The ATBC and CARET study results suggest that large supplemental doses of beta-carotene with or without retinyl palmitate have detrimental effects in current or former smokers and workers exposed to asbestos. The relevance of these results to people who have never smoked or to the effects of beta-carotene or retinol from food or multivitamins (which typically have modest amounts of beta-carotene) is not known. More research is needed to determine the effects of vitamin A on prostate, lung, and other types of cancer.
Tangrea, J. A., Edwards, B. K., Taylor, P. R., Hartman, A. M., Peck, G. L., Salasche, S. J., Menon, P. A., Benson, P. M., Mellette, J. R., Guill, M. A., and . Long-term therapy with low-dose isotretinoin for prevention of basal cell carcinoma: a multicenter clinical trial. Isotretinoin-Basal Cell Carcinoma Study Group. J Natl Cancer Inst. 3-4-1992;84(5):328-332. View abstract.
Goodman, G. E., Thornquist, M. D., Balmes, J., Cullen, M. R., Meyskens, F. L., Jr., Omenn, G. S., Valanis, B., and Williams, J. H., Jr. 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. 12-1-2004;96(23):1743-1750. View abstract.
Chintu, C., Bhat, G. J., Walker, A. S., Mulenga, V., Sinyinza, F., Lishimpi, K., Farrelly, L., Kaganson, N., Zumla, A., Gillespie, S. H., Nunn, A. J., and Gibb, D. M. Co-trimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian children (CHAP): a double-blind randomised placebo-controlled trial. Lancet 11-20-2004;364(9448):1865-1871. View abstract.
Unlike preformed vitamin A, beta-carotene is not known to be teratogenic or lead to reproductive toxicity [1]. And even large supplemental doses (20–30 mg/day) of beta-carotene or diets with high levels of carotenoid-rich food for long periods are not associated with toxicity. The most significant effect of long-term, excess beta-carotene is carotenodermia, a harmless condition in which the skin becomes yellow-orange [1,25]. This condition can be reversed by discontinuing beta-carotene ingestion.
During the late 18th and early 19th centuries, the use of deprivation studies allowed scientists to isolate and identify a number of vitamins. Lipid from fish oil was used to cure rickets in rats, and the fat-soluble nutrient was called "antirachitic A". Thus, the first "vitamin" bioactivity ever isolated, which cured rickets, was initially called "vitamin A"; however, the bioactivity of this compound is now called vitamin D.[59] In 1881, Russian medical doctor Nikolai I. Lunin [ru] studied the effects of scurvy at the University of Tartu. He fed mice an artificial mixture of all the separate constituents of milk known at that time, namely the proteins, fats, carbohydrates, and salts. The mice that received only the individual constituents died, while the mice fed by milk itself developed normally. He made a conclusion that "a natural food such as milk must therefore contain, besides these known principal ingredients, small quantities of unknown substances essential to life." However, his conclusions were rejected by his advisor, Gustav von Bunge.[60] A similar result by Cornelius Pekelharing appeared in a Dutch medical journal in 1905, but it was not widely reported.[60]
Most countries place dietary supplements in a special category under the general umbrella of foods, not drugs. As a result, the manufacturer, and not the government, has the responsibility of ensuring that its dietary supplement products are safe before they are marketed. Regulation of supplements varies widely by country. In the United States, a dietary supplement is defined under the Dietary Supplement Health and Education Act of 1994.[47] There is no FDA approval process for dietary supplements, and no requirement that manufacturers prove the safety or efficacy of supplements introduced before 1994.[29][30] The Food and Drug Administration must rely on its Adverse Event Reporting System to monitor adverse events that occur with supplements.[48] In 2007, the US Code of Federal Regulations (CFR) Title 21, part III took effect, regulating Good Manufacturing Practices (GMPs) in the manufacturing, packaging, labeling, or holding operations for dietary supplements. Even though product registration is not required, these regulations mandate production and quality control standards (including testing for identity, purity and adulterations) for dietary supplements.[49] In the European Union, the Food Supplements Directive requires that only those supplements that have been proven safe can be sold without a prescription.[50] For most vitamins, pharmacopoeial standards have been established. In the United States, the United States Pharmacopeia (USP) sets standards for the most commonly used vitamins and preparations thereof. Likewise, monographs of the European Pharmacopoeia (Ph.Eur.) regulate aspects of identity and purity for vitamins on the European market.
Pregnant women need extra vitamin A for fetal growth and tissue maintenance and for supporting their own metabolism [20]. The World Health Organization estimates that 9.8 million pregnant women around the world have xerophthalmia as a result of vitamin A deficiency [14]. Other effects of vitamin A deficiency in pregnant and lactating women include increased maternal and infant morbidity and mortality, increased anemia risk, and slower infant growth and development.

