substances in the vegetable food source and not necessarily the beta carotene itself.

 

Beta-carotene supplements:

A review and meta-analysis of 6 randomized controlled trials including 40,544 patients found no benefit of non-food beta-carotene supplementation on risk of cancer or cancer mortality. These results were confirmed in other primary and secondary prevention trials. Other analyses found that beta-carotene supplementation significantly increased the risk of urothelial cancer (cancer of the layer that lines the urinary tract, the bladder, and parts of the urethra), especially bladder cancer by 52%. Among current smokers, it also increased the risk of cancer by 7%. (13)

 

Beta-carotene and age related macular degeneration (AMD):

Beta-carotene plus other antioxidants for age related macular degeneration (AMD): Antioxidants have been shown to reduce the progression of age related macular degeneration (AMD) once it occurs. The antioxidants taken as part of the Age-Related Eye Disease Study (AREDS) included vitamin C, 500 mg; vitamin E, 400 IU; beta carotene, 15 mg; and zinc, 80 mg as zinc oxide with 2 mg of cupric oxide. Copper was added to prevent copper deficiency which can occur with high dose zinc intake. Subjects were followed for almost 7 years. A beneficial reduction of AMD progression was observed among subjects with Categories 3 and 4 AMD. There was no significant change seen in mild AMD subjects (Category 1 or 2) compared to placebo. The highest protective effect was seen the supplement treatment groups taking zinc plus antioxidants. OR=0.63 (99% CI; 0.44-0.92). The antioxidants have not yet been shown to prevent the development of AMD nor did they have any benefit in development of cataracts. (6)

 

Review of randomized controlled trials on antioxidants for age related macular degeneration (AMD):

A systematic review by Kansagara D et al evaluated seven randomized controlled trials which studied nutritional supplements in patients with AMD. The authors believed that studies with the longest duration and largest group of subjects were able to better identify benefit of the antioxidants because AMD occurs slowly. The smaller studies might have been of insufficient duration or power to detect a treatment effect. This review included the Age Related Eye Disease Study (AREDS) which demonstrated the antioxidants prevented functional vision loss. Additionally, lutein, zeaxanthin, B vitamins, and omega-3 fatty acids have also been reported to decrease AMD progression, while vitamin E and β-carotene where found to increase the risk of late AMD. (7)

 

The Age-Related Eye Disease Study (AREDS):

The AREDS found that subjects with AMD had an increase in mortality risk. After following patients for 6.5 years, 11% or 534 participants had died. This marked an increased mortality risk among participants with advanced AMD. However, participants randomly assigned to receive 80 mg zinc with 2 mg cupric oxide, whether alone or combined with antioxidants, had lower mortality than those not taking the mineral. In these AMD patients, they reported a 27% lower relative risk of mortality for zinc alone, and a 12% lower relative risk for those who took zinc combined with beta-carotene, vitamin C and vitamin E. The beneficial effect of zinc on mortality was associated with less death from respiratory causes. (4)

 

Age-Related Eye Disease Study 2 (AREDS2):

Results not available at the time of publication but this study will evaluate lutein plus zeaxanthin with or without polyunsaturated fatty acid in reduction of advanced AMD. This study will also look at the results of removing beta carotene and reducing zinc used in the previous AREDS study. Concern exists that beta-carotene may increase risk of late AMD. (8)

 

The National Eye Institute (NEI) recommendations:

The NEI has recommendations published online at http://www.nei.nih.gov/amd/summary.asp based on the Age Related Eye Disease Study (AREDS). The NEI recommends that the eye care professional evaluate your eyes for signs of AMD using a dilated eye exam and ask your physician whether you would benefit from these antioxidants. The NEI does not recommend a particular age to start surveillance for AMD. The NEI also reveiwed large clinical trials sponsored by the National Cancer Institute which showed that beta-carotene supplements increase risk of lung cancer in smokers. The NEI concludes that after review of the studies, beta-carotene use not only increases risk of lung cancer, but also may slightly increase risk of lung cancer for at least a period of several years after quitting smoking. (9)

 

Beta-carotene and photo-aging:

Researchers supplemented beta-carotene at a dose of either 30 mg/day or 90 mg/day for 90 days to women 50 years of age or older. The women were evaluated at the beginning of the study and again after the 3 months for facial wrinkles and elasticity, UV-related damage, and pro-collagen gene expression, which is the structural protein found in skin and other connective tissue. The results showed that in the low-dose group, elasticity and wrinkling was reduced, pro-collagen gene expression was increased (levels were significantly increased to 4.4 times the baseline level), and markers of UV-related damage were lower. The study authors stated that 30 mg/day of beta-carotene supplementation was the most beneficial in improving skin health and function that were impaired by photoaging. (12)

 

Common highest beta-carotene containing foods (mcg):

Carrot juice, canned, 1 cup                                                               21955 mcg
Pumpkin, canned, without salt, 1 cup                                            17003 mcg
Sweet potato, cooked, baked in skin, without salt, 1 potato           16803 mcg
Sweet potato, cooked, boiled, without skin, 1 potato                     14733 mcg
Spinach, frozen, cooked, boiled, drained, without salt, 1 cup        13750 mcg
Carrots, cooked, boiled, drained, without salt, 1 cup                    12998 mcg
Spinach, canned, regular pack, drained solids, 1 cup                  12585 mcg
Sweet potato, canned, vacuum pack, 1 cup                                 12215 mcg
Carrots, frozen, cooked, boiled, drained, without salt, 1 cup        11971 mcg
Collards, frozen, chopped, boiled, drained, w/o salt, 1 cup          11591 mcg
Kale, frozen, cooked, boiled, drained, without salt, 1 cup                11470 mcg
Spinach, cooked, boiled, drained, without salt, 1 cup                    11318 mcg
Sweet potato, canned, syrup pack, drained solids, 1 cup                10782 mcg
Kale, cooked, boiled, drained, without salt,1 cup                          10625 mcg
Turnip greens, frozen, boiled, drained, without salt, 1 cup              10593 mcg
Mustard greens, cooked, boiled, drained, without salt, 1 cup        10360 mcg
Vegetables, mixed, canned, drained solids, 1 cup                         9242 mcg
Carrots, raw, 1 cup                                                                          9114 mcg
Collards, cooked, boiled, drained, without salt, 1 cup                   8575 mcg
Carrots, canned, regular pack, drained solids, 1 cup                     7783 mcg
Pie, pumpkin, prepared from recipe, 1 piece                                   7366 mcg
Beet greens, cooked, boiled, drained, without salt, 1 cup              6610 mcg
Turnip greens, cooked, boiled, drained, without salt, 1 cup            6588 mcg
Carrots, raw, 1 carrot                                                                       5965 mcg
Squash, winter, all varieties, cooked, baked, without salt, 1 cup    5726 mcg
Pumpkin, cooked, boiled, drained, without salt, 1 cup                   5135 mcg
Cabbage, chinese (pak-choi), boiled, drained, w/o, salt,1 cup        4333 mcg
Dandelion greens, cooked, boiled, drained, without salt, 1 cup        4137 mcg
Sweet potato, cooked, candied, home-prepared, 1 piece               4051 mcg
Vegetables, mixed, frozen, boiled, drained, w/o salt, 1 cup `         3789 mcg
Lettuce, butterhead (boston and bibb types), raw, 1 head             3239 mcg
Melons, cantaloupe, raw, 1 cup                                                         3232 mcg
Lettuce, cos or romaine, raw, 1 cup                                                   2927 mcg
Soup, chunky vegetable, canned, ready-to-serve, 1 cup                 2875 mcg
Lettuce, green leaf, raw, 1 cup                                                           2488 mcg
Apricots, canned, juice pack, skin, solids and liquids, 1 cup            2464 mcg
Peppers, sweet, red, raw, 1 cup                                                         2420 mcg
Tomato products, canned, paste, without salt added, 1 cup          2361 mcg

Adapted from: Nutritive Value of Foods, United States Department of Agriculture, Agricultural Research Service, Home and Garden Bulletin Number 72. May be accessed at:https://www.ars.usda.gov/SP2UserFiles/Place/12354500/Data/SR25/nutrlist/sr25w321.pdf and http://www.nal.usda.gov/fnic/foodcomp/Data/HG72/hg72_2002.pdf

 

Assessment and Plan: Beta-Carotene and Carotenoids

 

 

 

 

 

 

References:

1.Greenberg ER, Baron JA, Karagas MR, Stukel TA, Nierenberg DW, Stevens MM, Mandel JS, Haile RW.Mortality associated with low plasma concentration of beta carotene and the effect of oral supplementation. JAMA. 1996 Mar 6;275(9):699-703. http://www.ncbi.nlm.nih.gov/pubmed/8594267

 

2.Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids : a report of the Panel on Dietary Antioxidants and Related Compounds, Subcommittees on Upper Reference Levels of Nutrients and Interpretation and Uses of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. Institute of Medicine (US) Panel on Dietary Antioxidants and Related Compounds. Washington, D.C. : National Academy Press, c2000.  http://www.ncbi.nlm.nih.gov/nlmcatalog/100938980

 

3.Goodman GE, et al. The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements. J Natl Cancer Inst. 2004;96(23):1743-50. http://www.ncbi.nlm.nih.gov/pubmed/15572756

 

4.Martini MC, Campbell DR, Gross MD, Grandits GA, Potter JD, Slavin JL. Plasma carotenoids as biomarkers of vegetable intake: the University of Minnesota Cancer Prevention Research Unit Feeding Studies. Cancer Epidemiol Biomarkers Prev. 1995 Jul-Aug;4(5):491-6. http://www.ncbi.nlm.nih.gov/pubmed/7549804

 

5.Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev, 2012 Mar 14;3:CD007176. http://www.ncbi.nlm.nih.gov/pubmed/22419320

 

6.Age-Related Eye Disease Study Research Group. A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and E, Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss: AREDS Report No. 8. Arch Ophthalmol. 2001 Oct. http://www.ncbi.nlm.nih.gov/pubmed/11594942 , http://www.nei.nih.gov/news/pressreleases/101201.asp

 

7.Kansagara D, Gleitsmann K, Gillingham M, Freeman M, Quiñones A. Nutritional Supplements for Age-related Macular Degeneration: A Systematic Review. VA-ESP Project #05-225; 2011. http://www.ncbi.nlm.nih.gov/books/NBK84269/

 

8.AREDS2 Research Group, Chew EY, Clemons T, SanGiovanni JP, Danis R, Domalpally A, McBee W, Sperduto R, Ferris FL. The Age-Related Eye Disease Study 2 (AREDS2): study design and baseline characteristics (AREDS2 report number 1). Ophthalmology. 2012 Nov;119(11):2282-9. http://www.ncbi.nlm.nih.gov/pubmed/22840421

 

9.National Institutes of Health, National Eye Institute. The AREDS Formulation and Age-Related Macular Degeneration. Are These High Levels of Antioxidants and Zinc Right For You? Revised November of 2011. Accessed March 17, 2011. http://www.nei.nih.gov/amd/summary.asp

 

10.Druesne-Pecollo N. Latino-Martel P, Norat T, Barrandon E, Bertrais S, Galan P, Hercberg S. Beta-carotene supplementation and cancer risk: a systematic review and meta-analysis of randomized controlled trials. International Journal of Cancer 2010; 127(1): 172-184. http://www.ncbi.nlm.nih.gov/pubmed/19876916

 

11.Zhang S, Hunter DJ, Forman MR, Rosner BA, Speizer FE, Colditz GA, Manson JE, Hankinson SE, Willett WC. Dietary carotenoids and vitamins A, C, and E and risk of breast cancer. J Natl Cancer Inst. 1999 Mar 17;91(6):547-56. http://www.ncbi.nlm.nih.gov/pubmed/10088626

 

12.Cho S, Lee DH, Won CH, Kim SM, Lee S, Lee MJ, Chung JH. Differential effects of low-dose and high-dose beta-carotene supplementation on the signs of photoaging and type I procollagen gene expression in human skin in vivo. Dermatology. 2010;221(2):160-71. http://www.ncbi.nlm.nih.gov/pubmed/20516658

 

13.Jeon YJ, Myung SK, Lee EH, et al. Effects of beta-carotene supplements on cancer prevention: meta-analysis of randomized controlled trials. Nutr Cancer. 2011 Nov;63(8):1196-207. http://www.ncbi.nlm.nih.gov/pubmed/21981610

 

14.Karppi J, Kurl S, Mäkikallio TH, Ronkainen K, Laukkanen JA. Low levels of plasma carotenoids are associated with an increased risk of atrial fibrillation. Eur J Epidemiol. 2013 Jan;28(1):45-53. http://www.ncbi.nlm.nih.gov/pubmed/23238698

 

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