Despite the importance of the sun for vitamin D synthesis, it is prudent to limit exposure of skin to sunlight [22] and UV radiation from tanning beds [24]. UV radiation is a carcinogen responsible for most of the estimated 1.5 million skin cancers and the 8,000 deaths due to metastatic melanoma that occur annually in the United States [22]. Lifetime cumulative UV damage to skin is also largely responsible for some age-associated dryness and other cosmetic changes. The American Academy of Dermatology advises that photoprotective measures be taken, including the use of sunscreen, whenever one is exposed to the sun [25]. Assessment of vitamin D requirements cannot address the level of sun exposure because of these public health concerns about skin cancer, and there are no studies to determine whether UVB-induced synthesis of vitamin D can occur without increased risk of skin cancer [1].

There is considerable discussion of the serum concentrations of 25(OH)D associated with deficiency (e.g., rickets), adequacy for bone health, and optimal overall health, and cut points have not been developed by a scientific consensus process. Based on its review of data of vitamin D needs, a committee of the Institute of Medicine concluded that persons are at risk of vitamin D deficiency at serum 25(OH)D concentrations <30 nmol/L (<12 ng/mL). Some are potentially at risk for inadequacy at levels ranging from 30–50 nmol/L (12–20 ng/mL). Practically all people are sufficient at levels ≥50 nmol/L (≥20 ng/mL); the committee stated that 50 nmol/L is the serum 25(OH)D level that covers the needs of 97.5% of the population. Serum concentrations >125 nmol/L (>50 ng/mL) are associated with potential adverse effects [1] (Table 1).
Supplementation with beta-carotene, with or without retinyl palmitate, for 5–8 years has been associated with an increased risk of lung cancer and cardiovascular disease in current and former male and female smokers and in male current and former smokers occupationally exposed to asbestos [27,41]. In the ATBC study, beta-carotene supplements (20 mg daily) were also associated with increased mortality, mainly due to lung cancer and ischemic heart disease [27]. The CARET study ended early, after the investigators found that daily beta-carotene (30 mg) and retinyl palmitate (25,000 IU) supplements increased the risk of lung cancer and cardiovascular disease mortality [41].
An RAE cannot be directly converted into an IU without knowing the source(s) of vitamin A. For example, the RDA of 900 mcg RAE for adolescent and adult men is equivalent to 3,000 IU if the food or supplement source is preformed vitamin A (retinol). However, this RDA is also equivalent to 6,000 IU of beta-carotene from supplements, 18,000 IU of beta-carotene from food, or 36,000 IU of alpha-carotene or beta-cryptoxanthin from food. So a mixed diet containing 900 mcg RAE provides between 3,000 and 36,000 IU of vitamin A, depending on the foods consumed.
Aponte, J. J., Aide, P., Renom, M., Mandomando, I., Bassat, Q., Sacarlal, J., Manaca, M. N., Lafuente, S., Barbosa, A., Leach, A., Lievens, M., Vekemans, J., Sigauque, B., Dubois, M. C., Demoitie, M. A., Sillman, M., Savarese, B., McNeil, J. G., Macete, E., Ballou, W. R., Cohen, J., and Alonso, P. L. Safety of the RTS,S/AS02D candidate malaria vaccine in infants living in a highly endemic area of Mozambique: a double blind randomised controlled phase I/IIb trial. Lancet 11-3-2007;370(9598):1543-1551. View abstract.
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<>* These ULs, expressed in mcg and in IUs (where 1 mcg = 3.33 IU), only apply to products from animal sources and supplements whose vitamin A comes entirely from retinol or ester forms, such as retinyl palmitate. However, many dietary supplements (such as multivitamins) do not provide all of their vitamin A as retinol or its ester forms. For example, the vitamin A in some supplements consists partly or entirely of beta-carotene or other provitamin A carotenoids. In such cases, the percentage of retinol or retinyl ester in the supplement should be used to determine whether an individual's vitamin A intake exceeds the UL. For example, a supplement labeled as containing 10,000 IU of vitamin A with 60% from beta-carotene (and therefore 40% from retinol or retinyl ester) provides 4,000 IU of preformed vitamin A. That amount is above the UL for children from birth to 13 years but below the UL for adolescents and adults.
Furthermore, while serum 25(OH)D levels increase in response to increased vitamin D intake, the relationship is non-linear for reasons that are not entirely clear [1]. The increase varies, for example, by baseline serum levels and duration of supplementation. Increasing serum 25(OH)D to >50 nmol/L requires more vitamin D than increasing levels from a baseline <50 nmol/L. There is a steeper rise in serum 25(OH)D when the dose of vitamin D is <1,000 IU/day; a lower, more flattened response is seen at higher daily doses. When the dose is ≥1,000 IU/day, the rise in serum 25(OH)D is approximately 1 nmol/L for each 40 IU of intake. In studies with a dose ≤600 IU/day, the rise is serum 25(OH)D was approximately 2.3 nmol/L for each 40 IU of vitamin D consumed [1].
There is considerable discussion of the serum concentrations of 25(OH)D associated with deficiency (e.g., rickets), adequacy for bone health, and optimal overall health, and cut points have not been developed by a scientific consensus process. Based on its review of data of vitamin D needs, a committee of the Institute of Medicine concluded that persons are at risk of vitamin D deficiency at serum 25(OH)D concentrations <30 nmol/L (<12 ng/mL). Some are potentially at risk for inadequacy at levels ranging from 30–50 nmol/L (12–20 ng/mL). Practically all people are sufficient at levels ≥50 nmol/L (≥20 ng/mL); the committee stated that 50 nmol/L is the serum 25(OH)D level that covers the needs of 97.5% of the population. Serum concentrations >125 nmol/L (>50 ng/mL) are associated with potential adverse effects [1] (Table 1).
Cook, N. R., Albert, C. M., Gaziano, J. M., Zaharris, E., MacFadyen, J., Danielson, E., Buring, J. E., and Manson, J. E. A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women's Antioxidant Cardiovascular Study. Arch.Intern.Med. 8-13-2007;167(15):1610-1618. View abstract.
Photosynthesizing plants, algae and cyanobacteria synthesize tocochromanols, the chemical family of compounds made up of four tocopherols and four tocotrienols; in a nutrition context this family is referred to as Vitamin E. Biosynthesis starts with formation of the closed-ring part of the molecule as homogentisic acid (HGA). The side chain is attached (saturated for tocopherols, polyunsaturated for tocotrienols). The pathway for both is the same, so that gamma- is created and from that alpha-, or delta- is created and from that the beta- compounds.[44][45] Biosynthesis takes place in the plastids.[45]
Maraini, G., Williams, S. L., Sperduto, R. D., Ferris, F., Milton, R. C., Clemons, T. E., Rosmini, F., and Ferrigno, L. A randomized, double-masked, placebo-controlled clinical trial of multivitamin supplementation for age-related lens opacities. Clinical trial of nutritional supplements and age-related cataract report no. 3. Ophthalmology 2008;115(4):599-607. View abstract.
Karyadi, E., West, C. E., Schultink, W., Nelwan, R. H., Gross, R., Amin, Z., Dolmans, W. M., Schlebusch, H., and van der Meer, J. W. A double-blind, placebo-controlled study of vitamin A and zinc supplementation in persons with tuberculosis in Indonesia: effects on clinical response and nutritional status. Am J Clin Nutr 2002;75(4):720-727. View abstract.
A follow-up AREDS2 study confirmed the value of this supplement in reducing the progression of AMD over a median follow-up period of 5 years but found that adding lutein (10 mg) and zeaxanthin (2 mg) or omega-3 fatty acids to the formulation did not confer any additional benefits [33]. Importantly, the study revealed that beta-carotene was not a required ingredient; the original AREDS formulation without beta-carotene provided the same protective effect against developing advanced AMD. In a more detailed analysis of results, supplementation with lutein and zeaxanthin reduced the risk of advanced AMD by 26% in participants with the lowest dietary intakes of these two carotenoids who took a supplement containing them compared to those who did not take a supplement with these carotenoids [33]. The risk of advanced AMD was also 18% lower in participants who took the modified AREDS supplement containing lutein and zeaxanthin but not beta-carotene than in participants who took the formulation with beta-carotene but not lutein or zeaxanthin.
A meta-analysis from 2015 reported that for studies which reported serum tocopherol, higher serum concentration was associated with a 23% reduction in relative risk of age-related cataracts (ARC), with the effect due to differences in nuclear cataract rather than cortical or posterior subcapsular cataract - the three major classifications of age-related cataracts.[94] However, this article and a second meta-analysis reporting on clinical trials of alpha-tocopherol supplementation reported no statistically significant change to risk of ARC when compared to placebo.[94][95]
Once growth and development are completed, vitamins remain essential nutrients for the healthy maintenance of the cells, tissues, and organs that make up a multicellular organism; they also enable a multicellular life form to efficiently use chemical energy provided by food it eats, and to help process the proteins, carbohydrates, and fats required for cellular respiration.[3]